1. Castration Resistant Prostate Cancer in 2011: What are the Treatment Options? Lori Wood, MD, MSc, FRCP(C) Associate Professor of Medicine, Dalhousie University Medical Oncologist, Capital Health Cancer Care Program Halifax, Nova Scotia 15 th Annual Atlantic Canada Oncology Group Symposium June 23-25, 2011

2. Objectives u Understand the term “Castrate Resistant Prostate Cancer” (vs. HRPCa) u Review systemic treatment options pre-2010 u Prednisone u Mitoxantrone u Docetaxel u Bone targeted therapy – Zoledronic Acid* u Discuss systemic treatment options post-2010 u Abiraterone u MDV3100 u Cabazitaxel u Sipuleucel-T (Provenge) u Bone targeted therapy – Denosumab* u Learn about other new agents/trials

3. Disclosure u I have participated in advisory boards/ consultant meetings with u Pfizer, Novartis, Janssen, Amgen, AstraZeneca u No personal financial compensation u I have clinical trials with u Pfizer, Novartis, Janssen, Medivation, AstraZeneca u No personal financial compensation

4. Progression of Advanced Prostate Cancer Failed localized therapy SymptomaticBiochemicalAsymptomatic Clinical Metastases CRPC PSA rises 24+ months 12-36 months 6-24 months MoM+M+ Hormonal therapy Death

5. Prostate Cancer u PCa is an androgen receptor (AR) dependent disease u Blocking AR signalling = hallmark of treatment u Majority of men initially respond to androgen dependent therapy (ADT) when initiated u Progress after 12-48 months u Over time, the cancers “castrate resistant”

6. Castrate Resistant Prostate Cancer u In the past, we used terms like u Hormone Refractory u Androgen Independent u Androgen Resistant u Now … Castrate Resistant Prostate Cancer (CRPCa) u Why?

7. CRPCa u Even though patients have castrate levels of serum testosterone (  1.75 mmol/L), AR signalling is still happening u By our current methods of “castration”, they are resistant but these tumors are still responding to AR signalling u Current methods of castration (or ADT) u LHRH agonists u LHRH antagonists u Orchiectomy u  Nonsteroidal antiandrogens

8. How Do Cancers Maintain AR Signalling u Androgen receptor u Upregulation by gene amplification u Mutations u Intratumoral synthesis of testosterone u Overexpression of key enzymes u P-450c17 (CYP17) involved in extragonadal androgen biosynthesis u Others

9. Systemic Therapy for CRPCa Pre-2004 u Prednisone for palliation u n = 38; 38% improvement in pain u Antiandrogen withdrawal response u n = 9; 29% had a  50%  in PSA u Mitoxantrone and Prednisone for palliative u Phase III RCT, not blinded, n = 161 u Primary endpoint = palliative response Tannock et al. J Clin Oncol 1989;7:590-597. H.I. Scher and W.K. Kelly. J Clin Oncol 1993;11:1566-1572. Tannock et al. J Clin Oncol 1996;14:1756-1764.

10. Mitoxantrone and Prednisone: Results Prednisone (n=81) Mitoxantrone & Prednisone (n=80) p Value Palliative Response12%29%0.01 Duration of Response18 wks43 wks  0.0001 1° and 2° Palliative Response 21%38%0.025 PSA (  50% Decrease) 22%33%0.11 Overall Survival  10.3m 0.27 u Mitoxantrone and Prednisone became the new standard of care

11. Systemic Therapy for CRPCa 2004-2010 u Docetaxel u Bisphosphonates u Zoledronic Acid

12. Docetaxel u TAX 327 study Tannock et al. N Eng J Med 2004;351:1502-1512 u SWOG study Petrylak et al. N Eng J Med 2004;351:1513-1520

13. TAX-327 Study: Design Stratification: Pain level PPI ≥2 or AS ≥10 vs. PPI <2 or AS <10 KPS ≤70 vs. ≥80 Docetaxel 75 mg/m 2 q3 wkly + Prednisone 5 mg bid Mitoxantrone 12 mg/m 2 q3 wkly + Prednisone 5 mg bid RANDOMIZATIONRANDOMIZATION Docetaxel 30 mg/m 2 wkly 5 of 6 wks + Prednisone 5 mg bid Treatment duration in all 3 arms = 30 wks n=1,006 patients Tannock IF. N Engl J Med 2004;351:1502-1512.

14. TAX-327 Study: Results MITOX (n=337) TAX qw (n=334) TAX q3w (n=335) p Value PSA32%48%45%  0.001 Decreased Pain22%31%35%0.01 QOL13%23%22%0.009

15. TAX-327 Study: Overall Survival Median survival Hazard (mos) ratio p-value Combined:18.20.830.03 D 3 wkly: 18.90.760.009 Mitoxantrone16.4 –– 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 Mitoxantrone Eisenberger MA. Proc Am Soc Clin Oncol 2004;23:2, Abstract 4. Months

16. RANDOMIZATIONRANDOMIZATION SWOG 9916: Phase III Trial Survival Quality of life: –pain questionnaire and log of analgesic requirements Improved performance status n=770 patients Hormone-Refractory Advanced Prostate Cancer Mitoxantrone 12 mg/m 2 d1 + Prednisone 5 mg bid d1-21 q3 weekly Docetaxel 60 mg/m 2 d2 + Estramustine 280 mg tid d1-5 q3 weekly Petrylak DP. N Engl J Med 2004;351:1513-1520.

17. Conclusions Regarding TAX-327 and SWOG 9916 u For the first time, a survival benefit was clearly demonstrated in this patient population u Docetaxel chemotherapy given every three weeks increased overall survival u decreased risk of death by 24% u absolute increase in median survival of 2.5 months u Docetaxel chemotherapy demonstrated a higher rate of pain response, quality of life improvement and PSA Tannock IF. N Engl J Med 2004;351:1502-1512. Petrylak DP. N Engl J Med 2004;351:1513-1520.

18. Docetaxel “Plus” Phase III Trials u DN101 (high dose Vitamin D) Scher et al. J Clin Oncol 2011 June;29:2191-2198. u Bevacizumab Kelley et al. ASCO 2010 (Abstract 4511). u Sunitinib ASCO 2011 (Abstract 4515). u Risedronate ASCO 2011 (Abstract 4518).

19. Bisphosphonates u Option in the management of bone metastasis u Powerful inhibitor of osteoclast - mediated bone resorption u Zoledronic acid – first bisphosphonate to show efficacy in prostate cancer

20. Zoledronic Acid in PCa: Trial Design RANDOMIZEDRANDOMIZED placebo q 3 wk + daily oral vitamin D 400 IU and calcium 500 mg zoledronic acid 4 mg q 3 wk 015 months Core analysis 24 months Final analysis n=214 n= 208 zoledronic acid 8 mg q 3 wk n=221

21. Proportion (%) of Patients With a Skeletal Related Event Percent of patients p=0.021 Saad F. J Natl Cancer Inst 2004;96(11):879-882.

22. Time to First Skeletal Related Event nnnnnnn Zol 4 mg214149977047353 Placebo298128784432203 Saad F. J Natl Cancer Inst 2004 96(11):879-882. Median, daysp value ZOMETA ® 4 mg488.009 Placebo321

23. Systemic Therapy For CRPCa Since 2010

24. u Post-Docetaxel u Pre-Docetaxel

25. Abiraterone u Small molecule inhibitor of CYP17 u Therefore blocks testosterone and estradiol synthesis

26. Steroid Synthesis Cholesterol Pregnenolone Progesterone Corticosterone 17α-OH- pregnenolone DHEA Androstenedione Testosterone 17α –OH- progesterone Cortisol CYP17 C17,20-lyase CYP17 17α-hydroxylase Aldosterone Deoxy- corticosterone DHT 5α-reductase 11-Deoxy- cortisol CYP19: aromatase Estradiol Desmolase X X ACTH Attard et al. J Clin Oncol 2008.

27. Steroid Synthesis Cholesterol Pregnenolone Progesterone Corticosterone 17α-OH- pregnenolone DHEA Androstenedione Testosterone 17α –OH- progesterone Cortisol CYP17 C17,20-lyase CYP17 17α-hydroxylase Aldosterone Deoxy- corticosterone DHT 5α-reductase 11-Deoxy- cortisol 11β-Hydroxylase CYP19: aromatase Estradiol Desmolase X X ACTH Attard et al. J Clin Oncol 2008. Low-dose steroid replacement minimizes mineralocorticoid-related toxicity

28. Phase III COU-AA-301 Study Design  Stratification according to  ECOG performance status (0-1 vs. 2)  Worst pain over previous 24 hours (BPI short form; 0-3 [absent] vs. 4-10 [present])  Prior chemotherapy (1 vs. 2)  Type of progression (PSA only vs. radiographic progression with/without PSA progression) Abiraterone 1000 mg daily Prednisone 5 mg BID N=797 Primary end point: OS (25% improvement; HR 0.8; 12 mo vs 15 mo) Secondary end points (ITT): TTPP rPFS PSA response QoL ( FACT-P, EORTC-QLQ-C30 ) Efficacy endpoints (ITT) Placebo daily Prednisone 5 mg BID n=398 R A N D O M I Z E D 2:1 1195 patients with progressive, mCRPC Failed 1 or 2 chemotherapies, one of which contained docetaxel Patients de Bono et al. NEJM 2011 May;364:1995-2005.

29. AA (n = 797) Placebo (n = 398) Total (n = 1195) Median age, years (range) 69.0 (42-95) 69.0 (39-90) 69.0 (39-95) ECOG-PS 210.7%11.1%10.8% Significant pain present44.3%44.0%44.2% 2 Prior chemotherapies28.2%28.4%28.3% Radiographic Progression70.1%68.6%69.6% Baseline Demographics

30. AA (n = 797) Placebo (n = 398) Extent of disease Bone89.2%90.4% Node45.4%41.5% Visceral Metastases29.0%24.1% Liver11.3%7.6% Lung13.0%11.4% Other Visceral5.8%5.3% PSA (median, ng/mL)128.8137.7 Baseline Disease Characteristics

31.  All three criteria had to be met  PSA progression  Radiographic progression  Progression on bone scans  Soft tissue disease progression by modified RECIST criteria  Symptomatic or clinical progression  Pain progression  Development of a SRE  Increase/change in steroid use  Initiation of new systemic anti-cancer therapy Reasons to Stop Treatment

32.  The Independent Data Monitoring Committee’s (IDMC) recommendation to un-blind the study  Based on a pre-specified interim analysis  Demonstrated statistically significant improvement in OS (p< 0.0001)  HR for OS exceeded the trial HR (0.789)  Secondary endpoints also met  Acceptable expected safety profile, easily managed  Based on these results, IDMC also recommended that patients in the placebo arm be offered treatment with Abiraterone acetate COU-AA-301 Results: ESMO October 2010

33. Overall Survival Results (ESMO 2010) HR = 0.646 (0.54-0.77) P < 0.0001 Placebo: 10.9 months (95%CI: 10.2, 12.0) 0 100200 300 400 500 600700 0 20 40 60 80 100 Survival (%) Days from Randomization Abiraterone acetate: 14.8 months (95%CI: 14.1, 15.4) 2 Prior Chemo OS: 1 Prior Chemo OS 14.0 mos AA vs 10.3 mos placebo 15.4 mos AA vs 11.5 mos placebo

34. Overall Survival (NEJM 2011)

35. ASCO 2011 Update u Median follow-up = 20.2m u Median overall survival (Abstract 4517) u 15.8m vs. 11.2m (4.6m difference) u HR = 0.74, p  0.0001 u Palliation (Abstract 4520) u 44.4% vs. 27%, p=0.0002

36. VariableSubgroupNHR95% CI All subjectsAll11950.660.56-0.79 Baseline ECOG0-110680.640.53-0.78 21270.810.53-1.24 Baseline BPI< 46590.640.50-0.82  4 5360.680.53-0.85 No. of prior chemo regimens18330.630.51-0.78 23620.740.55-0.99 Type of progressionPSA only3630.590.42-0.82 Radiographic8320.690.56-0.84 Baseline PSA above medianYES5910.650.52-0.81 Visceral disease at entryYES7090.600.48-0.74 Baseline LDH above medianYES5810.710.58-0.88 Baseline ALK-P above medianYES5870.600.48-0.74 RegionNorth America6520.640.51-0.80 Other5430.690.54-0.90 0.50.7511.5 Favors AA Favors placebo BPI; Brief Pain Inventory, ALK-P, alkaline phosphatase Survival Benefit Observed Across Patient Subgroups

37. AA (n = 797) Placebo (n = 398) HR 95% CI p Value TTPP (months) 10.26.60.58 (0.46, 0.73) < 0.0001 rPFS (months)5.63.6 0.67 (0.59, 0.78) < 0.0001 PSA response rate Total38.0%10.1%< 0.0001 Confirmed29.1%5.5%< 0.0001 Secondary Endpoints

38. AAPlaceboHRp Value Time to SRE (days)3011500.640.0006 Pain Palliation44.4%27.0%0.0002 Time to Pain Progression (days) 2251420.690.0051 Tertiary Endpoints

39. AA (n = 791) Placebo (n = 394) All GradesGrades 3/4All GradesGrades 3/4 Fluid retention30.5%2.3%22.3%1.0% Hypokalemia17.1%3.8%8.4%0.8% LFT abnormalities10.4%3.5%8.1%3.0% Hypertension9.7%1.3%7.9%0.3% Cardiac disorders13.3%4.1%10.4%2.3% LFT, liver function test Toxicity

40. Pearls of Wisdom u Available through Health Canada SAP u Blood work q4 weeks u LFT’s and lytes q2 weeks x first and third cycles u Need Prednisone 5 mg b.i.d. with it

41. MDV3100 u MDV3100 is a potent androgen receptor antagonist u Blocks DHT from binding to AR u Impairs nuclear translocation u Inhibits binding to DNA u Well-tolerated

43. Scher et al. Lancet, 2010 April;375:1437-1446. Phase II Results

44. Phase III AFFIRM Study Design Patients u mCRPCa u Failed 1 or 2 prior chemo- therapies, one of which was docetaxel u n=1680 R A N D O M I Z E D 2:1 MDV3100 160 mg p.o. qd + Prednisone Placebo + Prednisone Efficacy Endpoints u Overall survival

45. Results u Study closed to accrual u Results pending u Toxicity – very well-tolerated

46. Cabazitaxel u Tubulin binding taxane u Activity against Docetaxel resistant tumors

47. Phase III TROPIC Study Design Primary endpoint: OS Secondary endpoints: Progression-free survival (PFS), response rate, and safety cabazitaxel 25 mg/m² q 3 wk + prednisone * for 10 cycles (n=378) mitoxantrone 12 mg/m² q 3 wk + prednisone * for 10 cycles (n=377) Stratification factors ECOG PS (0, 1 vs. 2) Measurable vs. non-measurable disease mCRPC patients who progressed during and after treatment with a docetaxel-based regimen (N=755) de Bono et al. Lancet 2010 October;376:1147-1154.

48. TROPIC Baseline Demographics MitoxantroneCabazitaxel n377378 Median age (years)6768 ECOG PS 0-191%93% Bone Metastases87%80% Visceral Metastases25% Pain at Baseline45%46%

49. TROPIC Results MitoxantroneCabazitaxelHRp Value OS12.7m15.1m0.70  0.0001 RECIST RR4.4%14.4%0.0005 PSA RR17.8%39.2%0.0002 Pain Response7.7%9.2%0.63

50. Overall Survival Results MP37730018867111 CBZP37832123190284 Number at risk Proportion of OS (%) 80 60 40 20 0 100 0 months 6 months12 months18 months24 months30 months 15.1 12.7 Median OS (months) 0.59 – 0.83 95% CI <.0001 P-value 0.70 Hazard Ratio CBZP MP

51. TROPIC Toxicity (Grade  3) MitoxantroneCabazitaxel Neutropenia58%82% Febrile Neutropenia1.1%8% Anemia5%11% Diarrhea  1% (11% all grades) 6% (47% all grades) Neuropathy1% Deaths Due to AE Within 30 Days of Last Dose 1% (3 patients) 7.9% (18 patients)

52. Pearls of Wisdom u Really have to watch for neutropenia and diarrhea u Watch prior doses of chemotherapy and RT

53. Sipuleucel-T (Provenge) u Active cellular immunotherapy u “Cancer vaccine” u Autologous PBMC (including APC’s) u The APC have been activated with a fusion protein (PA2024) u PA2024 is a combination of u Prostate antigen u Prostatic acid phosphatase u GMCSF (an immune cell activator) u Leukopharesis weeks 0, 2, 4 and infusion 3 days later u Manufactured centrally

54. Sipuleucel-T Background u RCT, placebo-controlled, double-blind, n = 127 metastatic CRPCa patients; 2:1 randomization u Overall survival HR = 0.59 (95% CI: 0.39-0.88); p = 0.01 u RCT, placebo-controlled, n = 98 u Trend towards  survival u No effect on time to progression which was the primary endpoint in both studies Small et al. JCO 2006;24:3089-94. Higano et al. Cancer 2009;115:3670-9.

55. Phase III IMPACT Study Design u RCT, double-blind, placebo-controlled u n = 512 metastatic CRPCa; 2:1 randomization u Primary Endpoint = overall survival (not initially) u Patients u Gleason score  7 (initially) u Asymptomatic (initially) u ECOG 0, 1 u No visceral metastases; SCC u Could have had chemotherapy u There was crossover u Statistics u Power = 88%; 2-sided  = 0.05; HR = 0.69

56. IMPACT Trial Baseline Demographics u August 2003 – November 2007 u 75 centres u Median follow-up = 34.1m Sipuleucel-TPlacebo n341171 ECOG PS = 082.1%81.3% Gleason  7 75.4% Chemotherapy19.6%15.2% Pain = 051.5%48.5% Kantoff et al. NEJM 2010;363:411-22.

57. IMPACT Trial Results Sipuleucel-TPlacebop ValueHR Overall Survival25.8m21.7m0.03 0.78 (0.61-0.98) Median Time to Objective Response 3.7m3.6m0.630.95 Time to Clinical Progression 0.400.92 PSA Response2.6%1.3%NS

58. Overall Survival (NEJM 2010)

59. Pearl of Wisdom u Ever a reality in Canada?

60. Denosumab u Human monoclonal antibody to RANK ligand u RANK ligand is an essential mediator of osteoclast formation, function and survival u q4 weeks s.c.

61. Study Design u Phase III RCT, placebo-controlled, double- blind u Primary endpoint = time to first SRE u n = 1901 Fizazi et al. Lancet 2011 March;377:813-822.

62. Study Results Denosumab Zoledronic Acid HRp Value n950951 Median Time on Study12.2m11.2m Median Time to First SRE 20.7m (18.8-24.9) 17.1m (15.0-19.4) 0.82 0.0002 Inferiority 0.0008 Superiority # of SRE’s341 (36%)386 (41%) Radiation Therapy177 (19%)203 (21%) Pathological Fracture137 (14%)143 (15%) Spinal Cord Compression 26 (3%)36 (4%) Surgery to Bone 1 (  1%)4 (  1%)

63. Summary u Pre-2004: u Prednisone, antiandrogen withdrawal u Mitoxantrone u 2004-2010: u Docetaxel; Zoledronic Acid u 2010: u Abiraterone Acetate, MDV3100, Cabazitaxel, Provenge, Denosumab u Beyond: u New drugs u New indications

64. New Drugs: Phase III Trials in CRPCa u Pre-chemotherapy u Ipilimumab (CTLA4) u Orteronel (TAK-700), (AR) u Tasquinimod (angiogenesis) u PROSTVAC (poxiviral vaccine) u EMD525797 (integrin inhibitor) u With chemotherapy u Docetaxel  Lenalidomide (immunovaccine) u Docetaxel  OGX-011 (apoptosis) u Docetaxel  Zibotentan (Endothelin-A Receptor Antagonist) u Post-Chemotherapy u Orteronel u Ipilimumab

65. New Drugs: ASCO 2011 u Cabozantinib (Abstract 4516) u TKI of MET and VEGFR u Phase II randomized discontinuation trial u 122/171 had clinical benefit and accrual discontinuation u 75% bone scan improvements (19% CR, 56% PR) u 67% pain improvement u 74% RECIST RR to soft tissue

66. New Indications: Phase III Trials in CRPCa u Pre-Docetaxel u Abiraterone u MDV3100 u Instead of Docetaxel u Docetaxel vs. Cabazitaxel

67. Summary u Exciting times on the horizon for prostate cancer u Pre-clinically u Clinically

68. Objectives u Understand the term “Castrate Resistant Prostate Cancer” (vs. HRPCa) u Review systemic treatment options pre-2010 u Prednisone u Mitoxantrone u Docetaxel u Bone targeted therapy – Zoledronic Acid* u Discuss systemic treatment options post-2010 u Abiraterone u MDV3100 u Cabazitaxel u Sipuleucel-T (Provenge) u Bone targeted therapy – Denosumab* u Learn about other new agents/trials