1. 1 Castration Resistant Prostate Cancer Charles J Ryan, MD Associate Professor of Medicine and Urology Helen Diller Family Comprehensive Cancer Center University of California, San Francisco U C S F

2. 1. How do we define Castration Resistant Prostate Cancer? Progression of Disease despite a suppressed (castrate) testosterone level (<50ng/dL) 2. What makes prostate cancer lethal and how do we assess prognosis in patients? += Lethal Prostate cancer

3. Lethal Prostate Cancer = Castration Resistant AND Metastatic “Despite regressions of great magnitude, it is obvious that there are many failures of endocrine therapy to control the disease.” Nobel Lecture. Dec 13, 1966 Lymph Node Bone Metastasis

4. Overview of Treatment Options for CRPC Immunotherapy Chemotherapy mCRPC 1 st line Chemotherapy Androgen Synthesis Inhibitor mCRPC post Docetaxel Sipuleucel T (Prostvac Tricom- phIII) Docetaxel Abiraterone (Standard) Abiraterone (Tak 700) Cabazitaxel mCRPC Pre- Chemotherapy Mitox- antrone Androgen Deprivation (LHRH) Leutinizing Hormone Releasing Hormone Agonists/ Antagonists Sipuleucel T (Asymptomatic or Minimally Symptomatic) Non-met CRPC Anti-Apoptosis Tyrosine Kinase Inhibitor Androgen Receptor Antagonist Radio-isotopes (Alpharadin) (Cabozantanib) OGX-011 +Docetaxel Enzalutamide (Enzalutamide) (ARN-509)

5. The Human Endocrine System Drives Prostate Cancer Growth Hypothalamus (Brain) LHRH Pituitary Gland FSH, LH Testicles Testosterone DHT PROSTATE CANCER CELLS Adrenal gland Ketoconazole Antiandrogens: Casodex Flutamide Nilutamide, MDV3100, ARN-509 orchiectomy LHRH agonists (Lupron, Zoladex) Estrogen Abiraterone TAK-700

6. New Treatments for Advanced Prostate Cancer U C S F Androgen Synthesis Inhibitors AR antagonists Second line chemotherapy C-Met inhibitor (?) Radio-isotopes

7. New Treatments for Advanced Prostate Cancer U C S F Targeting the T Cell

8. Theoretical Kinetics of Treatment Response: Cytotoxic Therapy vs Immunotherapy  Cytotoxic chemotherapy quickly debulks tumors – Resistance and tumor regrowth may occur  Immunotherapy activates the immune system – Clinical effect may take time to develop – Responses may be sustained due to immunologic memory Time Chemotherapy Immunotherapy Time on treatment Tumor size Progression Webster et al. J Clin Oncol. 2005;23:8262.

9. Provenge: Background Small EJ et al., J Clin Oncol 18: 3894, 2000

10. Provenge: (second) Pivotal Trial Results † Control was nonactivated, autologous, peripheral blood mononuclear cells. Kantoff PW et al. N Engl J Med. 2010;363:411-422. U C S F Adverse Events Phase 3 design allowed for crossover from placebo to vaccine

11. Provenge: (second) Pivotal Trial Results: Peak effect at 3 years Kantoff PW et al. N Engl J Med. 2010;363:411-422. U C S F

12. Sipuleucel-T in CRPC: How do we use it? Sipuleucel-T prolongs life in patients with asymptomatic met CRPC Sipuleucel-T is extremely well tolerated For use only in asymptomatic CRPC with no visceral mets Not remission inducing My bias – use it early before advancing to prednisone-containing regimens (abiraterone, docetaxel, cabazetaxel, mitoxantrone all require steroids) U C S F

13. ProstVac-VF: Antigen-Specific Immunotherapy Drake. Nat Rev Immunol. 2010;10(8):580-593.

14. ProstVac-VF: Phase 2 Trial Asymptomatic or minimally symptomatic mCRPC (N = 125) ProstVac-VF TriCom + GM- CSF (n = 84) Empty vector + Placebo (n = 41) PROGRESSIONPROGRESSION SURVIVALSURVIVAL Treated at physician’s discretion Crossover Kantoff et al. J Clin Oncol. 2010;28(5):1099-1105. 2:1

15. Overall survival. Kantoff P W et al. JCO 2010;28:1099-1105 ©2010 by American Society of Clinical Oncology Prostvac randomized phase II – Overall Survival

16. New Treatments for Advanced Prostate Cancer U C S F CYP-17 Inhibitors

17. Matching Biology to Therapy along the Path to AR signaling Androgen Production AR Binding Signaling Event Intervention Conversion to DHT Androgen Transport/ Circulation/ Uptake SCC Inhibitors CYP 17 Inihibitors Block Transport 5-Alpha Reductase inhibitors Ketoconazole - Abiraterone Tak-700 Tok-001 Drugs Dutasteride MDV-3100 ARN-509 Tok-001 Novel AR Inhibitors Pre -Receptor Receptor Intracrine Production Polymorphisms Amplified 5 Alpha Reductase Amplified AR Splice Variant AR Aberration None

18. Prostate Cancer can make its own androgens Montgomery RB et alCancer Res. 2008 Jun 1;68(11):4447-54

20. 20 COU-AA-301: Abiraterone Acetate Improves Overall Survival in post chemotherapy mCRPC HR = 0.646 (0.54-0.77) P < 0.0001 Abiraterone acetate: 14.8 months Placebo: 10.9 months 0 100200 300 400 500 600700 0 20 40 60 80 100 AA Placebo Survival (%) Days From Randomization AA 797728631475204250 Placebo3983522961806981 U C S F

21. Overall Study Design of COU-AA-302 Phase 3 multicenter, randomized, double-blind, placebo-controlled study conducted at 151 sites in 12 countries; USA, Europe, Australia, Canada Stratification by ECOG performance status 0 vs 1 AA 1000 mg daily Prednisone 5 mg BID (Actual n = 546) AA 1000 mg daily Prednisone 5 mg BID (Actual n = 546) Co-Primary: rPFS by central review OS Secondary: Time to opiate use (cancer- related pain) Time to initiation of chemotherapy Time to ECOG-PS deterioration TTPP Efficacy end points Placebo daily Prednisone 5 mg BID (Actual n = 542) Placebo daily Prednisone 5 mg BID (Actual n = 542) R A N D O M I Z E D 1:1 R A N D O M I Z E D 1:1 Progressive chemo- naïve mCRPC patients (Planned N = 1088) Asymptomatic or mildly symptomatic Patients Ryan et al Proc ASCO 2012

22. Treatment Arms Evenly Matched AA + P (n = 546) Placebo + P (n = 542) Median age, years (range)71 (44-95)70 (44-90) Median time from initial diagnosis to first dose (years)5.55.1 Median PSA (ng/mL)42.037.7 Median testosterone (ng/dL)4.0 Median alkaline phosphatase (IU/L)93.090.0 Median hemoglobin (g/dL)13.013.1 Median lactate dehydrogenase (IU/L)187.0184.0 Gleason score (≥8) at initial diagnosis53.9%50.0% Extent of disease Bone Metastases  >10 bone lesions Soft tissue or node 83% 48% 49.1% 80% 47% 50% Pain (BPI Short Form) 0-1 2-3 66% 32% 64% 33% Ryan et al Proc ASCO 2012

23. Statistically Significant Improvement in rPFS Primary End Point NR, not reached; PL, placebo. Data cutoff 12/20/2010. 100 80 60 40 20 0 0 Progression-Free (%) 369151812 546 542 489 400 340 204 164 90 12 3 0000 AA PL 46 30 Time to Progression or Death (Months) AA + P PL + P AA + P (median, mos):NR PL + P (median, mos):8.3 HR (95% CI):0.43 (0.35-0.52) P value:< 0.0001 Ryan et al Proc ASCO 2012

24. Strong Trend in OS Primary End Point Pre-specified significance level by O’Brien-Fleming Boundary = 0.0008. 546 542 538 534 482 465 452 437 27 25 0000 524 509 503 493 0202 120 106 258 237 412 387 100 80 60 40 20 0 0 Survival (%) 3121527 Time to Death (Months) 33 AA + P PL + P 6930242118 AA PL AA + P (median, mos):NR PL + P (median, mos):27.2 HR (95% CI):0.75 (0.61-0.93) P value:0.0097 Data cutoff 12/20/2011. Ryan et al Proc ASCO 2012

25. Abiraterone Doubled the Maximal Decline in PSA (≥ 50%) Relative to Prednisone Alone 25 29% of patients on the prednisone control arm had a decline in PSA by ≥ 50% 69% of patients on the abiraterone arm had a decline in PSA by ≥ 50% -25 Maximal Decline From Baseline (%) -50 -75 -100 0 25 50 75 100 Abiraterone + Prednisone Placebo + Prednisone IA3 data. A negative percent indicates a decline in PSA. A positive percent indicates that the subject never has a decline in PSA.

26. Serologic and Clinical Responses AA + P (n = 546) Placebo + P (n = 542) RR (95% CI)P Value PSA decline ≥50%62%24%NA<0.0001 N=220N=218 RECIST: Defined objective response Complete response Partial response Stable disease Progressive disease 36% 11% 25% 61% 2% 16% 4% 12% 69% 15% 2.273 (1.591, 3.247) <0.0001 Ryan et al Proc ASCO 2012

27. Time to All Landmarks Favored Abiraterone Baseline PSA Progression Tumor/Bone Progression Pain Death Adapted from Halabi S, J Clin Oncol 2009;27: 2766-2771. Chemotherapy ECOG PS Decline Primary Endpoints: rPFS and OS Secondary Endpoints ECOG PS = Eastern Cooperative Oncology Group Performance Status. 24-48 months p = 0.001p < 0.0001p = 0.0053 p < 0.0001 p = 0.0097 Ryan et al Proc ASCO 2012

28. Median Times to Functional Status Degradation Basche et al Proc ESMO 2012

29. Can we cure prostate cancer medically?

30. AA and LHRHa in Newly Diagnosed Intermediate and High Risk CaP Undergoing Radical Prostatectomy Newly Diagnosed Intermediate and High Risk CaP Positive biopsies (≥ 3) Gleason score ≥ 7 (4 + 3), T3, PSA ≥ 20 ng/mL or PSA velocity > 2 ng/mL/yr Newly Diagnosed Intermediate and High Risk CaP Positive biopsies (≥ 3) Gleason score ≥ 7 (4 + 3), T3, PSA ≥ 20 ng/mL or PSA velocity > 2 ng/mL/yr 12 weeks AA/ LHRHa/pred Radical Prostatectomy Pathologic response Prostate androgen levels AR signaling Confirm pathology 12 weeks LHRHa Biopsy Pathology Prostate androgen levels (primary aim) AR signaling 12 weeks AA/LHRHa/pred 5 mg qd Supported by grants from Janssen R&D (formerly Ortho Biotech Oncology R&D [unit of Cougar Biotechnology]) and from a Prostate Cancer Foundation Challenge Award to Drs Balk and Nelson. AA, abiraterone acetate; LHRHa, leuprolide acetate; pred, prednisone. Taplin et al Proc ASCO 2012

31. Pathology Results 12 weeks AA/ 24 weeks LHRHa (n = 28) 24 weeks AA/ 24 weeks LHRHa (n = 30) Resultsn = 27n = 29p Value pCR 1/27 (4%)3/29 (10%)0.6120 Near CR (tumor ≤ 5 mm)3/27 (11%)7/29 (24%)0.2992 Total pCR/near pCR4/27 (15%)10/29 (34%) 0.0894 pT3 16/27 (59%)14/29 (48%)- Positive nodes3/27 (11%)8/29 (28%) - Positive margins5/27 (19%)5/29 (17%) - Taplin et al Proc ASCO 2012

32. Abiraterone in CRPC: How do we use it? Abiraterone prolongs life in patients with met CRPC pre and post chemotherapy Treatment delays the need for chemotherapy, time to pain, preserves QOL Can it be combined with other therapies? Should it be continued after disease progression? What are the mechanisms of resistance? –Pharmaco-kinetic? –Pharmaco-genomic? –Alternate signaling paths? –AR mediated progression? U C S F

33. Enzalutamide Second-generation AR antagonist Binds AR more potently than does bicalutamide Not a partial agonist of AR Inhibits translocation of AR into nucleus and decreases AR binding to DNA Oral agent; 160 mg daily (seizures at higher doses) Compared with placebo in ongoing randomized phase 3 trial (post-chemotherapy, ketoconazole-naïve) Tran et al. Science. 2009;324(5928):787-790. Clinicaltrials.gov. NCT00974311. Accessed December 28, 2010. Scher et al. Lancet. 2010;375(9724):1437-1446.

34. Enzalutamide (MDV3100) Oral drug rationally designed to target AR signaling, impacting multiple steps in AR signaling pathway. No demonstrated agonist effects in pre-clinical models. Enzalutamide 1 T AR T Cell nucleus Inhibits Binding of Androgens to AR Inhibits Nuclear Translocation of AR Inhibits Association Of AR with DNA AR Cell cytoplasm Tran et al. Science 2009;324:787–90. 23

35. 35 U C S F Higher AR levels in CRPC tumors AR expression in Bone Marrow Mets Stanbrough et al Cancer Research 2006 Holzberlein et al Am J Pathology Friedlander et al At autopsy – 73% of 15 samples exhibit AR amplification. Friedlander/Paris et al CRPC samples have robust AR expression Mohler et al

36. MDV-3100 Time to PSA Progression Scher HI et al. Lancet. 2010;375:1437.

37. MDV3100 160 mg once daily + prednisone 5 mg twice daily Placebo once daily + prednisone 5 mg twice daily RANDOMIZERANDOMIZE N = 1170 Men with docetaxel- pretreated mCRPC (keto- naïve) 2 1 Clinicaltrials.gov. NCT00974311. Accessed December 28, 2010. Primary objective: OS Enzalutamide - AFFIRM

38. Kaplan–Meier Estimates of Primary and Secondary End Points in the Intention-to- Treat Population. Scher HI et al. N Engl J Med 2012. DOI: 10.1056/NEJMoa1207506 MDV3100: Phase 3 Trial (AFFIRM)

39. Combination Phase III: Alliance: A031201 - PI Michael Morris Total of 616 deaths, log-rank statistic 90% power (one sided type I error rate of 0.025) to detect HR of 0.77 in favor of arm B Stratification factor: prior chemo Arm A: Enzalutamide Arm B: Enzalutamide Abiraterone Prednisone

40. ARN-509 in Men with High Risk Non-Metastatic Castration-Resistant Prostate Cancer Abstract 107237 Smith MR, 1 Antonarakis ES, 2 Ryan CJ, 3 Berry W, 4 Shore ND, 5 Liu G, 6 Alumkal J, 7 Higano C, 8 Chow Maneval E, 9 Rathkopf DE 10 1 Massachusetts General Hospital and the Harvard Medical School, Boston, MA; 2 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD; 3 UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; 4 Cancer Centers of North Carolina, Raleigh, NC; 5 Carolina Urologic Research Center, Myrtle Beach, SC; 6 University of Wisconsin Carbone Cancer Center, Madison, WI; 7 Oregon Health & Science University Knight Cancer Institute, Portland, OR; 8 Seattle Cancer Care Alliance and the University of Washington, Seattle, WA; 9 Aragon Pharmaceuticals, San Diego, CA; 10 Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York, NY

41. Background  ARN-509 is a potent and selective antagonist of the androgen receptor (AR) that is being developed for the treatment of men with castration-resistant prostate cancer (CRPC)  ARN-509 inhibits AR nuclear translocation and DNA binding to androgen response elements  In contrast to bicalutamide, ARN-509 shows no significant agonist properties in the context * Clegg N et al., Cancer Res 2012; 72:1-10 In murine tumor models of CRPC, ARN-509 showed dose- dependent tumor regressions superior to bicalutamide

42. ARN -509 - Phase II Design  Here we report preliminary results for the cohort of high risk non-metastatic (M0) CRPC patients  47 patients were enrolled between Nov 2011 and Jun 2012  Data cut-off 10 Jan 2013  Patients received ARN-509 at 240 mg/day on a continuous 28-day dosing cycle  PSA assessments performed every month  Tumor assessments performed every 4 months Post-Abi Metastatic CRPC patients 1º Endpoint: 12-week PSA response 2º Endpoints: Time to PSA Progression, safety Tx-Naïve Metastatic (n = 90) Non-Metastatic (M0) Smith MR, Proc GU ASCO 2013

43. ARN-509 - PSA Response % Change in PSA from baseline At 12 Weeks At 24 Weeks Smith MR, Proc GU ASCO 2013

44. Cabozantanib –cMET + VEGFr inhibitor Smith et al JCO 2012

45. Cabozantanib –cMET + VEGFr inhibitor Smith et al JCO 2012

46. Cabozantanib –cMET + VEGFr inhibitor Smith et al JCO 2012

47. Cabozantanib –cMET + VEGFr inhibitor http://www.cometclinicaltrials.com/index. html

48. New Treatments for Advanced Prostate Cancer U C S F Chemotherapy

49. Tax 327 Primary Objective: Overall Survival OS Docetaxel: 18.2 p = 0.03 Mitoxantrone: 16.4 –– Months Probability of Surviving 0612182430 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 U C S F

50. DocetaxelCabazitaxel (XRP6258) (C 45 H 57 NO 14 ) Cabazitaxel is a 7,10 dimethoxy analogue of docetaxel Two Different Chemical Entities Mita AC, et al. Clin Cancer Res 2009;15:723-730; Ojima I, et al. J Med Chem 1996;39:3889-3896; Greenberger LM, Sampath D. Resistance to taxanes. In: Teicher BA, ed. Cancer Drug Discovery and Development: Cancer Drug Resistance. Totowa, New Jersey: Humana Press; 2006:329-358; Raub TJ. Mol Pharm 2005;3:3-25; www.Taxotere.com.www.Taxotere.com (C 43 H 53 NO 14 ) Docetaxel is an esterified product of 10-deacetyl baccatin III

51. The TROPIC study: cabazitaxel or mitoxantrone with prednisone in patients with metastatic CRPC previously treated with docetaxel (De Bono et al) Primary objective: Overall survival Secondary objectives: PFS (tumor progression, pain progression, PSA progression, or death from any cause), response rate, safety Mitoxantrone 12 mg/m² q 3 wk + prednisone for 10 courses (MP, n=377) Cabazitaxel 25 mg/m² q 3 wk + prednisone for 10 courses (CBZP, n=378) Men with metastatic CRPC progressing during and after docetaxel (N=755) RANDOMIZERANDOMIZE U C S F

52. Primary Endpoint (Overall Survival) Met Time (months) Proportion of OS (%) 100 80 60 40 20 0 0612182430 MPCBZP Median OS (months)12.715.1 Hazard ratio0.72 95% CI0.61–0.84 P-value<.0001 Censored MP CBZP Combined median follow-up: 13.7 months U C S F

53. Summary of Hematologic AEs 53 Hematologic AEs a JEVTANA® 25 mg/m² q 3 wk + prednisone 10 mg qd (n=371) mitoxantrone 12 mg/m² q 3 wk + prednisone 10 mg qd (n=371) Grade 1–4, n (%)Grade 3–4, n (%)Grade 1–4, n (%)Grade 3–4, n (%) Neutropenia b 347 (94%)303 (82%)325 (87%)215 (58%) Febrile neutropenia27 (7%) 5 (1%) Anemia b 361 (98%)39 (11%)302 (82%)18 (5%) Leukopenia b 355 (96%)253 (69%)343 (93%)157 (42%) Thrombocytopenia b 176 (48%)15 (4%)160 (43%)6 (2%) a In ≥5% of patients. b Based on laboratory values: JEVTANA® (n=369), mitoxantrone (n=370). JEVTANA® Prescribing Information. Bridgewater, NJ: sanofi-aventis U.S. LLC; June 2010. Data on file. Clinical study report/EFC6193 (TROPIC). Protocol did not permit primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) at cycle 1

54. Chemotherapy: How do we use it? 1.Palliation 2.Rapid progression/ Symptoms/ Need for ‘debulking’ 3.Intermittent vs Continuous 4.Special populations - Anaplastic, Small cell etc U C S F

55. New Treatments for Advanced Prostate Cancer U C S F Radium 223

56. Radium-223 Targets Bone Metastases Radium-223 acts as a calcium mimic Naturally targets new bone growth in and around bone metastases Radium-223 is excreted by the small intestine Ra Ca

57. Radium-223 Targets Bone Metastases Alpha-particles induce double-strand DNA breaks in adjacent tumour cells 1 –Short penetration of alpha emitters (2-10 cell diameters) = highly localised tumour cell killing and minimal damage to surrounding normal tissue Range of alpha-particle Radium-223 Bone surface 1. Perez et al. Principles and Practice of Radiation Oncology. 5th ed. Lippincott Williams & Wilkins; 2007:103.

58. TREATMENT 6 injections at 4-week intervals Radium-223 (50 kBq/kg) + Best standard of care Placebo (saline) + Best standard of care RANDOMISEDRANDOMISED 2:1 N = 922 PATIENTS Confirmed symptomatic CRPC ≥ 2 bone metastases No known visceral metastases Post-docetaxel or unfit for docetaxel Confirmed symptomatic CRPC ≥ 2 bone metastases No known visceral metastases Post-docetaxel or unfit for docetaxel ALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study Design Clinicaltrials.gov identifier: NCT00699751. Total ALP: < 220 U/L vs ≥ 220 U/L Bisphosphonate use: Yes vs No Prior docetaxel: Yes vs No Total ALP: < 220 U/L vs ≥ 220 U/L Bisphosphonate use: Yes vs No Prior docetaxel: Yes vs No STRATIFICATION Planned follow-up is 3 years

59. Month0369121518212427 Radium- 22354145033021312072301530 Placebo26821814789492815730 ALSYMPCA Overall Survival 0 10 20 30 40 50 60 70 80 90 100 % Radium-223, n = 541 Median OS: 14.0 months Placebo, n = 268 Median OS: 11.2 months HR 0.695; 95% CI, 0.552-0.875 P = 0.00185

60. SRE Prevention – Denosumab and Zoledronic acid both approved. Fizazi et al, 2011.

61. Overarching Principles of CRPC management No Standards of care exist on how to manage patients without radiographic evidence of metastases. Maintain ADT in all patients (LHRH agonists/antagonist or orchiectomy) Allowing asymptomatic mCRPC to go untreated until symptoms develop is no longer advised given the efficacy and tolerability of new agents. Consider bone targeted therapy in patients at risk for skeletal combinations. Consider that progression can be ‘mixed’ or in a focal site despite systemic control of disease – focal sites of progression can be treated with radiation therapy. Molecularly driven treatment selection is being developed and enrollment in clinical trials that test this is ideal.