Uma Viagem ao Novo Mundo do Câncer de Próstata UPTODATE Brasília

1. Fernando CotaitMalufDiretor do Departamento de OncologiaClínicaHospital São José-Beneficência PortuguesaDoutoremUrologia FMUSPMédicoIntegranteClínicaOncovida UmaViagemao Novo Mundo do Câncer de Próstata UPTODATE Brasília

2. Deprivação Androgência Intermitente versus Contínua no Câncer de Próstata Metastático Ref.: Hussain M et al. J Clin Oncol 30, 2012 (suppl; abstr 4)

3. Deprivação Androgência Intermitente versus Contínua no Câncer de Próstata Metastático Ref.: Hussain M et al. J Clin Oncol 30, 2012 (suppl; abstr 4)

4. Deprivação Androgência Intermitente versus Contínua no Câncer de Próstata Metastático Ref.: Hussain M et al. J Clin Oncol 30, 2012 (suppl; abstr 4)

5. Câncer de Próstata Hormone-SensívelProgressão após Tratamento Tx Hormonal 2nd linha Hormônio - Sensível Supressão Testosterona Hormônio- Refratário Hormônio- Sensível Hormônio- Refratário Tx 10 linha

6. Câncer de PróstataDoença Androgênio “Resistente” • Hormônioterapia • Segunda linha • Manutenção da castração • Quimioterapia • Manutenção da castração • Bisfosfonados • Radioterapia Paliativa • Externa • Radiofármacos

7. Câncer de Próstata Doença Androgênio “Resistente”: Tratamentos Hormonais de 2nd-Linha

8. Respostas ClínicaManipulação Hormonal de Segunda-linha • Retirada de Anti-androgênio 15-30% • Bicalutamida 25% • Nilutamida 25% (?) • DES 30-55% • PC-SPES 40-50% • Ketoconazole (+ corticóide) 20-60% • Glucocorticóide 20-80% • Acetato Megestrol 15%

9. Manipulação Hormonal de Segunda-linhaQuestões / Aspectos • Duração média é limitada (2-4 m) • Impacto a longo prazo até 2012 ?

10. CJ Ryan,1 MR Smith,2 JS de Bono,3 A Molina,4 C Logothetis,5P De Souza,6 K Fizazi,7 P Mainwaring,8 JR Piulats,9 S Ng,10 J Carles,11 PFA Mulders,12 T Kheoh4, T Griffin4, EJ Small,1 HI Scher,13 D Rathkopf,13on behalf of the COU-AA-302 investigators 1Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA; 2Massachusetts General Hospital Cancer Center, Boston, MA; 3Royal Marsden Hospital, Sutton, UK; 4Janssen Research & Development, Los Angeles, CA; 5MD Anderson Cancer Center, Houston, TX; 6St. George Private Hospital, Kogarah, Australia; 7Institut GustaveRoussy, University of Paris Sud, Villejuif, France; 8Haematology and Oncology Clinics of Australia, Brisbane, Australia; 9Institut Catalàd'Oncologia de l'Hospitalet, Barcelona, Spain; 10St. John of God Hospital, Subiaco, Australia; 11Hospital UniversitariValld´Hebron, Barcelona, Spain; 12Radboud University Medical Centre, Nijmegen, Netherlands; 13Memorial Sloan-Kettering Cancer Center, New York, NY Interim Analysis Results of COU-AA-302, a Randomized, Phase 3 Study of Abiraterone Acetate (AA) in Chemotherapy-Naïve Patients With Metastatic Castration-Resistant Prostate Cancer (mCRPC) Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

11. Abiraterone Acetate Is an Androgen Biosynthesis Inhibitor Cholesterol Pregnenolone Aldosterone Abiraterone 17OH- Pregnenolone Cortisol Abiraterone Androstenedione Testosterone DHEA DHT Androgens Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

12. 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 Overall Study Design of COU-AA-302 RANDOMIZED 1:1 Efficacy end points Patients 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 • Progressive chemo-naïve mCRPC patients(Planned N = 1088) • Asymptomatic or mildly symptomatic Placebo daily Prednisone 5 mg BID (Actual n = 542) Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

13. Statistically Significant Improvement in rPFS Primary End Point 100 80 60 Progression-Free (%) 40 20 AA + P PL + P 0 3 6 9 12 15 18 0 Time to Progression or Death (Months) AA PL 546 542 489 400 340 204 164 90 46 30 12 3 0 0 Data cutoff 20/12/2010 Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

14. Strong Trend in OS Primary End Point 100 80 60 Survival (%) 40 20 AA + P PL + P 0 3 6 9 12 15 18 21 24 27 30 33 0 Time to Death (Months) 546 542 538 534 524 509 503 493 482 465 452 437 412 387 258 237 120 106 27 25 0 2 0 0 AA PL Pre-specified significance level by O’Brien-Fleming Boundary = 0.0008 Data cutoff 20/12/2011 Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

15. Serologic and Clinical Responses Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

16. No New Safety Concerns Identified with Longer AA Treatment than in 301 Study Most ALT and AST increases occurred during the first 3 months of treatment Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

17. Câncer de Próstata Hormone-SensívelProgressão após Tratamento Tx Hormonal 2nd linha Hormônio - Sensível Supressão Testosterona Hormônio- Refratário Hormônio- Sensível Hormônio- Refratário Tx 10 linha

18. Câncer de Próstata Androgênio Resistente QuimioterapiaNovos Agentes e Novos Resultados

19. Estudo Europeu 134 pts HFRT Prednisona 5mg 2 xdiaPrednisona 5mg 2 xdia + Docetaxel 30mg/m2d1,8,15,22,29 (cada 6 semanasx 6 ciclos) • Objetivo Primário: • Resposta PSA 6 semanas: esperado 40%-D/P vs 20%-P • Objetivos Secundários: • SVG, SLP, toxicidade, qualidade de vida • Forç estatística 80%, p=0.05

20. Estudo EuropeuEficácia Fossa et al. Prostate ASCO, 2006

21. Estudo EuropeuQualidade de Vida Fossa et al. Prostate ASCO, 2006

22. Estudo EuropeuSobrevida Fossa et al. Prostate ASCO, 2006

23. TAX 327 1006 pts HFRT (supressão de testosterona) P P P Docetaxel 75mg/m2Docetaxel 30mg/m2 Mitoxantrona 12mg/m2 (cada 3 semanas) (5 sem/ cada 6 sem) (cada 3 semanas) • Estratificação: • KPS: ≤ 70 vs > 80 • Grau de dor: PPI ≥ 2 ou AS ≥ 10 vs PPI < 2 ou AS < 10 • Objetivos: • * SVG (força estatística 90%, HR: 0,75, two-sided, 0.05) • Resposta PSA, melhora de dor óssea, QOL, toxicidade

24. TAX 327Eficácia

25. TAX 327Eficácia Sobrevida Global

26. Câncer de Próstata Androgênio Resistente Questões de Ordem Prática

27. Quando iniciar quimioterapia no câncer de próstata androgênio-resistente ?

28. Tratamento de Segunda-linhaPeríodo de “Férias” (do Oncologista e da Quimioterapia)

29. Câncer de Próstata Tratamento de Segunda-linha após falha a Docetaxel

30. Tratamento de Segunda-linha Taxano Não-Taxano ÓtimaRR Ausência RR Re-tx Estudo Clínico Taxano Férias de QT

31. Tratamento de Segunda-linha Taxano Não-Taxano ÓtimaRR Ausência RR Re-tx Cabazitaxel Taxano Férias de QT

32. Cabazitaxel Foi Selecionado para Superar a Resistência à Quimioterapia • Atividade demonstrada em modelos de tumor insensíveisà quimioterapia, incluindo docetaxel1,2 • Dados pré-clínicos mostram que o cabazitaxel é3,4: • Mais citotóxico in vitro que o docetaxel em células tumorais expressandoo gene 1 (mdr-1) de múltipla resistência à drogas, assim como em linhagenscelulares com resistência adquirida à doxorrubicina, vincristina, vimblastina e paclitaxel • Ativo in vivo em modelos de tumor pouco sensíveis, insensíveis eresistentes ao docetaxel e ixabepilona • Capaz de cruzar a barreira hematoencefálica in vivo • Dados pré-clínicos sustentam o desenvolvimento clínico no CPCRm após tratamento com docetaxel 1. Bissery MC, et al. Proc Am Assoc Cancer Res. 2000;41:214. Abstract 1364. 2. Dados em arquivo. Relatório de estudo clínico. EFC6193 (TROPIC). 3. Bissery MC, et al. Proc Am Assoc Cancer Res. 1995;36:316. Abstract 1882. 4. Informações para prescrição do cabazitaxel nos EUA. Bridgewater, NJ: sanofi-aventis EUA LLC; junho de 2010.

33. TROPIC: Phase III Registration Study 146 Sites in 26 Countries mCRPC patients who progressed during and after treatment with a docetaxel-based regimen (N=755) Stratification factors ECOG PS (0, 1 vs. 2) • Measurable vs. non-measurable disease 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) *Oral prednisone/prednisolone: 10 mg daily. Primary endpoint: OS Secondary endpoints: Progression-freesurvival (PFS), response rate, and safety Inclusion: Patients with measurable disease must have progressed by RECIST; otherwise must have had new lesions or PSA progression

34. MP CBZP Median PFS (months) 1.4 2.8 Hazard Ratio 0.74 95% CI 0.64–0.86 P-value <.0001 PFS composite endpoint: PSA progression, pain progression, tumor progression, symptom deterioration, or death. Progression-Free Survival (PFS) Results 100 Proportionof PFS (%) 80 60 40 20 0 0 months 3 months 6 months 9 months 12 months 15 months 18 months 21 months Numberat risk

35. 100 MP CBZP Median OS (months) 12.7 15.1 Hazard Ratio 0.70 80 95% CI 0.59–0.83 P-value <.0001 60 40 20 0 6 months 12 months 18 months 24 months 30 months 0 months Primary Endpoint: Overall Survival (ITT Analysis) Proportionof OS (%) Numberat risk

36. Secondary Endpoints Response Rates and Time to Progression (TTP) NR: Not reached. *Determined only for subjects with pain or PSA ≥20 or measurable disease at baseline, respectively.NR=Not reached.

37. Most Frequent Grade ≥3 Treatment-Emergent AEs*Safety Population *Sorted by decreasing frequency of events grade ≥3 in the CBZP arm.

38. Tratamento de Segunda-linha Taxano Não-Taxano ÓtimaRR Ausência RR Re-tx Abiraterona Taxano Férias de QT

39. Abiraterone acetate plus low dose prednisone improves overall survival in patients with metastatic castration-resistant prostate cancer (CRPC) who have progressed after docetaxel-based chemotherapy Results of COU-AA-301, a randomized double-blind placebo-controlled phase 3 study de Bono et al. N Engl J Med 2011; 346(21): 1995-2005

40. COU-AA-301 Study Design Phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled study (147 sites in 13 countries; USA, Europe, Australia, Canada) TREAT UNT I L PROGRESS ION • 1195 patients with progressive, mCRPC • Failed 1 or 2 chemotherapy regimens, one of which contained docetaxel • Randomised 2:1 • Stratification by: • 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 or without PSA progression) Abiraterone acetate 1000 mg daily Prednisone 5mg twice daily Placebo daily Prednisone 5mg twice daily Primary endpoint: OS (25% improvement; HR 0.8) de Bono et al. N Engl J Med 2011; 346(21): 1995-2005

41. Overall Survival – Interim Analysis Hazard ratio = 0.65 (0.54-0.77) P < 0.001 100 Abiraterone acetate: 14.8 months (95% CI, 14.1-15.4) 80 60 Survival (%) Placebo: 10.9 months (95% CI, 10.2-12.0) 40 20 AA Placebo 0 0 3 6 9 12 15 18 21 Time to Death (Months) AA 797 736 657 520 282 68 2 0 Placebo 398 355 306 210 105 30 3 0 de Bono et al. N Engl J Med 2011; 346(21): 1995-2005

42. Survival by Baseline ECOG Status Favors AA for ECOG 0-1, but not for ECOG 2; May be Attributed by the Small Sample Size ECOG 0-1 ECOG 2 (10% of patients) 100 100 Abiraterone: 17 months 80 80 Abiraterone: 7.3 months 60 60 Survival (%) Survival (%) 40 40 Placebo: 12.3 months Placebo: 7 months 20 20 AA Placebo AA Placebo 0 0 0 6 12 18 24 30 0 6 12 18 24 30 Time to Death (Months) Time to Death (Months) 715 353 608 281 452 174 263 97 14 6 0 0 82 45 49 25 21 9 10 3 1 0 0 0 Median OS – AA vs. Placebo ECOG 0-1: 17 vs. 12.3 months (HR=0.74; 95% CI: 0.63-0.86) ECOG 2: 7.3 vs. 7 months (HR=0.77; 95% CI: 0.50-1.17) Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

43. Survival Benefit Observed With AA for Subgroups With and Without Pain at Study Entry Pain(0-3 [absent]) Pain(4-10 [present]) 100 100 80 80 Abiraterone: 13.3 months Abiraterone: 18.4 months 60 60 Survival (%) Survival (%) 40 40 Placebo: 13.9 months Placebo: 9.3 months 20 20 AA Placebo AA Placebo 0 0 0 6 12 18 24 30 0 6 12 18 24 30 Time to Death (Months) Time to Death (Months) 440 219 382 181 293 118 186 65 9 3 0 0 357 179 275 125 180 65 87 35 6 3 0 0 Median OS – AA vs. Placebo Pain absent: 18.4 vs. 13.9 months (HR=0.69; 95% CI: 0.56-0.85) Pain present: 13.3 vs. 9.3 months (HR=0.78; 95% CI: 0.63-0.96) Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

44. Survival Benefit Observed With AA for Subgroups with 1 or 2 Prior Lines of Chemotherapy at Study Entry 1 Prior Line of Chemotherapy 2 Prior Lines of Chemotherapy 100 100 80 80 Abiraterone: 14.2 months Abiraterone: 17.1 months Placebo: 11.7 months Placebo: 10.4 months 60 60 Survival (%) Survival (%) 40 40 20 20 AA Placebo AA Placebo 0 0 0 6 12 18 24 30 0 6 12 18 24 30 Time to Death (Months) Time to Death (Months) 557 275 467 214 348 130 210 72 9 5 0 0 240 123 190 92 125 53 63 28 6 1 0 0 Median OS – AA vs. Placebo 1 prior line of chemotherapy: 17.1 vs. 11.7 months (HR=0.71; 95% CI:0.59-0.85) 2 prior lines of chemotherapy: 14.2 vs. 10.4 months (HR=0.80; 95% CI: 0.61-1.03) Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

45. Survival Benefit Observed With AA for Subgroups With PSA Progression Only or Radiographic Progression at Study Entry PSA Only Radiographic 100 100 80 80 Abiraterone: 14.8 months Abiraterone: 18.3 months 60 60 Survival (%) Survival (%) 40 40 Placebo: 13.6 months Placebo: 10.5 months 20 20 AA Placebo AA Placebo 0 0 0 6 12 18 24 30 0 6 12 18 24 30 Time to Death (Months) Time to Death (Months) 238 125 205 100 155 66 96 39 5 3 0 0 559 273 452 206 318 117 177 61 10 3 0 0 Median OS – AA vs. Placebo: PSA only: 18.3 vs. 13.6 months (HR=0.63; 95% CI: 0.47-0.84) Radiographic: 14.8 vs. 10.5 months (HR=0.78; 95% CI: 0.65-0.93) Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

46. Survival Benefit Observed With AA Across All Age Groups < 65 Years ≥ 75 Years ≥ 65 Years 100 100 100 80 80 80 Abiraterone: 16.2 months Abiraterone: 15.6 months Abiraterone: 15.0 months 60 60 60 Survival (%) Survival (%) Survival (%) Placebo: 11.2 months Placebo: 9.3 months Placebo: 11.1 months 40 40 40 20 20 20 AA Placebo AA Placebo AA Placebo 0 0 0 0 6 12 18 24 30 0 6 12 18 24 30 0 6 12 18 24 30 Time to Death (Months) Time to Death (Months) Time to Death (Months) 232 119 183 88 137 55 75 22 2 0 0 0 565 278 474 218 336 128 198 78 13 6 0 0 220 111 180 82 131 44 76 27 6 4 0 0 Median OS – AA vs. Placebo: < 65 years: 15.0 vs. 11.2 months (HR=0.69; 95% CI: 0.53-0.91) ≥ 65 years: 16.2 vs. 11.1 months (HR=0.76; 95% CI: 0.63-0.90) ≥ 75 years: 15.6 vs. 9.3 months (HR=0.64; 95% CI: 0.48-0.85) Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

47. Survival Benefit Observed With AA for Subgroups With and Without Visceral Disease at Study Entry Without Visceral Disease With Visceral Disease 100 100 80 80 Abiraterone: 12.9 months Abiraterone: 17.1 months 60 60 Survival (%) Survival (%) 40 40 Placebo: 12.3 months Placebo: 8.3 months 20 20 AA Placebo AA Placebo 0 0 0 6 12 18 24 30 0 6 12 18 24 30 Time to Death (Months) Time to Death (Months) 544 299 466 242 345 146 202 78 15 5 0 0 253 99 191 64 128 37 71 22 0 1 0 0 Median OS – AA vs. Placebo: Without visceral disease: 17.1 vs. 12.3 months (HR = 0.69; 95% CI: 0.58-0.82) With visceral disease: 12.9 vs. 8.3 months (HR = 0.79; 95% CI: 0.59-1.05) Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

48. All Secondary End Points Achieved Statistical Significance de Bono et al. N Engl J Med 2011; 346(21): 1995-2005

49. AEs of Special Interest de Bono et al. N Engl J Med 2011; 346(21): 1995-2005

50. Pain and Time to Skeletal Events