Prostate Cancer: What’s New 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

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

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

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

Conventional categories 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

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

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

Side Effects 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

Other Hormonal Manipulations 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 options: ketoconazole + prednisone or hydrocortisone Scholz M et al. J Urol. 2005 Jun;173(6):1947-52. 78 patients 0 1 to 3, >3 lesions bone scan 25, 35, and 18 patients Fig. 5. Kaplan-Meier representation of survival time. Group 1 denotes men with less then 50% decrease in PSA. Group 2 denotes men with PSA decrease between 50% and 75%. Group 3 denotes men with log PSA decrease greater than 75%. 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.

NEW Hormonal Manipulations! 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

Other hormonal manipulations Prednisone Ketoconazole Abiraterone

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

MDV3100/ Enzalutamide / Xtandi AR modulation MDV3100/ Enzalutamide / Xtandi This is an AR receptor antagonist (oral ) which inhibits both the translocation of the AR receptor to the nucleus and the binding of the AR complex to DNA. Casodex does not do this. Induces apoptosis

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

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

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

ARN-509 versus MDV3100

ARN-509 versus MDV3100

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

experienced ≥ 50% reduction in PSA at 12 weeks PSA Response Rates Dose 30 mg 60 mg 90 mg 120 mg 180 mg 240 mg 300 mg 390 mg 480 mg 14 out of 29 patients (48.3%) experienced ≥ 50% reduction in PSA at 12 weeks

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

Ongoing Phase 2 Trial ASCO GU 2013

Immunotherapies Provenge Prostvac CARs

IMPACT trial of sipuleucel-T for metastatic castration-resistant prostate cancer 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

CARs (Chimeric Antigen and T cell Receptor)(Carl June) 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

XL184 (Cabozantanib) 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) 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

XL 184 Cases

XL 1129-2408 Screening Week 6 Original Normalized CAD Annotated

XL 1129-2426 Screening Week 6 Original Normalized CAD Annotated

XL 1522-2459 Screening Week 6 Original Normalized CAD Annotated

XL 1521-2565 Screening Week 6 Original Normalized CAD Annotated

The Landscape TKIs +ADT ADT Provenge Cabazetaxel Docetaxel ECOG 2809 Adjuvant/ Neoadjuvant Rising PSA Only Rising PSA and metastatic disease (noncastrate) Progression after ADT (castrate) Progression after Docetaxel TKIs +ADT ADT Provenge Cabazetaxel Docetaxel ECOG 2809 ketoconazole mitoxantrone and prednisone abiraterone docetaxel enzalutamide Strive Prevail XL184? Radium chloride

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

Hormone Sensitive v. Hormone Refractory Prostate Cancer Clinical Trials Open or Planned at UPENN Biology Hormone Sensitive Hormone Refractory 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 And I would like to close with this slide which summarizes our research plan for the next year. We hope to open a number of clinical trials that will give new options for patients with PSa recurrence and metastatic prostate cancer. We hope that we can be at the forefront of identifying new apporaches for this disease, but we need your help. Whether it is participation in clinical research, or participation in patient support groups in person or on line, continued progress in the treatment of this disease can only happen with the involvement of the corageous men with prostate cancer and their families.

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