Prostate Cancer Diagnosis and Treatment PowerPoint Presentation

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Prostate Cancer: What’s New?Treatment Options For Advanced Castrate Resistant Disease Naomi B Haas, MD Associate Professor of Medicine Abramson Cancer Center April 24, 2013

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Modulation of androgen and testosterone New therapies for castrate resistant prostate cancer Objectives: to discuss the new modulation of androgen and the androgen receptor for prostate cancer

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Intratumoral testosterone Androgen receptor (AR) mutations and splice variants Ligand modulation (things that influence the AR) Targets in advance disease Overcoming resistance mechanisms in prostate cancer:

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Castrate-treated with androgen deprivation therapy Non-castrate- not previously treated with androgen deprivation therapy Semantics

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Rising PSA after surgery or radiation or both New metastatic disease and rising PSA :non- castrate (not previously treated with androgen deprivation therapy) Metastatic castrate prostate cancer Conventional categories

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Orchiectomy LHRH (GHRH) (Luteinizing hormone releasing hormone) agonists Anti-androgens Androgen deprivation Therapy

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ADT Anti-androgen LHRH Pills Implants and shots LHRH antagonist- degarelix

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Tiredness Metabolic syndrome- weight gain, high blood pressure and high blood sugar Osteopenia-decreased bone density Secondary risks for heart attack, blood clot or stroke Mood changes Loss of sex drive (libido) Hot flashes Side Effects

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Prednisone 10 mg by mouth two times a day can decrease PSA by more than 50% in approximately 1/3 of patients with hormone-refractory progressive prostate cancer (Sartor O et al, The Journal of Urology Vol161, Issue 1, January 1999, Page 360 Other Hormonal Manipulations

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Other options: ketoconazole + prednisone or hydrocortisone Scholz M et al. J Urol. 2005 Jun;173(6):1947-52. Median and mean time to PSA progression was 6.7 and 14.5 months. Median and mean survival time was 38.0 and 42.4 months, respectively. Response time and survival were highly correlated (r = 0.799). A total of 34 (44%) men had a greater than 75% decrease in PSA. The median survival times in men with more vs less than a 75% decrease were 60 vs 24 months, respectively. 78 patients 0 1 to 3, >3 lesions bone scan 25, 35, and 18 patients

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Lyase inhibitors- get rid of intratumoral testosterone and residual sources of testosterone/androgens Abiraterone acetate and prednisone Tax 700 Toc 1 (dual lyase and AR inhibitor) AR inhibitors- address mutations in the receptor, splice variants MDV3100 Aragon agent Other AR Modulators HSP 90 inhibitors HDAC inhibitors NEW Hormonal Manipulations!

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Prednisone Ketoconazole Abiraterone Other hormonal manipulations

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AA (Zytiga) 1000mg qd + pred 5mg twice daily 14 of 35 pts had decrease in PSA of >50% Phase III trial completed post chemotherapy showed overall survival improvement of almost 5 months in a study of 1000+ patients, leading to FDA approval Abiraterone acetate and prednisone in patients (Pts) with progressive metastatic castration resistant prostate cancer (CRPC) after failure of docetaxel-based chemotherapy.JClin Oncol 26: 2008 (May 20 suppl; abstr 5019)

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Dizziness Fatigue Low or high blood pressure Fluid retention Elevation of liver enzymes Low potassium Abiraterone side effects

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MDV3100/ Enzalutamide / Xtandi AR modulation

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MDV 3100 Phase II trial Decline docetaxel or are not suitable for docetaxel 1:1 randomization MDV3100 Something else ? patients Coming soon

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MDV 3100 Phase III “AFFIRM” trial Failed 1 or 2 prior chemotherapies (docetaxel) 2:1 randomization MDV3100 Placebo 1170 patients Improvement in overall survival of more than 5 months

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MDV 3100 Phase III “PREVAIL” trial Asymptomatic Castrate metastatic disease 2:1 randomization MDV3100 Placebo 850 patients Closed to accrual in the US

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ARN-509 versus MDV3100

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ARN-509 versus MDV3100

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PK week Continuous Daily Dosing Wk 1 2 3 4 5 9 13 Cycle 1 2 3 ARN-509 Single Dose Tumor Evaluation Q 12 wks Disease Progression DLT period for dose escalation PSA and CTC Q 4 wks ARN-509 dose escalation cohorts (n=3-6/cohort): 30, 60, 90, 120, 180, 240, 300, 390 and 480 mg ARN-509 once daily until progression PK D1-6 Optional FDHT-PET at Baseline, 4 and 12 wks Phase 1 Study Design

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14 out of 29 patients (48.3%) experienced ≥ 50% reduction in PSA at 12 weeks Dose PSA Response Rates

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Baseline 4 Weeks F-DHT-PET: Pharmacodynamic Marker OF AR INHIBITION IN RESPONSE TO ARN-509

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Ongoing Phase 2 Trial ASCO GU 2013

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Provenge Prostvac CARs Immunotherapies

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randomized (2:1) to receive 3 doses of sipuleucel-T (n = 341) or placebo (n = 171) intravenously at 2-week intervals median survival of 25.8 and 21.7 months survival probability at 36 months of 32.1% and 23.0% in the sipuleucel-T and placebo arms Kantoff GU ASCO 2010 IMPACT trial of sipuleucel-T for metastatic castration-resistant prostate cancer

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Harness antigens expressed uniquely by a cancer (for example Prostate specific membrane antigen, prostate specific stem cell antigen, F77, c-met ) and link to T cells to turn on immunity against the antigen ongoing trials in leukemia, pancreatic cancer Can be given IV or into the tumor CARs (Chimeric Antigen and T cell Receptor)(Carl June)

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Targets c-met and VEGFR2 both important targets in prostate cancer c-met is overexpressed in bone metastases as a later event in men on androgen deprivation therapy VEGF expressed in aggressive prostate cancer XL184 (Cabozantanib)

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RDT trial in patients previously treated with docetaxel showed 86% had response in bone scan; 65% had improvement in pain Expanded prostate trial 64% (51/80 pts evaluable) had a PR on bone scans, 24 pts (30%) SD at 100mg daily other cohort treated at 39 mg daily results pending Two new phase III trials of XL184 coming XL184 (Cabozantanib)

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XL 184 Cases

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Original Normalized CAD Annotated Screening Week 6 XL 1129-2408

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XL 1129-2426 Original CAD Annotated Normalized Screening Week 6

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XL 1522-2459 Original CAD Annotated Normalized Screening Week 6

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XL 1521-2565 Original Normalized Screening Week 6 CAD Annotated

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The Landscape

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Biopsy with molecular profile Treatment with chemotherapy or targeted agents or more hormonal therapy depending on your molecular profile The future

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Hormone Sensitive v. Hormone Refractory Prostate Cancer Biology Clinical Trials Open or Planned at UPENN 1. High risk RT+ ADT+/- docetaxel trial 2. everolimus + salvage XRT 3. Phase I Docetaxel/ cmet inhibitor trial 4. CAR-T cells in advanced disease 5. TKI258 plus INC280

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Combines VEGFR+ FGF inhibitor with a C-met inhibitor. Phase I/II planned TKI258 + INC280