The document discusses drug development in prostate cancer, including settings for clinical trials and endpoints accepted by regulatory agencies. It provides examples of both successful and failed phase 2 and 3 clinical trials, demonstrating the challenges of developing effective drugs to treat prostate cancer. Key approvals in 2010 included sipuleucel-T, cabazitaxel, and denosumab, representing progress after many failed drug candidates in prior years.

1. Drug development in prostate cancer Pr Karim Fizazi, MD, PhD Institut Gustave Roussy Villejuif, France

2. Clinically Localised prostate cancer Rising PSA Hormonal sensitive Clinical metastases Hormonal sensitive Clinical metastases Castration resistant asymptomatic Clinical metastases Castration resistant Docetaxel-pretreated (Abiraterone, Cabazitaxel) Clinical metastases Castration resistant 1st line Docetaxel-based chemotherapy Androgen deprivation therapy Castration resistant prostate cancer Rising PSA Castration-resistant ( M0 CRPC )

3. A variety of settings for drug development Metastatic, hormone-naïve Metastatic CRPC Non-metastatic CRPC Metastases Pre-Doc With Doc Post-Doc Symptoms Zoledronic acid Docetaxel Castration Resistant Prostate Cancer (CRPC): Progression while on Androgen Deprivation Therapy

4. First-line Docetaxel: Overall Survival Tannock IF, et al: NEJM 351:1502-12, 2004

5. Zoledronate: Time to Skeletal Related Event in CRPC Median, days P value ZOMETA ® 4 mg 488 .009 Placebo 321 Zol 4 mg 214 149 97 70 47 35 3 Placebo 298 128 78 44 32 20 3 over 5 Months delay Saad et al. JNCI 2004; 96:879 488 321 Zoledronate Placebo 0.009

6. Drug approval (phase III) What the FDA/EMA would approve: Overall survival Time to skeletal-related events (SRE) What the FDA/EMA may approve: Time to metastases (M0 setting) Time to metastases (localized setting) What is currently not acceptable for approval: Progression-free survival PSA-based endpoint

7. The cemetery of dead drugs in the struggle against prostate cancer Atrasentan Calcitriol G-VAX Oblimersen Satraplatin Bevacizumab

8. Proof of concept studies (R-Phase II) Rising PSA Non-toxic drug Design: Intermittent ADT +/- dr OK if drug alters PSA Endpoint: time to R-PSA ~ 18 months Ex: Thalidomide (toxic) CRPC M0 ~non toxic drug Design: vs placebo Endpoint: TT mets Limit: need to select high-risk Risk of early drop-off (PSA) Ex: none (phase III) Metastases, H-sensitive Forgotten setting Still exists (10-15% CaP) Toxicity more acceptable Endpoint: time to CRPC ( ~2 y) Undetectable PSA at 8 m Ex: none (phase III) CRPC M1 asymptomatic Crowded setting Toxicity more acceptable Design: bicalutamide (or other) +/- drug Endpoint: ?? (TT PSA prog if effect on PSA anticipated) Ex: Zibotentan, vaccines

9. Randomized phase II of Intermittent ADT with/without Thalidomide n= 159 with a PSA relapse after local treatment Randomization ( oral phase A ): 6 months ADT followed by placebo 6 months ADT followed by Thalidomide 200 mg/d When PSA progression: cross-over ( oral phase B ) Primary endpoint: Time to PSA Progression Figg WD, J Urol 2009, 181:1104-13 R

10. Maintenance Thalidomide: Results Oral phase A: Time to PSA progression: ADT: 9.6 mon ADT + Thalidomide: 15 mon (p=0.21) Oral phase B: Time to PSA progression: ADT: 6.6 mon ADT + Thalidomide: 17.6 mon (p=0.0002) No difference in time to normalisation of testosterone Figg WD, J Urol 2009, 181:1104-13

11. Time to PSA progression Figg WD, J Urol 2009, 181:1104-13 100 80 60 40 20 0 100 80 60 40 20 0 0 12 24 36 48 60 72 0 12 24 36 48 60 72 Months from start of oral Phase B Months from start of oral Phase A Percent progression-free Percent progression-free

12. Targeting Endothelin-1 Proportion of patients alive 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 ZD4054 15 mg versus placebo: HR=0.65 80%CI=(0.49, 0.86); P =0.052 ZD4054 10 mg versus placebo: HR=0.55 80%CI=(0.41, 0.73); P =0.008 Time to death (days) James N, Eur Urol 2008 50 100 150 200 250 300 350 500 450 400 550 600 650 700 750 800 850 ZD4054 10mg ZD4054 15mg Placebo

13. Prostvac: Poxviral-based PSA targeted immunotherapy Post hoc survival assessment ? ASCO 2009 Abstr # 5013 Kantoff et al. PFS OS

14. Proof of concept studies (late stages) Metastatic CRPC, First-line docetaxel Most classical setting Design: docetaxel +/- Endpoint: ?? (OS in most R-phase II trials) Ex: OGX-011, Thalidomide Metastatic CRPC, docetaxel-pretreated Rapid and convincing signal if impact on PSA Non-comparative phase II design Ex: Abiraterone, MDV 3100, Ipilimumab

15. Randomized phase II docetaxel w/wt thalidomide in CRPC n=75 Docetaxel 30 mg/m2/w (3w/5) +/- Thalidomide 200 mg/d PSA response: 37% vs 53% Dahut WL, J Clin Oncol 2004; 22: 2532-39 OS: 14.7 vs 28.9 months PFS: 3.7 vs 5.9 months

16. Randomized phase II docetaxel w/wt thalidomide in CRPC n=75 Doc 30 mg/m2/w (3w/5) +/- Thalidomide 200 mg/d PSA response: 37% vs 53% Dahut WL, J Clin Oncol 2004; 22: 2532-39 OS: 14.7 vs 28.9 months PFS: 3.7 vs 5.9 months 0 0 Months from on-study date Percent survival Percent progression-free 6 12 18 24 30 20 40 60 80 100 0 20 40 60 80 100 0 6 12 18 24 30 Months from on-study date * Docetaxel *docetaxel/thalidomide * Docetaxel *docetaxel/thalidomide

17. Docetaxel-lenalidomide Phase III trial Primary endpoint: Overall survival Hypothesis: 30% improvement (from 19 to 25 months) Currently accruing Lenalidomide: Anti-angiogenesis effect Immune system modulation CRPC Patients N= 1,015 Randomize Docetaxel/Prednisone + Placebo Until Radiological Progression N ~ 500 Docetaxel/Prednisone + Lenalidomide Until Radiological Progression N ~ 500

18. Randomized Phase 2 Study Docetaxel-OGX-011-03 R A N D O M I Z E Arm A Docetaxel (75 mg/M 2 IV) q 21 days and OGX‑011 (640 mg IV ) weekly plus Prednisone (5 mg po bid) daily. Arm B Docetaxel (75 mg/M 2 IV) q 21 days plus Prednisone (5 mg po bid) daily. Continue treatment until disease progression or unacceptable toxicity. If removed from treatment for any reason, follow until death. P R D O I G S R E E A S S S E I O N S F U O R L V L I O V W A L U P n = 82 n = 41 n = 41 Chemonaïve HRPC Patients

19. Median for OGX-011: 23.8 95% C.I. [16.2 - .Inf] Median for Std Trt: 16.9 95% C.I. [12.8 - 25.8] 1 Variables predictive of OS on multivariate analysis: PS 0 vs 1 (P < 0.0001), presence of visceral metastasis (P = 0.01) and treatment assignment Unadjusted HR=0.61 [0.36-1.02], P=0.06 Multivariate analysis 1 HR=0.49 [0.28-0.85], P=0.01 First-Line CRPC Phase 2 Study OGX-011-03: Kaplan-Meier Survival Curves as of April 2009 Median survival times now final with only one patient lost to follow-up prior to 24 months Treatment completed

20. 30% PSA decline – 90.0% 50% PSA decline – 87.9% 90% PSA decline – 48.5% 30% PSA decline - 68.1% 50% PSA decline - 51.1% 90% PSA decline - 14.9% Abiraterone Phase II Pre Chemotherapy Post Chemotherapy Attard JCO 2009 Ryan ASCO 2009 Danila ASCO 2009 Reid ASCO 2009

21. MDV 3100: Phase II trial Chemotherapy-Naïve (n=65) Post-Chemotherapy (n=75) 62% (40/65) > 50% Decline 51% (38/75) > 50% Decline PSA Change from Baseline Scher HI et al. Clin Oncol 2009;27(15suppl):abstr 5011

22. Phase II trial of Ipilimumab in CRPC (MDX010-21) Slovin et al., ASCO 2009 Rationale : Anti-CTLA4 monoclonal Ab capable of enhancing anti-cancer immunity -28 1 IPI 22 IPI 43 IPI 64 IPI 85 421 (Days) (14 months) Or until PD -2 Screening 1 st Treatment Cycle Dosing q 3wk x 4 Follow Up or Additional Treatment Cycle(s); Assessments q 3 mos XRT XRT + 10 mg/kg IPI Chemo experienced n = 18 XRT + 10 mg/kg IPI Chemo naïve n = 16 10 mg/kg IPI n =16 Cohort 3 XRT in CHEMO Cohort 2 XRT in NoCHEMO Cohort 1 Mono

23. PSA response 11/43 responses (26%) 25/43 PSA control (58%) Slovin et al., ASCO 2009 10 mg/kg a Prior Chemotherapy +XRT Chemotherapy- Na ï ve +XRT Prior Chemotherapy a a a a

24. Standard of care in advanced prostate cancer before 2010 Docetaxel re-challenge None CRPC progressing after docetaxel Doc + estramustine Docetaxel Symptomatic CRPC Docetaxel, Endocrine manipulations None Asymptomatic CRPC Zoledronic acid Bone metastases Metastatic CRPC CAB ADT Metastases, hormone-naive Endocrine manipulations None (ADT) Non-metastatic CRPC Options Standard treatment Sub-setting Clinical setting

25. A decade of research in prostate cancer 2004-2009: No significant result 2010: - Sipuleucel-T Cabazitaxel Denosumab Abiraterone

26. Sipuleucel-T: Autologous APCs cultured with antigen fusion protein (PAP)

27. Sipuleucel-T autologous vaccine: Overall Survival p = 0.032 ( Cox model ) HR = 0.7 8 [95% CI: 0.61, 0.9 8 ] Kantoff PW, NEJM 2010, 363: 411-22 Small EJ, J Clin Oncol 2009; 24: 3089-94 Sipuleucel-T (n = 341) vs Placebo (n=171) Median OS: 25.8 vs 21.7 months

28. Docetaxel and Cabazitaxel ++ - Brain penetration ++ - Activity on Doc-resistant cells +++ +++ Activity on Doc-sensitive cells +++ +++ Anti-microtubule activity Caba Doc

29. Cabazitaxel in Second-line CRPC TROPIC Study R A N D O M I Z E Mitoxantrone 12mg/m2 q3w Prednisone 10mg qd mHRPC Progression after TXT Cabazitaxel 25mg/m2 q3w Prednisone 10mg qd 360 pts 360 pts R A N D O M I Z E Stratification factor : ECOG PS (0,1 vs 2) Mesurable/non_mesurable Primary Endpoint: Overall survival Secondary Endpoint: PSA response, PSA progression, PFS, RR, Pain progression, Safety, PK of cabazitaxel Enrollment closed: 745/720 pts Hypothesis: Reduction of 25% in the risk of death or median OS=10.67 months for cabazitaxel vs 8 months 511 events, duration 36 months

30. Progression-free survival Number at risk PFS (%) 80 60 40 20 0 100 0 months 3 months 9 mont h s 15 mont h s 18 mont h s 21 mont h s 6 mont h s 12 mont h s PFS endpoint composite: progression du PSA, progression de la douleur, progression tumorale, deterioration des symptômes, ou mort. 2.8 1.4 Median PFS (mo) 0.65–0.87 95% CI <.0002 P -value 0.75 Hazard Ratio CBZP MP De Bono et al. Lancet In Press 2010 26% risk reduction MP 377 115 52 27 9 6 4 2 CBZP 378 168 90 52 15 4 0 0

31. Cabazitaxel vs Mitoxantrone: Overall Survival Median FU: 13.7 mo MTX+PRED CBZ+PRED Proportion of Overall Survival 0 10 20 30 40 50 60 70 80 90 100 0 6 12 18 24 30 377 378 300 321 188 231 67 90 11 28 1 4 Number at Risk MTX + PRED CBZ + PRED 28% risk of death reduction Time (months) De Bono et al. Lancet 2010 MP CBZP Median OS (months) 12.7 15.1 Hazard ratio 0.72 95% CI 0.61–0.84 P -value <.0001

32. Denosumab may interrupt the “vicious cycle” of bone metastases PDGF, BMPs TGF-β, IGFs FGFs Osteoblasts RANKL RANK Denosumab Tumor Cell Formation Inhibited Apoptotic Osteoclast PTHrP, BMP, TGF-β, IGF, FGF, VEGF, ET1, WNT Adapted from Roodman D. N Engl J Med . 2004;350:1655.

33. RANKL and OPG Expression in Osteoblasts When Co-cultured With Prostate Cancer Cells OPG RANKL CTR CTR OSB + 2b OSB + 2a OSB + LNCaP OSB + PC3 Fizazi et al, Clin Cancer Res 2003;9:2587–2597

34. Bone metastases from solid tumours Patients receiving bisphosphonates and uNTX >50 nM/mM Cr 45 patients per group (n=135) Targeting RANK-L with Denosumab: randomized phase II study Randomization Denosumab 180 mg SC Q4W Denosumab 180 mg SC Q12W Bisphosphonate IV Q4W Primary endpoint: uNTx <50 (at week 13) uNTx >50

35. Denosumab vs bisphosphonate: Time to achieve uNTx < 50 Study Week Probability (%) of Subjects Achieving uNTx < 50 nM BCE/mM Cr IV BP Q4W 180 mg Q4W Dmab 180 mg Q12W Dmab Total Dmab 0 2 0 4 0 6 0 8 0 1 0 0 0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 1 5 1 6 1 7 1 8 1 9 2 0 2 1 2 2 2 3 2 4 2 5 2 6 2 7 Fizazi et al., J Clin Oncol 2009; 27: 1564-71 uNTX normalized in 71% vs 29%; p<0.001

36. Skeletal Related Events (SRE) in men with bone metastases from prostate cancer Pathologic Fracture 25% Pain requiring Radiation to Bone 33% Surgery to Bone 4% Spinal Cord Compression 8% Saad, et al. J Urol 2003;169(Suppl).

37. Prostate SRE Phase III Study Design *IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine (per Zometa ® label) Time to first on-study SRE (non-inferiority) Primary Endpoint Time to first on-study SRE (superiority) Time to first and subsequent on-study SRE (superiority) Supplemental Calcium and Vitamin D Secondary Endpoints n= 1901 patients Denosumab 120 mg SC and Placebo IV* every 4 weeks (N = 1912) Zoledronic acid 4 mg IV* and Placebo SC every 4 weeks (N = 1910) Castration resistant prostate cancer and bone metastases Key Inclusion Current or prior intravenous bisphosphonate administration Key Exclusion

38. Time to First SRE Subjects at risk: 0 1.00 Proportion of Subjects Without SRE 0 3 6 9 12 15 18 21 24 27 0.25 0.50 0.75 KM Estimate of Median Months Denosumab Zoledronic acid 20.7 17.1 HR 0.82 (95% CI: 0.71, 0.95) P = 0.0002 (Non-inferiority) P = 0.008 (Superiority) Study Month Risk Reduction Fizazi et al., Lancet 2011 Zoledronic Acid 951 733 544 407 299 207 140 93 64 47 Denosumab 950 758 582 472 361 259 168 115 70 39 18%

39. Time to First and Subsequent SRE *Events occurring at least 21 days apart Rate Ratio = 0.82 (95% CI: 0.71, 0.94) Study Month 0.0 2.0 0 3 6 9 12 15 18 21 24 27 Cumulative Mean Number of SREs per Patient 30 33 36 0.2 0.6 1.0 1.4 1.8 0.4 0.8 1.2 1.6 Denosumab Zoledronic acid 584 494 Events P = 0.008 Risk Reduction Fizazi et al., Lancet 2011 18%

40. Placebo Median time to first SRE (months) Zoledronic acid Zoledronic acid Denosumab 10.7 16.0 17.1 20.7 10 20 Saad, et al. J Natl Cancer Inst 2004;96:879-82; Fizazi, et al. J Clin Oncol 2010;28 (suppl 18) LBA4507. Denosumab (120 mg Q4W) is not approved for use in patients with advanced cancer to delay SREs. Denosumab is investigational in that setting. 2000-2010: A decade of progress in preventing SRE in men with prostate cancer

41. Androgen Biosynthesis Inhibitors Androgens are produced at 3 critical sites: Testes Adrenal gland Prostate cancer cells 1. Attard G et al, J Clin Oncol, 2008; 2. Attard G et al. J Clin Oncol. 2009; 3. Reid AH et al. J Clin Oncol. 2010; 4. Ryan C et al, J Clin Oncol, 2009; 5. Danila D et al, J Clin Oncol, 2010.

42. Androgen Receptor, the Target, is Still Expressed in CRPC Prostate cancer in intact animal After castration Castration-resistant Xenograft model of MDA PCa 2b prostate cancer Navone and Fizazi, unpublished data Androgen Receptor

44. CYP17 blockade inhibits androgen synthesis b

45. 30% PSA decline – 90.0% 50% PSA decline – 87.9% 90% PSA decline – 48.5% 30% PSA decline - 68.1% 50% PSA decline - 51.1% 90% PSA decline - 14.9% Abiraterone Phase II Pre Chemotherapy Post Chemotherapy Attard JCO 2009 Ryan ASCO 2009 Danila ASCO 2009 Reid ASCO 2009

46. Clinical benefit of abiraterone October 2008 January 2010 Images courtesy of Dr Fizazi.

47. Abiraterone COU 301 Phase III Study AA 1000 mg daily Prednisone 5 mg BID n = 797 Placebo daily Prednisone 5 mg BID n = 398 Randomize 2:1 Progressing mCRPC patients Failed 1 or 2 chemotherapy regimens, 1 of which contained docetaxel (N=1195) Clinicaltrials.gov identifier: NCT00638690. BPI, Brief Pain Inventory; ECOG, Eastern Cooperative Oncology Group; ITT, intent to treat; PS, performance status. Stratification factors ECOG PS; worse pain over previous 24 hrs; prior chemotherapy; type of progression Primary end point (ITT): OS (25% improvement; HR 0.8) Secondary end points (ITT): PSA; TTPP; rPFS

48. Overall Survival Median OS, days (95%CI): Abiraterone: 450 (430-470) Placebo: 332 (310-366) P < 0.0001 HR = 0.646 (0.54-0.77) % S u r v i v a l Placebo A A A A C e n s o r e d 7 9 7 0 0 2 0 4 0 6 0 8 0 1 0 0 1 0 0 4 0 0 3 0 0 2 0 0 5 0 0 6 0 0 7 0 0 3 9 8 7 2 8 3 5 2 6 3 1 2 9 6 4 7 5 1 8 0 2 0 4 6 9 2 5 8 0 1 D a y s F r o m R a n d o m i z a t i o n Placebo Abiraterone: 14.8 months (95%CI: 14.1, 15.4) Placebo: 10.9 months (95%CI: 10.2, 12.0) De Bono, ESMO 2010

49. Standard of care in advanced prostate cancer (2011) Clinical trial None (ADT) CRPC progressing after caba/abi Docetaxel rechallenge Cabazitaxel Abiraterone CRPC progressing after docetaxel Doc + estramustine Docetaxel Symptomatic CRPC Docetaxel Sipuleucel-T Asymptomatic CRPC Zoledronic acid Denosumab Bone metastases Metastatic CRPC CAB ADT Metastases, hormone-naive Endocrine manipulations None (ADT) Non-metastatic CRPC Options Standard treatment Sub-setting Clinical setting

50. The effects of MDV3100 on the Androgen Receptor are distinct from Bicalutamide Ligand 1 2 Chen, et al. 3 4 DNA POL II HSP 90 LBD HD DBD NTD 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: -

51. MDV 3100: PSA response Chemotherapy-Naïve (n=65) Post-Chemotherapy (n=75) 62% (40/65) > 50% Decline 51% (38/75) > 50% Decline PSA Change from Baseline Scher HI et al., Lancet Oncol 2010

52. Targeting CTLA4: Ipilimumab: Mr T, CRPC, docetaxel-pretreated Ipilimumab + XRT

53. What about the (near) future? Clinical trial None (ADT) CRPC progressing after caba/abi Docetaxel Cabazitaxel Abiraterone MDV? TAK 700? Ipi? CRPC progressing after docetaxel Doc +estramustine Docetaxel + VEGF-Trap? + Zibotentan? + Dasatinib? Symptomatic CRPC Docetaxel Sipuleucel-T Abiraterone? Asymptomatic CRPC Zoledronic acid Denosumab Alpharadin? Bone metastases Metastatic CRPC CAB ADT Docetaxel? Metastases, hormone-naive Endocrine manipulation None (ADT) Denosumab? Non-metastatic CRPC Options Standard treatment Sub-setting Clinical setting

54. There Is Not Just One Prostate Cancer Move toward personalized, biologically-oriented medicine in prostate cancer? About 50% of CaP Do gene fusion-positive prostate cancers react differently to hormone manipulations than gene fusion-negative prostate cancers?

55. PTEN loss AR amplif. mutation MYC amplification Molecular classification and Target-oriented therapy BRACness ERG transl ? Early metastatic prostate cancer Prostate Tumor (PR, biopsy, metastases) Circulating Tumor Cells VERIDEX: CellSearch™ System ISET TM System (Isolation by Size of Epithelial Tumor cell) Personalized Medicine +other biomarkers

56. Conclusion: Advanced prostate cancer is now a chronic disease After 5 years without significant progress, 4 drugs have shown phase III positive results in 2010! Cabazitaxel (overall survival) Denosumab (SRE) Abiraterone (overall survival) Sipuleucel-T (overall survival) More to come! TAK 700, MDV 3100 Ipilimumab Cabozantinib…