Prostate Cancer Clinical Updates PowerPoint Presentation

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die.

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis.

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S.

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US?

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic.

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy.

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality)

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery

Slide 27 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002)

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms

Slide 29 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival.

Slide 30 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30

Slide 31 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival

Slide 32 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease.

Slide 33 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time.

Slide 34 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34

Slide 35 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use.

Slide 36 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC

Slide 37 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT

Slide 38 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus.

Slide 39 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression

Slide 40 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein.

Slide 41 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC

Slide 42 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function.

Slide 43 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response”

Slide 44 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity

Slide 45 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen

Slide 46 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations

Slide 47 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47

Slide 48 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response

Slide 49 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996

Slide 50 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996 Castration Resistant Prostate Cancer RANDOMIZE Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily 1006 Patients Entered TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996 Castration Resistant Prostate Cancer RANDOMIZE Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily 1006 Patients Entered TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer TAX 327: Survival Advantage Only Shown for Q3W Docetaxel Median survival Hazard (mos) ratio P-value D 3wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996 Castration Resistant Prostate Cancer RANDOMIZE Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily 1006 Patients Entered TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer TAX 327: Survival Advantage Only Shown for Q3W Docetaxel Median survival Hazard (mos) ratio P-value D 3wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Cabazitaxel Novel taxane active in docetaxel resistant cell lines 755 men with metastatic CRPC who had progressed on or following docetaxel randomized to cabazitaxel vs. mitoxantrone. Patients in both arms received prednisone. Worse toxicity in Cabazitaxel arm with grade 3/4 neutropenia in 82% vs. 58%. About 5% treatment related deaths in Cabazitaxel arm.

Slide 53 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996 Castration Resistant Prostate Cancer RANDOMIZE Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily 1006 Patients Entered TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer TAX 327: Survival Advantage Only Shown for Q3W Docetaxel Median survival Hazard (mos) ratio P-value D 3wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Cabazitaxel Novel taxane active in docetaxel resistant cell lines 755 men with metastatic CRPC who had progressed on or following docetaxel randomized to cabazitaxel vs. mitoxantrone. Patients in both arms received prednisone. Worse toxicity in Cabazitaxel arm with grade 3/4 neutropenia in 82% vs. 58%. About 5% treatment related deaths in Cabazitaxel arm. Primary Endpoint: Overall Survival (ITT Analysis)

Slide 54 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996 Castration Resistant Prostate Cancer RANDOMIZE Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily 1006 Patients Entered TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer TAX 327: Survival Advantage Only Shown for Q3W Docetaxel Median survival Hazard (mos) ratio P-value D 3wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Cabazitaxel Novel taxane active in docetaxel resistant cell lines 755 men with metastatic CRPC who had progressed on or following docetaxel randomized to cabazitaxel vs. mitoxantrone. Patients in both arms received prednisone. Worse toxicity in Cabazitaxel arm with grade 3/4 neutropenia in 82% vs. 58%. About 5% treatment related deaths in Cabazitaxel arm. Primary Endpoint: Overall Survival (ITT Analysis) Progression-Free Survival (PFS) Results

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996 Castration Resistant Prostate Cancer RANDOMIZE Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily 1006 Patients Entered TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer TAX 327: Survival Advantage Only Shown for Q3W Docetaxel Median survival Hazard (mos) ratio P-value D 3wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Cabazitaxel Novel taxane active in docetaxel resistant cell lines 755 men with metastatic CRPC who had progressed on or following docetaxel randomized to cabazitaxel vs. mitoxantrone. Patients in both arms received prednisone. Worse toxicity in Cabazitaxel arm with grade 3/4 neutropenia in 82% vs. 58%. About 5% treatment related deaths in Cabazitaxel arm. Primary Endpoint: Overall Survival (ITT Analysis) Progression-Free Survival (PFS) Results Abiraterone

Slide 56 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996 Castration Resistant Prostate Cancer RANDOMIZE Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily 1006 Patients Entered TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer TAX 327: Survival Advantage Only Shown for Q3W Docetaxel Median survival Hazard (mos) ratio P-value D 3wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Cabazitaxel Novel taxane active in docetaxel resistant cell lines 755 men with metastatic CRPC who had progressed on or following docetaxel randomized to cabazitaxel vs. mitoxantrone. Patients in both arms received prednisone. Worse toxicity in Cabazitaxel arm with grade 3/4 neutropenia in 82% vs. 58%. About 5% treatment related deaths in Cabazitaxel arm. Primary Endpoint: Overall Survival (ITT Analysis) Progression-Free Survival (PFS) Results Abiraterone Randomized trial of Prednisone with Abiraterone vs. Placebo

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996 Castration Resistant Prostate Cancer RANDOMIZE Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily 1006 Patients Entered TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer TAX 327: Survival Advantage Only Shown for Q3W Docetaxel Median survival Hazard (mos) ratio P-value D 3wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Cabazitaxel Novel taxane active in docetaxel resistant cell lines 755 men with metastatic CRPC who had progressed on or following docetaxel randomized to cabazitaxel vs. mitoxantrone. Patients in both arms received prednisone. Worse toxicity in Cabazitaxel arm with grade 3/4 neutropenia in 82% vs. 58%. About 5% treatment related deaths in Cabazitaxel arm. Primary Endpoint: Overall Survival (ITT Analysis) Progression-Free Survival (PFS) Results Abiraterone Randomized trial of Prednisone with Abiraterone vs. Placebo Randomized trial of Prednisone with Abiraterone vs. Polaceb

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996 Castration Resistant Prostate Cancer RANDOMIZE Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily 1006 Patients Entered TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer TAX 327: Survival Advantage Only Shown for Q3W Docetaxel Median survival Hazard (mos) ratio P-value D 3wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Cabazitaxel Novel taxane active in docetaxel resistant cell lines 755 men with metastatic CRPC who had progressed on or following docetaxel randomized to cabazitaxel vs. mitoxantrone. Patients in both arms received prednisone. Worse toxicity in Cabazitaxel arm with grade 3/4 neutropenia in 82% vs. 58%. About 5% treatment related deaths in Cabazitaxel arm. Primary Endpoint: Overall Survival (ITT Analysis) Progression-Free Survival (PFS) Results Abiraterone Randomized trial of Prednisone with Abiraterone vs. Placebo Randomized trial of Prednisone with Abiraterone vs. Polaceb AR Binding Affinity DHT ~ 5nM Bicalutamide ~160 nM MDV3100 ~35 nM Nuclear Import DHT: ++++ Bicalutamide: ++++ MDV3100: ++ DNA Binding DHT: ++++ Bicalutamide: ++ MDV3100: - Coactivator recruitment DHT: ++++ Bicalutamide: ++ MDV3100: - Effects of MDV3100 on the Androgen Receptor Are Distinct from Bicalutamide

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996 Castration Resistant Prostate Cancer RANDOMIZE Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily 1006 Patients Entered TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer TAX 327: Survival Advantage Only Shown for Q3W Docetaxel Median survival Hazard (mos) ratio P-value D 3wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Cabazitaxel Novel taxane active in docetaxel resistant cell lines 755 men with metastatic CRPC who had progressed on or following docetaxel randomized to cabazitaxel vs. mitoxantrone. Patients in both arms received prednisone. Worse toxicity in Cabazitaxel arm with grade 3/4 neutropenia in 82% vs. 58%. About 5% treatment related deaths in Cabazitaxel arm. Primary Endpoint: Overall Survival (ITT Analysis) Progression-Free Survival (PFS) Results Abiraterone Randomized trial of Prednisone with Abiraterone vs. Placebo Randomized trial of Prednisone with Abiraterone vs. Polaceb AR Binding Affinity DHT ~ 5nM Bicalutamide ~160 nM MDV3100 ~35 nM Nuclear Import DHT: ++++ Bicalutamide: ++++ MDV3100: ++ DNA Binding DHT: ++++ Bicalutamide: ++ MDV3100: - Coactivator recruitment DHT: ++++ Bicalutamide: ++ MDV3100: - Effects of MDV3100 on the Androgen Receptor Are Distinct from Bicalutamide Waterfall Plot of Percent PSA Change from Baseline Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75) 62% (40/65) >50% Decline 51% (38/75) >50% Decline

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996 Castration Resistant Prostate Cancer RANDOMIZE Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily 1006 Patients Entered TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer TAX 327: Survival Advantage Only Shown for Q3W Docetaxel Median survival Hazard (mos) ratio P-value D 3wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Cabazitaxel Novel taxane active in docetaxel resistant cell lines 755 men with metastatic CRPC who had progressed on or following docetaxel randomized to cabazitaxel vs. mitoxantrone. Patients in both arms received prednisone. Worse toxicity in Cabazitaxel arm with grade 3/4 neutropenia in 82% vs. 58%. About 5% treatment related deaths in Cabazitaxel arm. Primary Endpoint: Overall Survival (ITT Analysis) Progression-Free Survival (PFS) Results Abiraterone Randomized trial of Prednisone with Abiraterone vs. Placebo Randomized trial of Prednisone with Abiraterone vs. Polaceb AR Binding Affinity DHT ~ 5nM Bicalutamide ~160 nM MDV3100 ~35 nM Nuclear Import DHT: ++++ Bicalutamide: ++++ MDV3100: ++ DNA Binding DHT: ++++ Bicalutamide: ++ MDV3100: - Coactivator recruitment DHT: ++++ Bicalutamide: ++ MDV3100: - Effects of MDV3100 on the Androgen Receptor Are Distinct from Bicalutamide Waterfall Plot of Percent PSA Change from Baseline Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75) 62% (40/65) >50% Decline 51% (38/75) >50% Decline Prostate cancer survival curve

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996 Castration Resistant Prostate Cancer RANDOMIZE Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily 1006 Patients Entered TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer TAX 327: Survival Advantage Only Shown for Q3W Docetaxel Median survival Hazard (mos) ratio P-value D 3wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Cabazitaxel Novel taxane active in docetaxel resistant cell lines 755 men with metastatic CRPC who had progressed on or following docetaxel randomized to cabazitaxel vs. mitoxantrone. Patients in both arms received prednisone. Worse toxicity in Cabazitaxel arm with grade 3/4 neutropenia in 82% vs. 58%. About 5% treatment related deaths in Cabazitaxel arm. Primary Endpoint: Overall Survival (ITT Analysis) Progression-Free Survival (PFS) Results Abiraterone Randomized trial of Prednisone with Abiraterone vs. Placebo Randomized trial of Prednisone with Abiraterone vs. Polaceb AR Binding Affinity DHT ~ 5nM Bicalutamide ~160 nM MDV3100 ~35 nM Nuclear Import DHT: ++++ Bicalutamide: ++++ MDV3100: ++ DNA Binding DHT: ++++ Bicalutamide: ++ MDV3100: - Coactivator recruitment DHT: ++++ Bicalutamide: ++ MDV3100: - Effects of MDV3100 on the Androgen Receptor Are Distinct from Bicalutamide Waterfall Plot of Percent PSA Change from Baseline Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75) 62% (40/65) >50% Decline 51% (38/75) >50% Decline Prostate cancer survival curve Alpharadin

Slide 62 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996 Castration Resistant Prostate Cancer RANDOMIZE Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily 1006 Patients Entered TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer TAX 327: Survival Advantage Only Shown for Q3W Docetaxel Median survival Hazard (mos) ratio P-value D 3wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Cabazitaxel Novel taxane active in docetaxel resistant cell lines 755 men with metastatic CRPC who had progressed on or following docetaxel randomized to cabazitaxel vs. mitoxantrone. Patients in both arms received prednisone. Worse toxicity in Cabazitaxel arm with grade 3/4 neutropenia in 82% vs. 58%. About 5% treatment related deaths in Cabazitaxel arm. Primary Endpoint: Overall Survival (ITT Analysis) Progression-Free Survival (PFS) Results Abiraterone Randomized trial of Prednisone with Abiraterone vs. Placebo Randomized trial of Prednisone with Abiraterone vs. Polaceb AR Binding Affinity DHT ~ 5nM Bicalutamide ~160 nM MDV3100 ~35 nM Nuclear Import DHT: ++++ Bicalutamide: ++++ MDV3100: ++ DNA Binding DHT: ++++ Bicalutamide: ++ MDV3100: - Coactivator recruitment DHT: ++++ Bicalutamide: ++ MDV3100: - Effects of MDV3100 on the Androgen Receptor Are Distinct from Bicalutamide Waterfall Plot of Percent PSA Change from Baseline Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75) 62% (40/65) >50% Decline 51% (38/75) >50% Decline Prostate cancer survival curve Alpharadin Survival curve

Slide 63 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996 Castration Resistant Prostate Cancer RANDOMIZE Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily 1006 Patients Entered TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer TAX 327: Survival Advantage Only Shown for Q3W Docetaxel Median survival Hazard (mos) ratio P-value D 3wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Cabazitaxel Novel taxane active in docetaxel resistant cell lines 755 men with metastatic CRPC who had progressed on or following docetaxel randomized to cabazitaxel vs. mitoxantrone. Patients in both arms received prednisone. Worse toxicity in Cabazitaxel arm with grade 3/4 neutropenia in 82% vs. 58%. About 5% treatment related deaths in Cabazitaxel arm. Primary Endpoint: Overall Survival (ITT Analysis) Progression-Free Survival (PFS) Results Abiraterone Randomized trial of Prednisone with Abiraterone vs. Placebo Randomized trial of Prednisone with Abiraterone vs. Polaceb AR Binding Affinity DHT ~ 5nM Bicalutamide ~160 nM MDV3100 ~35 nM Nuclear Import DHT: ++++ Bicalutamide: ++++ MDV3100: ++ DNA Binding DHT: ++++ Bicalutamide: ++ MDV3100: - Coactivator recruitment DHT: ++++ Bicalutamide: ++ MDV3100: - Effects of MDV3100 on the Androgen Receptor Are Distinct from Bicalutamide Waterfall Plot of Percent PSA Change from Baseline Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75) 62% (40/65) >50% Decline 51% (38/75) >50% Decline Prostate cancer survival curve Alpharadin Survival curve Therapeutic Vaccines

Slide 64 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996 Castration Resistant Prostate Cancer RANDOMIZE Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily 1006 Patients Entered TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer TAX 327: Survival Advantage Only Shown for Q3W Docetaxel Median survival Hazard (mos) ratio P-value D 3wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Cabazitaxel Novel taxane active in docetaxel resistant cell lines 755 men with metastatic CRPC who had progressed on or following docetaxel randomized to cabazitaxel vs. mitoxantrone. Patients in both arms received prednisone. Worse toxicity in Cabazitaxel arm with grade 3/4 neutropenia in 82% vs. 58%. About 5% treatment related deaths in Cabazitaxel arm. Primary Endpoint: Overall Survival (ITT Analysis) Progression-Free Survival (PFS) Results Abiraterone Randomized trial of Prednisone with Abiraterone vs. Placebo Randomized trial of Prednisone with Abiraterone vs. Polaceb AR Binding Affinity DHT ~ 5nM Bicalutamide ~160 nM MDV3100 ~35 nM Nuclear Import DHT: ++++ Bicalutamide: ++++ MDV3100: ++ DNA Binding DHT: ++++ Bicalutamide: ++ MDV3100: - Coactivator recruitment DHT: ++++ Bicalutamide: ++ MDV3100: - Effects of MDV3100 on the Androgen Receptor Are Distinct from Bicalutamide Waterfall Plot of Percent PSA Change from Baseline Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75) 62% (40/65) >50% Decline 51% (38/75) >50% Decline Prostate cancer survival curve Alpharadin Survival curve Therapeutic Vaccines APC Vaccine: Sipuleucel-T (Provenge). On day 1 Leukapheresis is is performed at a Center. On day 2-3 sipuleucel-T is manufactured at a company. On day 3-4 the patient is infused at the Doctor’s office.

Slide 65 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996 Castration Resistant Prostate Cancer RANDOMIZE Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily 1006 Patients Entered TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer TAX 327: Survival Advantage Only Shown for Q3W Docetaxel Median survival Hazard (mos) ratio P-value D 3wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Cabazitaxel Novel taxane active in docetaxel resistant cell lines 755 men with metastatic CRPC who had progressed on or following docetaxel randomized to cabazitaxel vs. mitoxantrone. Patients in both arms received prednisone. Worse toxicity in Cabazitaxel arm with grade 3/4 neutropenia in 82% vs. 58%. About 5% treatment related deaths in Cabazitaxel arm. Primary Endpoint: Overall Survival (ITT Analysis) Progression-Free Survival (PFS) Results Abiraterone Randomized trial of Prednisone with Abiraterone vs. Placebo Randomized trial of Prednisone with Abiraterone vs. Polaceb AR Binding Affinity DHT ~ 5nM Bicalutamide ~160 nM MDV3100 ~35 nM Nuclear Import DHT: ++++ Bicalutamide: ++++ MDV3100: ++ DNA Binding DHT: ++++ Bicalutamide: ++ MDV3100: - Coactivator recruitment DHT: ++++ Bicalutamide: ++ MDV3100: - Effects of MDV3100 on the Androgen Receptor Are Distinct from Bicalutamide Waterfall Plot of Percent PSA Change from Baseline Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75) 62% (40/65) >50% Decline 51% (38/75) >50% Decline Prostate cancer survival curve Alpharadin Survival curve Therapeutic Vaccines APC Vaccine: Sipuleucel-T (Provenge). On day 1 Leukapheresis is is performed at a Center. On day 2-3 sipuleucel-T is manufactured at a company. On day 3-4 the patient is infused at the Doctor’s office. 65 IMPACT: Randomized Phase 3 Trial (IMmunotherapy Prostate AdenoCarcinoma Treatment). Patients (342) will be treated with Sipuleucel-T (Q 2 weeks x 3). Patients (170) will be treated with Placebo (Q2 weeks x 3). The primary endpoint is overall survival and the secondary endpoint it time to objective disease progression.

Slide 66 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996 Castration Resistant Prostate Cancer RANDOMIZE Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily 1006 Patients Entered TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer TAX 327: Survival Advantage Only Shown for Q3W Docetaxel Median survival Hazard (mos) ratio P-value D 3wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Cabazitaxel Novel taxane active in docetaxel resistant cell lines 755 men with metastatic CRPC who had progressed on or following docetaxel randomized to cabazitaxel vs. mitoxantrone. Patients in both arms received prednisone. Worse toxicity in Cabazitaxel arm with grade 3/4 neutropenia in 82% vs. 58%. About 5% treatment related deaths in Cabazitaxel arm. Primary Endpoint: Overall Survival (ITT Analysis) Progression-Free Survival (PFS) Results Abiraterone Randomized trial of Prednisone with Abiraterone vs. Placebo Randomized trial of Prednisone with Abiraterone vs. Polaceb AR Binding Affinity DHT ~ 5nM Bicalutamide ~160 nM MDV3100 ~35 nM Nuclear Import DHT: ++++ Bicalutamide: ++++ MDV3100: ++ DNA Binding DHT: ++++ Bicalutamide: ++ MDV3100: - Coactivator recruitment DHT: ++++ Bicalutamide: ++ MDV3100: - Effects of MDV3100 on the Androgen Receptor Are Distinct from Bicalutamide Waterfall Plot of Percent PSA Change from Baseline Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75) 62% (40/65) >50% Decline 51% (38/75) >50% Decline Prostate cancer survival curve Alpharadin Survival curve Therapeutic Vaccines APC Vaccine: Sipuleucel-T (Provenge). On day 1 Leukapheresis is is performed at a Center. On day 2-3 sipuleucel-T is manufactured at a company. On day 3-4 the patient is infused at the Doctor’s office. 65 IMPACT: Randomized Phase 3 Trial (IMmunotherapy Prostate AdenoCarcinoma Treatment). Patients (342) will be treated with Sipuleucel-T (Q 2 weeks x 3). Patients (170) will be treated with Placebo (Q2 weeks x 3). The primary endpoint is overall survival and the secondary endpoint it time to objective disease progression. Sipuleucel-T: IMPACT Overall Survival: Primary Endpoint Intent-to-Treat Population P = 0.032 (Cox model) HR = 0.775 [95% CI: 0.614, 0.979] Median Survival Benefit = 4.1 Mos.

Slide 67 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996 Castration Resistant Prostate Cancer RANDOMIZE Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily 1006 Patients Entered TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer TAX 327: Survival Advantage Only Shown for Q3W Docetaxel Median survival Hazard (mos) ratio P-value D 3wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Cabazitaxel Novel taxane active in docetaxel resistant cell lines 755 men with metastatic CRPC who had progressed on or following docetaxel randomized to cabazitaxel vs. mitoxantrone. Patients in both arms received prednisone. Worse toxicity in Cabazitaxel arm with grade 3/4 neutropenia in 82% vs. 58%. About 5% treatment related deaths in Cabazitaxel arm. Primary Endpoint: Overall Survival (ITT Analysis) Progression-Free Survival (PFS) Results Abiraterone Randomized trial of Prednisone with Abiraterone vs. Placebo Randomized trial of Prednisone with Abiraterone vs. Polaceb AR Binding Affinity DHT ~ 5nM Bicalutamide ~160 nM MDV3100 ~35 nM Nuclear Import DHT: ++++ Bicalutamide: ++++ MDV3100: ++ DNA Binding DHT: ++++ Bicalutamide: ++ MDV3100: - Coactivator recruitment DHT: ++++ Bicalutamide: ++ MDV3100: - Effects of MDV3100 on the Androgen Receptor Are Distinct from Bicalutamide Waterfall Plot of Percent PSA Change from Baseline Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75) 62% (40/65) >50% Decline 51% (38/75) >50% Decline Prostate cancer survival curve Alpharadin Survival curve Therapeutic Vaccines APC Vaccine: Sipuleucel-T (Provenge). On day 1 Leukapheresis is is performed at a Center. On day 2-3 sipuleucel-T is manufactured at a company. On day 3-4 the patient is infused at the Doctor’s office. 65 IMPACT: Randomized Phase 3 Trial (IMmunotherapy Prostate AdenoCarcinoma Treatment). Patients (342) will be treated with Sipuleucel-T (Q 2 weeks x 3). Patients (170) will be treated with Placebo (Q2 weeks x 3). The primary endpoint is overall survival and the secondary endpoint it time to objective disease progression. Sipuleucel-T: IMPACT Overall Survival: Primary Endpoint Intent-to-Treat Population P = 0.032 (Cox model) HR = 0.775 [95% CI: 0.614, 0.979] Median Survival Benefit = 4.1 Mos. Developed at NCI CRADA with BN PSA Pox Vector Vaccine: PSA TRICOM (PROSTVAC)

Slide 68 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996 Castration Resistant Prostate Cancer RANDOMIZE Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily 1006 Patients Entered TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer TAX 327: Survival Advantage Only Shown for Q3W Docetaxel Median survival Hazard (mos) ratio P-value D 3wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Cabazitaxel Novel taxane active in docetaxel resistant cell lines 755 men with metastatic CRPC who had progressed on or following docetaxel randomized to cabazitaxel vs. mitoxantrone. Patients in both arms received prednisone. Worse toxicity in Cabazitaxel arm with grade 3/4 neutropenia in 82% vs. 58%. About 5% treatment related deaths in Cabazitaxel arm. Primary Endpoint: Overall Survival (ITT Analysis) Progression-Free Survival (PFS) Results Abiraterone Randomized trial of Prednisone with Abiraterone vs. Placebo Randomized trial of Prednisone with Abiraterone vs. Polaceb AR Binding Affinity DHT ~ 5nM Bicalutamide ~160 nM MDV3100 ~35 nM Nuclear Import DHT: ++++ Bicalutamide: ++++ MDV3100: ++ DNA Binding DHT: ++++ Bicalutamide: ++ MDV3100: - Coactivator recruitment DHT: ++++ Bicalutamide: ++ MDV3100: - Effects of MDV3100 on the Androgen Receptor Are Distinct from Bicalutamide Waterfall Plot of Percent PSA Change from Baseline Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75) 62% (40/65) >50% Decline 51% (38/75) >50% Decline Prostate cancer survival curve Alpharadin Survival curve Therapeutic Vaccines APC Vaccine: Sipuleucel-T (Provenge). On day 1 Leukapheresis is is performed at a Center. On day 2-3 sipuleucel-T is manufactured at a company. On day 3-4 the patient is infused at the Doctor’s office. 65 IMPACT: Randomized Phase 3 Trial (IMmunotherapy Prostate AdenoCarcinoma Treatment). Patients (342) will be treated with Sipuleucel-T (Q 2 weeks x 3). Patients (170) will be treated with Placebo (Q2 weeks x 3). The primary endpoint is overall survival and the secondary endpoint it time to objective disease progression. Sipuleucel-T: IMPACT Overall Survival: Primary Endpoint Intent-to-Treat Population P = 0.032 (Cox model) HR = 0.775 [95% CI: 0.614, 0.979] Median Survival Benefit = 4.1 Mos. Developed at NCI CRADA with BN PSA Pox Vector Vaccine: PSA TRICOM (PROSTVAC) 68 Randomized Controlled Double Blind Phase II Study. Patients (84) will be treated with PSA-TRICOM + GM-CSF. Patients (42) will be treated with empty vector + placebo. The primary endpoint is progression free survival. The secondary endpoint is overall survival.

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996 Castration Resistant Prostate Cancer RANDOMIZE Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily 1006 Patients Entered TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer TAX 327: Survival Advantage Only Shown for Q3W Docetaxel Median survival Hazard (mos) ratio P-value D 3wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Cabazitaxel Novel taxane active in docetaxel resistant cell lines 755 men with metastatic CRPC who had progressed on or following docetaxel randomized to cabazitaxel vs. mitoxantrone. Patients in both arms received prednisone. Worse toxicity in Cabazitaxel arm with grade 3/4 neutropenia in 82% vs. 58%. About 5% treatment related deaths in Cabazitaxel arm. Primary Endpoint: Overall Survival (ITT Analysis) Progression-Free Survival (PFS) Results Abiraterone Randomized trial of Prednisone with Abiraterone vs. Placebo Randomized trial of Prednisone with Abiraterone vs. Polaceb AR Binding Affinity DHT ~ 5nM Bicalutamide ~160 nM MDV3100 ~35 nM Nuclear Import DHT: ++++ Bicalutamide: ++++ MDV3100: ++ DNA Binding DHT: ++++ Bicalutamide: ++ MDV3100: - Coactivator recruitment DHT: ++++ Bicalutamide: ++ MDV3100: - Effects of MDV3100 on the Androgen Receptor Are Distinct from Bicalutamide Waterfall Plot of Percent PSA Change from Baseline Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75) 62% (40/65) >50% Decline 51% (38/75) >50% Decline Prostate cancer survival curve Alpharadin Survival curve Therapeutic Vaccines APC Vaccine: Sipuleucel-T (Provenge). On day 1 Leukapheresis is is performed at a Center. On day 2-3 sipuleucel-T is manufactured at a company. On day 3-4 the patient is infused at the Doctor’s office. 65 IMPACT: Randomized Phase 3 Trial (IMmunotherapy Prostate AdenoCarcinoma Treatment). Patients (342) will be treated with Sipuleucel-T (Q 2 weeks x 3). Patients (170) will be treated with Placebo (Q2 weeks x 3). The primary endpoint is overall survival and the secondary endpoint it time to objective disease progression. Sipuleucel-T: IMPACT Overall Survival: Primary Endpoint Intent-to-Treat Population P = 0.032 (Cox model) HR = 0.775 [95% CI: 0.614, 0.979] Median Survival Benefit = 4.1 Mos. Developed at NCI CRADA with BN PSA Pox Vector Vaccine: PSA TRICOM (PROSTVAC) 68 Randomized Controlled Double Blind Phase II Study. Patients (84) will be treated with PSA-TRICOM + GM-CSF. Patients (42) will be treated with empty vector + placebo. The primary endpoint is progression free survival. The secondary endpoint is overall survival. PROSTVAC Significantly Extended Overall Survival by 8.5 months 20 40 60 80 100 0 12 24 36 48 60 Overall survival (% patients) 0 Months Control PROSTVAC

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996 Castration Resistant Prostate Cancer RANDOMIZE Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily 1006 Patients Entered TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer TAX 327: Survival Advantage Only Shown for Q3W Docetaxel Median survival Hazard (mos) ratio P-value D 3wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Cabazitaxel Novel taxane active in docetaxel resistant cell lines 755 men with metastatic CRPC who had progressed on or following docetaxel randomized to cabazitaxel vs. mitoxantrone. Patients in both arms received prednisone. Worse toxicity in Cabazitaxel arm with grade 3/4 neutropenia in 82% vs. 58%. About 5% treatment related deaths in Cabazitaxel arm. Primary Endpoint: Overall Survival (ITT Analysis) Progression-Free Survival (PFS) Results Abiraterone Randomized trial of Prednisone with Abiraterone vs. Placebo Randomized trial of Prednisone with Abiraterone vs. Polaceb AR Binding Affinity DHT ~ 5nM Bicalutamide ~160 nM MDV3100 ~35 nM Nuclear Import DHT: ++++ Bicalutamide: ++++ MDV3100: ++ DNA Binding DHT: ++++ Bicalutamide: ++ MDV3100: - Coactivator recruitment DHT: ++++ Bicalutamide: ++ MDV3100: - Effects of MDV3100 on the Androgen Receptor Are Distinct from Bicalutamide Waterfall Plot of Percent PSA Change from Baseline Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75) 62% (40/65) >50% Decline 51% (38/75) >50% Decline Prostate cancer survival curve Alpharadin Survival curve Therapeutic Vaccines APC Vaccine: Sipuleucel-T (Provenge). On day 1 Leukapheresis is is performed at a Center. On day 2-3 sipuleucel-T is manufactured at a company. On day 3-4 the patient is infused at the Doctor’s office. 65 IMPACT: Randomized Phase 3 Trial (IMmunotherapy Prostate AdenoCarcinoma Treatment). Patients (342) will be treated with Sipuleucel-T (Q 2 weeks x 3). Patients (170) will be treated with Placebo (Q2 weeks x 3). The primary endpoint is overall survival and the secondary endpoint it time to objective disease progression. Sipuleucel-T: IMPACT Overall Survival: Primary Endpoint Intent-to-Treat Population P = 0.032 (Cox model) HR = 0.775 [95% CI: 0.614, 0.979] Median Survival Benefit = 4.1 Mos. Developed at NCI CRADA with BN PSA Pox Vector Vaccine: PSA TRICOM (PROSTVAC) 68 Randomized Controlled Double Blind Phase II Study. Patients (84) will be treated with PSA-TRICOM + GM-CSF. Patients (42) will be treated with empty vector + placebo. The primary endpoint is progression free survival. The secondary endpoint is overall survival. PROSTVAC Significantly Extended Overall Survival by 8.5 months 20 40 60 80 100 0 12 24 36 48 60 Overall survival (% patients) 0 Months Control PROSTVAC Therapeutic vaccines vs. Conventional therapy. ●Conventional therapy targets the tumor or its microenvironment. The action is immediate but is limited by toxicity. ●Therapeutic vaccines target the immune system. The action requires a memory response and is delayed but requires an adequate immune system.

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996 Castration Resistant Prostate Cancer RANDOMIZE Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily 1006 Patients Entered TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer TAX 327: Survival Advantage Only Shown for Q3W Docetaxel Median survival Hazard (mos) ratio P-value D 3wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Cabazitaxel Novel taxane active in docetaxel resistant cell lines 755 men with metastatic CRPC who had progressed on or following docetaxel randomized to cabazitaxel vs. mitoxantrone. Patients in both arms received prednisone. Worse toxicity in Cabazitaxel arm with grade 3/4 neutropenia in 82% vs. 58%. About 5% treatment related deaths in Cabazitaxel arm. Primary Endpoint: Overall Survival (ITT Analysis) Progression-Free Survival (PFS) Results Abiraterone Randomized trial of Prednisone with Abiraterone vs. Placebo Randomized trial of Prednisone with Abiraterone vs. Polaceb AR Binding Affinity DHT ~ 5nM Bicalutamide ~160 nM MDV3100 ~35 nM Nuclear Import DHT: ++++ Bicalutamide: ++++ MDV3100: ++ DNA Binding DHT: ++++ Bicalutamide: ++ MDV3100: - Coactivator recruitment DHT: ++++ Bicalutamide: ++ MDV3100: - Effects of MDV3100 on the Androgen Receptor Are Distinct from Bicalutamide Waterfall Plot of Percent PSA Change from Baseline Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75) 62% (40/65) >50% Decline 51% (38/75) >50% Decline Prostate cancer survival curve Alpharadin Survival curve Therapeutic Vaccines APC Vaccine: Sipuleucel-T (Provenge). On day 1 Leukapheresis is is performed at a Center. On day 2-3 sipuleucel-T is manufactured at a company. On day 3-4 the patient is infused at the Doctor’s office. 65 IMPACT: Randomized Phase 3 Trial (IMmunotherapy Prostate AdenoCarcinoma Treatment). Patients (342) will be treated with Sipuleucel-T (Q 2 weeks x 3). Patients (170) will be treated with Placebo (Q2 weeks x 3). The primary endpoint is overall survival and the secondary endpoint it time to objective disease progression. Sipuleucel-T: IMPACT Overall Survival: Primary Endpoint Intent-to-Treat Population P = 0.032 (Cox model) HR = 0.775 [95% CI: 0.614, 0.979] Median Survival Benefit = 4.1 Mos. Developed at NCI CRADA with BN PSA Pox Vector Vaccine: PSA TRICOM (PROSTVAC) 68 Randomized Controlled Double Blind Phase II Study. Patients (84) will be treated with PSA-TRICOM + GM-CSF. Patients (42) will be treated with empty vector + placebo. The primary endpoint is progression free survival. The secondary endpoint is overall survival. PROSTVAC Significantly Extended Overall Survival by 8.5 months 20 40 60 80 100 0 12 24 36 48 60 Overall survival (% patients) 0 Months Control PROSTVAC Therapeutic vaccines vs. Conventional therapy. ●Conventional therapy targets the tumor or its microenvironment. The action is immediate but is limited by toxicity. ●Therapeutic vaccines target the immune system. The action requires a memory response and is delayed but requires an adequate immune system. Time Tumor Burden † † † Vaccine Cytotoxic Therapy Tumor Growth Rate

Slide 72 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996 Castration Resistant Prostate Cancer RANDOMIZE Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily 1006 Patients Entered TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer TAX 327: Survival Advantage Only Shown for Q3W Docetaxel Median survival Hazard (mos) ratio P-value D 3wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Cabazitaxel Novel taxane active in docetaxel resistant cell lines 755 men with metastatic CRPC who had progressed on or following docetaxel randomized to cabazitaxel vs. mitoxantrone. Patients in both arms received prednisone. Worse toxicity in Cabazitaxel arm with grade 3/4 neutropenia in 82% vs. 58%. About 5% treatment related deaths in Cabazitaxel arm. Primary Endpoint: Overall Survival (ITT Analysis) Progression-Free Survival (PFS) Results Abiraterone Randomized trial of Prednisone with Abiraterone vs. Placebo Randomized trial of Prednisone with Abiraterone vs. Polaceb AR Binding Affinity DHT ~ 5nM Bicalutamide ~160 nM MDV3100 ~35 nM Nuclear Import DHT: ++++ Bicalutamide: ++++ MDV3100: ++ DNA Binding DHT: ++++ Bicalutamide: ++ MDV3100: - Coactivator recruitment DHT: ++++ Bicalutamide: ++ MDV3100: - Effects of MDV3100 on the Androgen Receptor Are Distinct from Bicalutamide Waterfall Plot of Percent PSA Change from Baseline Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75) 62% (40/65) >50% Decline 51% (38/75) >50% Decline Prostate cancer survival curve Alpharadin Survival curve Therapeutic Vaccines APC Vaccine: Sipuleucel-T (Provenge). On day 1 Leukapheresis is is performed at a Center. On day 2-3 sipuleucel-T is manufactured at a company. On day 3-4 the patient is infused at the Doctor’s office. 65 IMPACT: Randomized Phase 3 Trial (IMmunotherapy Prostate AdenoCarcinoma Treatment). Patients (342) will be treated with Sipuleucel-T (Q 2 weeks x 3). Patients (170) will be treated with Placebo (Q2 weeks x 3). The primary endpoint is overall survival and the secondary endpoint it time to objective disease progression. Sipuleucel-T: IMPACT Overall Survival: Primary Endpoint Intent-to-Treat Population P = 0.032 (Cox model) HR = 0.775 [95% CI: 0.614, 0.979] Median Survival Benefit = 4.1 Mos. Developed at NCI CRADA with BN PSA Pox Vector Vaccine: PSA TRICOM (PROSTVAC) 68 Randomized Controlled Double Blind Phase II Study. Patients (84) will be treated with PSA-TRICOM + GM-CSF. Patients (42) will be treated with empty vector + placebo. The primary endpoint is progression free survival. The secondary endpoint is overall survival. PROSTVAC Significantly Extended Overall Survival by 8.5 months 20 40 60 80 100 0 12 24 36 48 60 Overall survival (% patients) 0 Months Control PROSTVAC Therapeutic vaccines vs. Conventional therapy. ●Conventional therapy targets the tumor or its microenvironment. The action is immediate but is limited by toxicity. ●Therapeutic vaccines target the immune system. The action requires a memory response and is delayed but requires an adequate immune system. Time Tumor Burden † † † Vaccine Cytotoxic Therapy Tumor Growth Rate PROSTVAC – Interesting Case History Age PSA Radical prostatectomy Vaccine treatment External beam radiation Second vaccine treatment -No other therapy for prostate cancer -Normal testosterone

Slide 73 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996 Castration Resistant Prostate Cancer RANDOMIZE Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily 1006 Patients Entered TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer TAX 327: Survival Advantage Only Shown for Q3W Docetaxel Median survival Hazard (mos) ratio P-value D 3wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Cabazitaxel Novel taxane active in docetaxel resistant cell lines 755 men with metastatic CRPC who had progressed on or following docetaxel randomized to cabazitaxel vs. mitoxantrone. Patients in both arms received prednisone. Worse toxicity in Cabazitaxel arm with grade 3/4 neutropenia in 82% vs. 58%. About 5% treatment related deaths in Cabazitaxel arm. Primary Endpoint: Overall Survival (ITT Analysis) Progression-Free Survival (PFS) Results Abiraterone Randomized trial of Prednisone with Abiraterone vs. Placebo Randomized trial of Prednisone with Abiraterone vs. Polaceb AR Binding Affinity DHT ~ 5nM Bicalutamide ~160 nM MDV3100 ~35 nM Nuclear Import DHT: ++++ Bicalutamide: ++++ MDV3100: ++ DNA Binding DHT: ++++ Bicalutamide: ++ MDV3100: - Coactivator recruitment DHT: ++++ Bicalutamide: ++ MDV3100: - Effects of MDV3100 on the Androgen Receptor Are Distinct from Bicalutamide Waterfall Plot of Percent PSA Change from Baseline Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75) 62% (40/65) >50% Decline 51% (38/75) >50% Decline Prostate cancer survival curve Alpharadin Survival curve Therapeutic Vaccines APC Vaccine: Sipuleucel-T (Provenge). On day 1 Leukapheresis is is performed at a Center. On day 2-3 sipuleucel-T is manufactured at a company. On day 3-4 the patient is infused at the Doctor’s office. 65 IMPACT: Randomized Phase 3 Trial (IMmunotherapy Prostate AdenoCarcinoma Treatment). Patients (342) will be treated with Sipuleucel-T (Q 2 weeks x 3). Patients (170) will be treated with Placebo (Q2 weeks x 3). The primary endpoint is overall survival and the secondary endpoint it time to objective disease progression. Sipuleucel-T: IMPACT Overall Survival: Primary Endpoint Intent-to-Treat Population P = 0.032 (Cox model) HR = 0.775 [95% CI: 0.614, 0.979] Median Survival Benefit = 4.1 Mos. Developed at NCI CRADA with BN PSA Pox Vector Vaccine: PSA TRICOM (PROSTVAC) 68 Randomized Controlled Double Blind Phase II Study. Patients (84) will be treated with PSA-TRICOM + GM-CSF. Patients (42) will be treated with empty vector + placebo. The primary endpoint is progression free survival. The secondary endpoint is overall survival. PROSTVAC Significantly Extended Overall Survival by 8.5 months 20 40 60 80 100 0 12 24 36 48 60 Overall survival (% patients) 0 Months Control PROSTVAC Therapeutic vaccines vs. Conventional therapy. ●Conventional therapy targets the tumor or its microenvironment. The action is immediate but is limited by toxicity. ●Therapeutic vaccines target the immune system. The action requires a memory response and is delayed but requires an adequate immune system. Time Tumor Burden † † † Vaccine Cytotoxic Therapy Tumor Growth Rate PROSTVAC – Interesting Case History Age PSA Radical prostatectomy Vaccine treatment External beam radiation Second vaccine treatment -No other therapy for prostate cancer -Normal testosterone Current and Emerging Therapies in CRPC

Slide 74 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996 Castration Resistant Prostate Cancer RANDOMIZE Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily 1006 Patients Entered TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer TAX 327: Survival Advantage Only Shown for Q3W Docetaxel Median survival Hazard (mos) ratio P-value D 3wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Cabazitaxel Novel taxane active in docetaxel resistant cell lines 755 men with metastatic CRPC who had progressed on or following docetaxel randomized to cabazitaxel vs. mitoxantrone. Patients in both arms received prednisone. Worse toxicity in Cabazitaxel arm with grade 3/4 neutropenia in 82% vs. 58%. About 5% treatment related deaths in Cabazitaxel arm. Primary Endpoint: Overall Survival (ITT Analysis) Progression-Free Survival (PFS) Results Abiraterone Randomized trial of Prednisone with Abiraterone vs. Placebo Randomized trial of Prednisone with Abiraterone vs. Polaceb AR Binding Affinity DHT ~ 5nM Bicalutamide ~160 nM MDV3100 ~35 nM Nuclear Import DHT: ++++ Bicalutamide: ++++ MDV3100: ++ DNA Binding DHT: ++++ Bicalutamide: ++ MDV3100: - Coactivator recruitment DHT: ++++ Bicalutamide: ++ MDV3100: - Effects of MDV3100 on the Androgen Receptor Are Distinct from Bicalutamide Waterfall Plot of Percent PSA Change from Baseline Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75) 62% (40/65) >50% Decline 51% (38/75) >50% Decline Prostate cancer survival curve Alpharadin Survival curve Therapeutic Vaccines APC Vaccine: Sipuleucel-T (Provenge). On day 1 Leukapheresis is is performed at a Center. On day 2-3 sipuleucel-T is manufactured at a company. On day 3-4 the patient is infused at the Doctor’s office. 65 IMPACT: Randomized Phase 3 Trial (IMmunotherapy Prostate AdenoCarcinoma Treatment). Patients (342) will be treated with Sipuleucel-T (Q 2 weeks x 3). Patients (170) will be treated with Placebo (Q2 weeks x 3). The primary endpoint is overall survival and the secondary endpoint it time to objective disease progression. Sipuleucel-T: IMPACT Overall Survival: Primary Endpoint Intent-to-Treat Population P = 0.032 (Cox model) HR = 0.775 [95% CI: 0.614, 0.979] Median Survival Benefit = 4.1 Mos. Developed at NCI CRADA with BN PSA Pox Vector Vaccine: PSA TRICOM (PROSTVAC) 68 Randomized Controlled Double Blind Phase II Study. Patients (84) will be treated with PSA-TRICOM + GM-CSF. Patients (42) will be treated with empty vector + placebo. The primary endpoint is progression free survival. The secondary endpoint is overall survival. PROSTVAC Significantly Extended Overall Survival by 8.5 months 20 40 60 80 100 0 12 24 36 48 60 Overall survival (% patients) 0 Months Control PROSTVAC Therapeutic vaccines vs. Conventional therapy. ●Conventional therapy targets the tumor or its microenvironment. The action is immediate but is limited by toxicity. ●Therapeutic vaccines target the immune system. The action requires a memory response and is delayed but requires an adequate immune system. Time Tumor Burden † † † Vaccine Cytotoxic Therapy Tumor Growth Rate PROSTVAC – Interesting Case History Age PSA Radical prostatectomy Vaccine treatment External beam radiation Second vaccine treatment -No other therapy for prostate cancer -Normal testosterone Current and Emerging Therapies in CRPC Planned Phase III Randomize patients into Arm A: PSA TRICOM vaccine with GM-CSF (n = 400); Arm B: PSA TRICOM vaccine + placebo (n = 400); Arm C: Empty Vector + placebo GM-CSF (n = 400) Primary endpoint: OS Power = 90%  α = 0.005 Critical HR 0.82 74

Slide 75 -

Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996 Castration Resistant Prostate Cancer RANDOMIZE Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily 1006 Patients Entered TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer TAX 327: Survival Advantage Only Shown for Q3W Docetaxel Median survival Hazard (mos) ratio P-value D 3wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Cabazitaxel Novel taxane active in docetaxel resistant cell lines 755 men with metastatic CRPC who had progressed on or following docetaxel randomized to cabazitaxel vs. mitoxantrone. Patients in both arms received prednisone. Worse toxicity in Cabazitaxel arm with grade 3/4 neutropenia in 82% vs. 58%. About 5% treatment related deaths in Cabazitaxel arm. Primary Endpoint: Overall Survival (ITT Analysis) Progression-Free Survival (PFS) Results Abiraterone Randomized trial of Prednisone with Abiraterone vs. Placebo Randomized trial of Prednisone with Abiraterone vs. Polaceb AR Binding Affinity DHT ~ 5nM Bicalutamide ~160 nM MDV3100 ~35 nM Nuclear Import DHT: ++++ Bicalutamide: ++++ MDV3100: ++ DNA Binding DHT: ++++ Bicalutamide: ++ MDV3100: - Coactivator recruitment DHT: ++++ Bicalutamide: ++ MDV3100: - Effects of MDV3100 on the Androgen Receptor Are Distinct from Bicalutamide Waterfall Plot of Percent PSA Change from Baseline Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75) 62% (40/65) >50% Decline 51% (38/75) >50% Decline Prostate cancer survival curve Alpharadin Survival curve Therapeutic Vaccines APC Vaccine: Sipuleucel-T (Provenge). On day 1 Leukapheresis is is performed at a Center. On day 2-3 sipuleucel-T is manufactured at a company. On day 3-4 the patient is infused at the Doctor’s office. 65 IMPACT: Randomized Phase 3 Trial (IMmunotherapy Prostate AdenoCarcinoma Treatment). Patients (342) will be treated with Sipuleucel-T (Q 2 weeks x 3). Patients (170) will be treated with Placebo (Q2 weeks x 3). The primary endpoint is overall survival and the secondary endpoint it time to objective disease progression. Sipuleucel-T: IMPACT Overall Survival: Primary Endpoint Intent-to-Treat Population P = 0.032 (Cox model) HR = 0.775 [95% CI: 0.614, 0.979] Median Survival Benefit = 4.1 Mos. Developed at NCI CRADA with BN PSA Pox Vector Vaccine: PSA TRICOM (PROSTVAC) 68 Randomized Controlled Double Blind Phase II Study. Patients (84) will be treated with PSA-TRICOM + GM-CSF. Patients (42) will be treated with empty vector + placebo. The primary endpoint is progression free survival. The secondary endpoint is overall survival. PROSTVAC Significantly Extended Overall Survival by 8.5 months 20 40 60 80 100 0 12 24 36 48 60 Overall survival (% patients) 0 Months Control PROSTVAC Therapeutic vaccines vs. Conventional therapy. ●Conventional therapy targets the tumor or its microenvironment. The action is immediate but is limited by toxicity. ●Therapeutic vaccines target the immune system. The action requires a memory response and is delayed but requires an adequate immune system. Time Tumor Burden † † † Vaccine Cytotoxic Therapy Tumor Growth Rate PROSTVAC – Interesting Case History Age PSA Radical prostatectomy Vaccine treatment External beam radiation Second vaccine treatment -No other therapy for prostate cancer -Normal testosterone Current and Emerging Therapies in CRPC Planned Phase III Randomize patients into Arm A: PSA TRICOM vaccine with GM-CSF (n = 400); Arm B: PSA TRICOM vaccine + placebo (n = 400); Arm C: Empty Vector + placebo GM-CSF (n = 400) Primary endpoint: OS Power = 90%  α = 0.005 Critical HR 0.82 74 Summary Localized Disease RP, EBRT, Brachytherapy Androgen Deprivation Therapy (ADT) High risk disease with EBRT LN+ disease following RP Metastatic disease Sipuleucel-T Chemotherapy Docetaxel with prednisone Cabazitaxel with prednisone Abiraterone Enzalutamide Zoledronate or denosumab (decrease skeletal related events)

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Prostate Cancer: Clinical Update James L. Gulley M.D., Ph.D., F.A.C.P. Director, Clinical Trials Group & Deputy Chief Laboratory of Tumor Immunology and Biology Senior Investigator, Medical Oncology Branch Center for Cancer Research National Cancer Institute, NIH Presentation Outline Prostate Cancer detection and prognosis Standard Local Therapy Standard Systemic Therapy Androgen deprivation therapy (ADT) Chemotherapy Bone targeted therapy Immunotherapy Future Directions Disease Continuum in Prostate Cancer Tumor volume Time Castration Docetaxel* Death Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 2nd-line Hormonal therapy Sipuleucel-T* Cabazitaxel* Abiraterone* Enzalutamide* Alpharadin? 3 Death from Prostate Cancer Introduction ~241,740 new cases in 2012 ~28,170 deaths in 2012 1 in 6 men will develop clinically significant prostate cancer Risk Factors Age (median age 71 y/o; <15% younger than 65) Family History Geographic location Race For caucasians 16.6% of the men get prostate cancer and 3.5% die. For african americans 18.1% get prostate cancer and 4.3 % die. Detection May be detected due to symptoms, physical finding or through PSA screening. Most patients in the US are asymptomatic at the time of diagnosis. Digital Rectal Exam 250 200 150 100 50 0 1975 1980 1985 1990 1995 2000 New Prostate Cancer Cases and Deaths (per 100,000 men) New cases Deaths (G. Welch, “Should I Be Tested for Cancer?”, 2004) PSA Screening Incidence vs. Mortality Prostate Cancer in the U.S. Does Screening Save Lives? PLCO Trial N=76,693 men (screen vs. no screen) After 7 years 50 vs. 44 deaths from PC ?Too early PSA test too available? ERSPC Trial N=182,000 (screen vs. no screen) At a median of 9 years, a 20% reduction in PC death Different patient population than US? Histologic Grading Gleason Grade most common grading system Tumors are graded from 1-5 with the higher number indicates a more aggressive tumor Two most predominant patterns added together for a score from 2-10 Staging Stage I(A) has a T1a and is localized. Stage II (B) has a T1b, T1c, T2a, T2b and T2c and is localized to the prostate. Stage III (C) has a T3a and Teb and is locally advanced. Stage IV(D) has a T4N1M1 and is metastatic. Prognosis PSA at diagnosis, percent of tumor in a biopsy specimen, number of positive biopsies, Gleason Score and clinical stage are useful prognostic factors Nomograms are available to predict the likelihood of positive surgical margins, lymph node involvement and disease recurrence after local therapy. Treatment Patients with a life expectancy of less than 10 years and low grade/ low stage lesions may be candidates for active surveillance Active Surveillance The chance of dying of prostate cancer decreases with: Lower Gleason score Older age (more competing causes of mortality) ADT as Primary Therapy For patients who are not candidates for local therapy, immediate ADT offers better OS than waiting until symptomatic disease 985 pts randomized in EORTC trial HR 1.25 (favoring immediate ADT) No earlier time to CRPC despite earlier ADT Disease specific survival reportedly not different in this trial raising some questions Treatment - continued Eradication of the cancer is the goal of therapy in patients with a life expectancy greater than 10 years Radical Prostatectomy External-beam Radiation Brachytherapy Radical Prostatectomy Surgical removal of the prostate May be done with a retropubic, perineal, or laproscopic approach Most common side effects are impotence and incontinence Randomized Trial Comparing Surgery and Watchful Waiting Randomized Trial Comparing Surgery and Watchful Waiting External-beam Radiation Radiation to the prostate (and pelvis) from outside the body Evidence that higher doses are associated with better efficacy IMRT aims to increase radiation delivery and to decrease toxicity Most common side effects are impotence and rectal irritation Average multi-item sexual domain summary scores Prostate anatomy Average multi-item incontinence summary scores Average multi-item bowel summary scores Brachytherapy Radiation implants placed directly into the prostate under ultrasound or CT guidance Very high dose radiation to the prostate with little radiation outside the prostatic bed Acute urinary symptoms common, some patients with impotence Procedure completed in one day Treatment of Locally Advanced Disease Conservative management Hormonal therapy plus radiation Hormonal therapy plus surgery EORTC Trial Randomized trial of radiotherapy ± ADT Locally advanced prostate cancer (n=415) Concurrent + adjuvant ADT continued for 3 years Improved outcomes for combination: Local control metastases free survival overall survival (62% vs. 78% 5 yr survival p=0.0002) ECOG (Messing et al.) Randomized trial of immediate hormonal therapy vs. observation in men undergoing radical prostatectomy with evidence of positive lymph nodes 98 eligible patients enrolled Deaths by 11.9 years f/u 17/47 immediate anti-androgen 28/51 delayed therapy group (HR 1.84; p=0.04) Criticisms Adjuvant RT Randomized study of adjuvant RT vs. observation for T3N0M0 (n=425) For adjuvant RT of 214 patients 53% had Metastasis free survival and 59% had overall survival. For observation of 211 patients 46% had metastasis free survival and 48% had overall survival. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 30 Biochemical Recurrence May be occult local or metastatic disease Options include additional local therapy, hormonal treatment or watchful waiting Virtually impossible to predict the impact of treatment on survival Pound Data Probably the most important report on this population because of the limited use of radiation and hormonal therapy Over 15 years 1,997 patients underwent a radical prostatectomy, with 304 (15%) experiencing a PSA relapse. Of the 304, 103 (34 %) developed metastatic disease. Pound Data (continued) No patients received hormonal therapy without clinically evident metastatic disease. Median time from PSA elevation to metastatic disease was 8 years Median time to death after metastatic disease was 5 years. Prognostic factors predictive of outcome included the Gleason score in the surgical specimen, and PSA doubling time. Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 34 Metastatic PC Prostate Cancer tends to spread to bone and lymph nodes However metastatic lesions have been found in virtually every part of the body including brain, liver and lungs. Many patients do not have measurable lesions thus traditional response criteria (RECIST) are difficult to use. 1941 Charles Huggins showed that advanced PC was inhibited by decreasing Testosterone (castration or estrogen) and activated by adding testosterone. 1966 Nobel Prize in Medicine ADT Treatment of metastatic PC Action of Androgens in Prostate Cells. Testosterone is metabolized to DHT Action of Androgens in Prostate Cells. DHT receptor complex enters nucleus. Action of Androgens in Prostate Cells. DHT receptor complex alters gene expression Action of Androgens in Prostate Cells. mRNA is translated in cytosol into protein. Testosterone lowering therapies GnRH agonists (e.g., Leuprolide and Goserelin) Both agents are expensive May initially result in an increase in testosterone GnRH antagonist (e.g., Degarelix) Similar cost issues without an increase in testosterone Monthly injections Orchiectomy- outpatient procedure. Cost effective if ADT for 6 months or more. ADT Treatment of metastatic PC Side Effects of ADT. ●Sexual effects include decreased libido and erectile dysfunction. ●Physical effects include hot flashes, fatigue, weight gain, hair changes, breast pain, decreased muscle mass, bone mineral density and penis size. ●Metabolic changes include lipid changes, anemia and diabetes mellitus. ●Mental changes include lack of initiative, emotional lability, and decreased memory and cognitive function. Androgen Receptor Antagonists bicalutamide, nilutamide, flutamide and enzalutamide Do not ↓Testosterone, bind androgen receptor and prevent anabolic (growth related) effects Different dosing schedules and potency Different side effect profile Similar activity and all may show “withdrawal response” Combined Androgen Blockade Combination of anti-androgen with orchiectomy or GnRH-A Controversial results Not significantly more effective, but more expensive and may add toxicity 5-Year Survival in the 20 Randomized Trials of CAB (AS plus Nilutamide or Flutamide) vs AS Alone Treatment Better by 2.9% (SE 1.3) Logrank P=0.005 Time Since Randomization (Years) Proportion Alive (%) 24.7% 27.6% 6500 Men in 20 Trials of Nilutamide/Flutamide Androgen Suppression Only Androgen Suppression Antiandrogen Other Hormonal Agents Ketoconazole Abiraterone (recently approved) Patients may respond to multiple sequential hormonal manipulations Disease Continuum in Prostate Cancer Tumor volume Local Therapy Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive 47 Chemotherapy Studies prior to 2004 disappointing Quality of life measurements Difficulty in evaluating response Mitoxantrone + Glucocorticoids Improved quality of life when compared to Glucocorticoids alone No survival advantage FDA approval for the palliation of painful lesions in 1996 Castration Resistant Prostate Cancer RANDOMIZE Docetaxel 30mg/m2 Wkly + Prednisone 10mg orally given daily Docetaxel 75mg/m2 Q3 + Prednisone 10mg orally given daily Mitoxantrone 12mg/m2 Q3 + Prednisone 10mg orally given daily 1006 Patients Entered TAX327 A Multicenter, Randomized Phase III Study of Intermittent Docetaxel + Prednisone vs. Weekly Docetaxel + Prednisone vs. Mitoxantrone + Prednisone in Patients with Hormone-Refractory Prostate Cancer TAX 327: Survival Advantage Only Shown for Q3W Docetaxel Median survival Hazard (mos) ratio P-value D 3wkly: 18.9 0.76 0.009 D wkly: 17.3 0.91 0.3 Mitoxantrone 16.4 – – Months Probability of Surviving 0 6 12 18 24 30 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Docetaxel 3 wkly Docetaxel wkly Mitoxantrone Cabazitaxel Novel taxane active in docetaxel resistant cell lines 755 men with metastatic CRPC who had progressed on or following docetaxel randomized to cabazitaxel vs. mitoxantrone. Patients in both arms received prednisone. Worse toxicity in Cabazitaxel arm with grade 3/4 neutropenia in 82% vs. 58%. About 5% treatment related deaths in Cabazitaxel arm. Primary Endpoint: Overall Survival (ITT Analysis) Progression-Free Survival (PFS) Results Abiraterone Randomized trial of Prednisone with Abiraterone vs. Placebo Randomized trial of Prednisone with Abiraterone vs. Polaceb AR Binding Affinity DHT ~ 5nM Bicalutamide ~160 nM MDV3100 ~35 nM Nuclear Import DHT: ++++ Bicalutamide: ++++ MDV3100: ++ DNA Binding DHT: ++++ Bicalutamide: ++ MDV3100: - Coactivator recruitment DHT: ++++ Bicalutamide: ++ MDV3100: - Effects of MDV3100 on the Androgen Receptor Are Distinct from Bicalutamide Waterfall Plot of Percent PSA Change from Baseline Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75) 62% (40/65) >50% Decline 51% (38/75) >50% Decline Prostate cancer survival curve Alpharadin Survival curve Therapeutic Vaccines APC Vaccine: Sipuleucel-T (Provenge). On day 1 Leukapheresis is is performed at a Center. On day 2-3 sipuleucel-T is manufactured at a company. On day 3-4 the patient is infused at the Doctor’s office. 65 IMPACT: Randomized Phase 3 Trial (IMmunotherapy Prostate AdenoCarcinoma Treatment). Patients (342) will be treated with Sipuleucel-T (Q 2 weeks x 3). Patients (170) will be treated with Placebo (Q2 weeks x 3). The primary endpoint is overall survival and the secondary endpoint it time to objective disease progression. Sipuleucel-T: IMPACT Overall Survival: Primary Endpoint Intent-to-Treat Population P = 0.032 (Cox model) HR = 0.775 [95% CI: 0.614, 0.979] Median Survival Benefit = 4.1 Mos. Developed at NCI CRADA with BN PSA Pox Vector Vaccine: PSA TRICOM (PROSTVAC) 68 Randomized Controlled Double Blind Phase II Study. Patients (84) will be treated with PSA-TRICOM + GM-CSF. Patients (42) will be treated with empty vector + placebo. The primary endpoint is progression free survival. The secondary endpoint is overall survival. PROSTVAC Significantly Extended Overall Survival by 8.5 months 20 40 60 80 100 0 12 24 36 48 60 Overall survival (% patients) 0 Months Control PROSTVAC Therapeutic vaccines vs. Conventional therapy. ●Conventional therapy targets the tumor or its microenvironment. The action is immediate but is limited by toxicity. ●Therapeutic vaccines target the immune system. The action requires a memory response and is delayed but requires an adequate immune system. Time Tumor Burden † † † Vaccine Cytotoxic Therapy Tumor Growth Rate PROSTVAC – Interesting Case History Age PSA Radical prostatectomy Vaccine treatment External beam radiation Second vaccine treatment -No other therapy for prostate cancer -Normal testosterone Current and Emerging Therapies in CRPC Planned Phase III Randomize patients into Arm A: PSA TRICOM vaccine with GM-CSF (n = 400); Arm B: PSA TRICOM vaccine + placebo (n = 400); Arm C: Empty Vector + placebo GM-CSF (n = 400) Primary endpoint: OS Power = 90%  α = 0.005 Critical HR 0.82 74 Summary Localized Disease RP, EBRT, Brachytherapy Androgen Deprivation Therapy (ADT) High risk disease with EBRT LN+ disease following RP Metastatic disease Sipuleucel-T Chemotherapy Docetaxel with prednisone Cabazitaxel with prednisone Abiraterone Enzalutamide Zoledronate or denosumab (decrease skeletal related events) Future Directions Which patient needs treatment? Adjuvant systemic therapy for high risk patients Timing of hormonal therapy Multimodality therapy New agents / combinations / sequencing