Uma Viagem ao Novo Mundo do Câncer de Próstata

Apresentação em tema: "Uma Viagem ao Novo Mundo do Câncer de Próstata"— Transcrição da apresentação:

1 Uma Viagem ao Novo Mundo do Câncer de Próstata
UPTODATE Brasília Fernando Cotait Maluf Diretor do Departamento de Oncologia Clínica Hospital São José-Beneficência Portuguesa Doutor em Urologia FMUSP Médico Integrante Clínica Oncovida

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 Tratamento da Doença Androgênio-resistente
Fernando Cotait Maluf Diretor do Departamento de Oncologia Clínica Centro de Oncologia-Hospital São José Doutor em Urologia FMUSP

6 Câncer de Próstata Hormone-Sensível Progressão após Tratamento
Tx Hormonal 2nd linha Hormônio - Sensível Supressão Testosterona Hormônio- Refratário Hormônio- Sensível Hormônio- Refratário Tx 10 linha

7 Câncer de Próstata Doença Androgênio “Resistente”
Hormônioterapia Segunda linha Manutenção da castração Quimioterapia Bisfosfonados Radioterapia Paliativa Externa Radiofármacos

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

9 Respostas Clínica Manipulação Hormonal de Segunda-linha
Retirada de Anti-androgênio 15-30% Bicalutamida % Nilutamida % (?) DES % PC-SPES % Ketoconazole (+ corticóide) % Glucocorticóide % Acetato Megestrol %

10 Manipulação Hormonal de Segunda-linha Questões / Aspectos
Duração média é limitada (2-4 m) Impacto a longo prazo até 2012 ?

11 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) CJ Ryan,1 MR Smith,2 JS de Bono,3 A Molina,4 C Logothetis,5 P 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,13 on 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 Gustave Roussy, University of Paris Sud, Villejuif, France; 8Haematology and Oncology Clinics of Australia, Brisbane, Australia; 9Institut Català d'Oncologia de l'Hospitalet, Barcelona, Spain; 10St. John of God Hospital, Subiaco, Australia; 11Hospital Universitari Vall d´Hebron, Barcelona, Spain; 12Radboud University Medical Centre, Nijmegen, Netherlands; 13Memorial Sloan- Kettering Cancer Center, New York, NY Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

12 Persistent Unmet Need in mCRPC
Current Therapies Have Limitations: Restricted to Post-Chemotherapy Setting OS Benefit in Chemo-Naïve Setting Without Objective Response or Impact on How a Patient Feels or Functions Limited Penetrance of Chemotherapy NCCN prostate cancer guidelines Version Kantoff P, N Engl J Med. 2011; 363: Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

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

14 Abiraterone Acetate: OS Benefit Shown in Post-Chemotherapy mCRPC Patients Median Survival was months Improved by 3.9 months over Prednisone control arm de Bono J, N Engl J Med. 2011; 364: Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

15 Landmarks of Disease Progression in mCRPC
Baseline PSA Progression Tumor/Bone Progression Pain Death Chemotherapy ECOG PS Decline Primary Endpoints: rPFS and OS Secondary Endpoints 24-48 months Adapted from Halabi S. J Clin Oncol. 2009;27: Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

16 Overall Study Design of COU-AA-302
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 (Actual n = 542) 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 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 Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation) 16

17 COU-AA-302: rPFS Definition
Progressive disease (PD) by bone scan: Adapted Prostate Cancer Working Group 2 Consensus Criteria Blinded central radiologist review < 12 weeks after randomization ≥ 2 new bone lesions plus 2 additional at confirmation (“2+2”) ≥ 12 weeks after randomization ≥ 2 new bone lesions with subsequent confirmation PD (soft tissue lesions) by CT or MRI by modified RECIST criteria Death from any cause Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

18 COU-AA-302 Statistical Plan
Overall Assumption rPFS OS α 0.01 0.04 Power 91% 85% HR 0.67 0.80 Expected events 378 773 Planned OS Analysis 1Q10 2Q10 3Q10 4Q10 1Q11 2Q11 3Q11 4Q11 1Q12 2Q12 3Q12 4Q12 IA1 (~15% OS Events) 116 Events  < IA2 (40% OS Events) 311 Events  = IA3 (55% OS events) 425 Events  = IA = interim analysis. Ho, HR=1.0. Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

19 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) 5.5 5.1 Median PSA (ng/mL) 42.0 37.7 Median testosterone (ng/dL) 4.0 Median alkaline phosphatase (IU/L) 93.0 90.0 Median hemoglobin (g/dL) 13.0 13.1 Median lactate dehydrogenase (IU/L) 187.0 184.0 Gleason score (≥8) at initial diagnosis 54% 50% Extent of disease Bone metastases >10 bone lesions Soft tissue or node 83% 48% 49% 80% 47% Pain (BPI Short Form) 0-1 2-3 66% 32% 64% 33% Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

20 Treatment Duration and Discontinuation
AA+P (n=540) Placebo + P (n=542) Median duration of follow up 22.3 months Median No. of cycles of therapy, range 15 (1-33) 9 (1-31) Treatment discontinued 69% 84% Reasons for Discontinuation Radiographic progression only 21% 30% Unequivocal clinical progression* only 25% Radiographic and unequivocal clinical progression 11% 10% Adverse event 7% 5% Withdrew consent 6% 9% Other 4% *Unequivocal clinical progression is one or more of the following: pain requiring opiates, chemotherapy, palliative radiation therapy, decline in ECOG PS, surgical intervention. Data from safety population. Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

21 Statistically Significant Improvement in rPFS Primary End Point
100 80 60 40 20 Progression-Free (%) 3 6 9 15 18 12 546 542 489 400 340 204 164 90 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 ( ) P value: < Data cutoff 20/12/2010 Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

22 rPFS Benefit Demonstrated Across Full Spectrum of Patient Subgroups
Favors AA Favors Placebo Median (months) Variable Subgroup AA Placebo HR 95% CI All subjects Baseline ECOG Baseline BPI Bone metastasis only at entry Age Baseline PSA above median Baseline LDH above median Baseline ALK-P above median Region ALL 1 0-1 2-3 YES NO < 65 ≥ 65 ≥ 75 N.A. Other NE 13.7 11.1 11.3 11.9 11.5 8.3 7.4 8.4 8.2 13.7 5.6 9.7 11.0 8.0 8.5 9.0 0.43 0.45 0.35 0.42 0.51 0.48 0.38 0.36 0.57 0.44 0.40 0.37 0.50 0.34 0.52 ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) 0.2 0.75 1 1.5 Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

23 Strong Trend in OS Primary End Point
546 542 538 534 482 465 452 437 27 25 524 509 503 493 2 120 106 258 237 412 387 100 80 60 40 20 Survival (%) 3 12 15 Time to Death (Months) 33 AA + P PL + P 6 9 30 24 21 18 AA PL AA + P (median, mos): NR PL + P (median, mos): 27.2 HR (95% CI): 0.75 ( ) P value: 0.0097 Pre-specified significance level by O’Brien-Fleming Boundary = Data cutoff 20/12/2011 Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

24 Point Estimates for OS Favor AA in All Patient Subgroups
Variable Subgroup Median (months) AA Placebo HR 95% CI Favors AA Favors Placebo NE 25.5 26.9 All subjects Baseline ECOG Baseline BPI Bone metastasis only at entry Age Baseline PSA above median Baseline LDH above median Baseline ALK-P above median Region 0.75 0.71 0.86 0.87 0.68 0.81 0.80 0.73 0.72 0.77 0.69 0.79 0.66 0.89 ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) 0.2 1 1.5 27.2 26.4 27.5 23.8 23.6 ALL 0-1 2-3 YES NO < 65 ≥ 65 ≥ 75 N.A. Other Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

25 Subsequent Therapy Was Common
AA + P (n = 546) n (%) Placebo + P (n = 542) n (%) No. with selected subsequent therapy for mCRPC 242 (44.3) 327 (60.3) Docetaxel 207 (37.9) 287 (53.0) Cabazitaxel 45 (8.2) 52 (9.6) Ketoconazole 39 (7.1) 63 (11.6) Sipuleucel-T 27 (4.9) 24 (4.4) Abiraterone acetate* 26 (4.8) 54 (10.0) *Prior to unblinding (e.g. not per protocol) Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

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=220 N=218 RECIST: Defined objective response Complete response Partial response Stable disease Progressive disease 36% 11% 25% 61% 2% 16% 4% 12% 69% 15% (1.591, 3.247) Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

27 Statistically Significant Improvement in All Secondary End Points
AA + P Placebo + P Median (months) HR (95% CI) P Value Time to opiate use (cancer related pain) NR 23.7 0.69 (0.57, 0.83) 0.0001 Time to chemotherapy initiation 25.2 16.8 0.58 (0.49, 0.69) <0.0001 Time to ECOG PS deterioration 12.3 10.9 0.82 (0.71, 0.94) 0.0053 Time to PSA progression 11.1 5.6 0.49 (0.42, 0.57) Note: All secondary end points remain significant after adjusting for multiplicity testing Patient Reported Outcomes favored AA +P vs. Placebo +P Full data to be reported Data cut off 20/12/2011 Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

28 No New Safety Concerns Identified with Longer AA Treatment than in 301 Study
AA + P (n = 542) % Placebo + P (n = 540) All Grades Grades 3/4 Fatigue 39 2 34 Fluid retention 28 0.7 24 1.7 Hypokalemia 17 13 Hypertension 22 4 3 Cardiac disorders 19 6 16 Atrial fibrillation 1.3 5 0.9 ALT increased 12 5.4 0.8 AST increased 11 3.0 Most ALT and AST increases occurred during the first 3 months of treatment Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

29 IDMC Unblinds Study at 2nd Interim Analysis
February 2012 Investigators and sponsors remained blinded Concluded that OS, rPFS, and secondary end points all favored AA Recommended unblinding study and that patients in placebo arm be offered treatment with AA Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

30 Landmarks of Disease Progression in mCRPC
Baseline PSA Progression Tumor/Bone Progression Pain Death Chemotherapy ECOG PS Decline Primary Endpoints: rPFS and OS Secondary Endpoints 24-48 months p = 0.001 p < p = p = Adapted from Halabi S. J Clin Oncol. 2009;27: Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

31 Summary In patients with asymptomatic and mildly symptomatic, chemotherapy-naïve mCRPC, treatment with abiraterone acetate plus prednisone: Delays disease progression Increases survival Extends time with minimal or no symptoms No new important safety signals Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

32 Abiraterona no Câncer de Próstata Metastático, Resistente a HT, e sem QT prévia
Ref.: Ryan CJ et al. J Clin Oncol 30, 2012 (suppl; abstr LBA4518)

33 Abiraterona no Câncer de Próstata Metastático, Resistente a HT, e sem QT prévia
Ref.: Ryan CJ et al. J Clin Oncol 30, 2012 (suppl; abstr LBA4518)

34 Abiraterona no Câncer de Próstata Metastático, Resistente a HT, e sem QT prévia
Ref.: Ryan CJ et al. J Clin Oncol 30, 2012 (suppl; abstr LBA4518)

35 Abiraterona no Câncer de Próstata Metastático, Resistente a HT, e sem QT prévia
AA (n = 546) Placebo (n = 542) HR 95% CI P Value Tempo para Uso Opióide (meses) NR 23.7 0.69 (0.57, 0.83) 0.0001 Tempo para Início de Quimioterapia (meses) 25.8 16.2 0.59 (0.49, 0.69) < 0.001 Resposta por PSA Total 62.0% 24.0% - < Resposta Objetiva (RECIST) 36.0% 16.0% 2.27 (1.59, 3.24) Ref.: Ryan CJ et al. J Clin Oncol 30, 2012 (suppl; abstr LBA4518)

36 Câncer de Próstata Hormone-Sensível Progressão após Tratamento
Tx Hormonal 2nd linha Hormônio - Sensível Supressão Testosterona Hormônio- Refratário Hormônio- Sensível Hormônio- Refratário Tx 10 linha

37 Câncer de Próstata Androgênio Resistente Quimioterapia Novos Agentes e Novos Resultados

38 Estudo Europeu 134 pts HFRT
Prednisona 5mg 2 x dia Prednisona 5mg 2 x dia + Docetaxel 30mg/m2 d1,8,15,22,29 (cada 6 semanas x 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

39 Estudo Europeu Eficácia
DCT/P (57 pts) P 52 (pts) p RR PSA 57% 26% .01 Diminuição Dor 50% 15% Melhora Qualidade Vida 32% 25% Fossa et al. Prostate ASCO, 2006

40 Estudo Europeu Qualidade de Vida
Fossa et al. Prostate ASCO, 2006

41 Estudo Europeu Sobrevida
Fossa et al. Prostate ASCO, 2006

42 (supressão de testosterona)
TAX 327 1006 pts HFRT (supressão de testosterona) P P P Docetaxel 75mg/m2 Docetaxel 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

43 TAX 327 Eficácia DCT 3 sem (335 pts) DCT sem (334 pts) M 3 sem
SVG média 18,9 m 17,4 m 16,5 m 0.009 HR Morte 0,76 (0,62 – 0,94) 0,91 (0,75 – 1,11) RR PSA 45% 48% 32% 0.0005 RR mens. 12% 8% 7% 0.1 RR Dor 35% 31% 22% 0.01

44 TAX 327 Eficácia DCT 3 sem (335 pts) DCT sem (334 pts) M 3 sem
SVG média 18,9 m 17,4 m 16,5 m 0.009 HR Morte 0,76 (0,62 – 0,94) 0,91 (0,75 – 1,11) Todos os Grupos RR PSA 45% 48% 32% 0.0005 RR mens. 12% 8% 7% 0.1 RR Dor 35% 31% 22% 0.01

45 TAX 327 Eficácia Sobrevida Global

46 TAX 327 Eficácia DCT 3 sem (335 pts) DCT sem (334 pts) M 3 sem
SVG média 18,9 m 17,4 m 16,5 m 0.009 HR Morte 0,76 (0,62 – 0,94) 0,91 (0,75 – 1,11) RR PSA 45% 48% 32% 0.0005 RR mens. 12% 8% 7% 0.1 RR Dor 35% 31% 22% 0.01

47 TAX 327 Eficácia DCT 3 sem (335 pts) DCT sem (334 pts) M 3 sem
SVG média 18,9 m 17,4 m 16,5 m 0.009 HR Morte 0,76 (0,62 – 0,94) 0,91 (0,75 – 1,11) RR PSA 45% 48% 32% 0.0005 RR mens. 12% 8% 7% 0.1 RR Dor 35% 31% 22% 0.01

48 > 16 pontos da FACT-P comparado com linha de base
TAX 327 Eficácia > 16 pontos da FACT-P comparado com linha de base DCT 3 sem (278 pts) DCT sem (270 pts) M 3 sem (267 pts) QOL 22% 23% 13% p 0.009 0.005

49 Câncer de Próstata Androgênio Resistente Questões de Ordem Prática

50 Quimioterapia Indicada
Quando iniciar quimioterapia no câncer de próstata androgênio-resistente ? Volume de Doença Sobrevida Média Quimioterapia Indicada Aumento de PSA ~ 4 a Não Doença M1 Assintomática (doença limitada) 18 – 24 m Doença M1 Assintomática (doença extensa) ~18 m Sim Doença M1 Sintomática 9 – 16 m

51 Quando iniciar/parar quimioterapia no câncer de próstata androgênio-resistente ?
Considerações: TAX 327: 30 semanas e SWOG 99-16: 36 semanas (arbitrário) Não se sabe quando interromper quimioterapia ! Ciclos: 4-6 Eficácia: até máxima resposta (± 2) Efeitos colaterais: neuropatia/mielosupressão Re-tratamento em pacientes “docetaxel-sensível”: Resposta a tratamento prévio: sim Tolerância ao tratamento prévio: ótima Tempo até progressão: ≥ 3-6 meses

52 Tratamento de Segunda-linha Período de “Férias” (do Oncologista e da Quimioterapia)

53 Câncer de Próstata Tratamento de Segunda-linha após falha a Docetaxel

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

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

56 Cabazitaxel Foi Selecionado para Superar a Resistência à Quimioterapia
Atividade demonstrada em modelos de tumor insensíveis à quimioterapia, incluindo docetaxel1,2 Dados pré-clínicos mostram que o cabazitaxel é3,4: Mais citotóxico in vitro que o docetaxel em células tumorais expressando o gene 1 (mdr-1) de múltipla resistência à drogas, assim como em linhagens celulares com resistência adquirida à doxorrubicina, vincristina, vimblastina e paclitaxel Ativo in vivo em modelos de tumor pouco sensíveis, insensíveis e resistentes 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 Dados em arquivo. Relatório de estudo clínico. EFC6193 (TROPIC). 3. Bissery MC, et al. Proc Am Assoc Cancer Res. 1995;36:316. Abstract Informações para prescrição do cabazitaxel nos EUA. Bridgewater, NJ: sanofi-aventis EUA LLC; junho de 2010.

57 TROPIC: Phase III Registration Study 146 Sites in 26 Countries
TROPIC slide deck. Slide6,10,13 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-free survival (PFS), response rate, and safety Inclusion: Patients with measurable disease must have progressed by RECIST; otherwise must have had new lesions or PSA progression

58 Progression-Free Survival (PFS) Results
TROPIC slide deck. Slide24 Proportion of PFS (%) 100 PFS composite endpoint: PSA progression, pain progression, tumor progression, symptom deterioration, or death. 2.8 1.4 Median PFS (months) 0.64–0.86 95% CI <.0001 P-value 0.74 Hazard Ratio CBZP MP 80 60 40 20 0 months 3 months 6 months 9 months 12 months 15 months 18 months 21 months Number at risk MP 377 115 52 27 9 6 4 2 CBZP 378 168 90 15

59 Primary Endpoint: Overall Survival (ITT Analysis)
TROPIC slide deck. Slide21 Proportion of OS (%) 80 60 40 20 100 0 months 6 months 12 months 18 months 24 months 30 months 15.1 12.7 Median OS (months) 0.59–0.83 95% CI <.0001 P-value 0.70 Hazard Ratio CBZP MP Number at risk MP 377 300 188 67 11 1 CBZP 378 321 231 90 28 4

60 Subgroup Overall Survival Analysis
TROPIC slide deck. Slide22 Factor Hazard ratio (95% CI)  f a v o r s C B Z P | f a v o r s M P  All patients 0.70 (0.59–0.83) ECOG status: 0,1 0.68 (0.57–0.82) ECOG status: 2 0.81 (0.48–1.38) Measurable disease: No 0.72 (0.55–0.93) Measurable disease: Yes 0.68 (0.54–0.85) No. of prior chemo: 1 0.67 (0.55–0.83) No. of prior chemo: ≥2 0.75 (0.55–1.02) Age: <65 0.81 (0.61–1.08) Age: ≥65 0.62 (0.50–0.78) Rising PSA: No 0.88 (0.61–1.26) Rising PSA: Yes 0.65 (0.53–0.80) Total docetaxel dose: <225 mg/m² 0.96 (0.49–1.86) Total docetaxel dose: ≥225 to 450 mg/m² 0.60 (0.43–0.84) Total docetaxel dose: ≥450 to 675 mg/m² 0.83 (0.60–1.16) Total docetaxel dose: ≥675 to 900 mg/m² 0.73 (0.48–1.10) Total docetaxel dose: ≥900 mg/m² 0.51 (0.33–0.79) Progression: During last docetaxel treatment 0.65 (0.47–0.90) Progression: <3 months since last docetaxel dose 0.70 (0.55–0.91) Progression: ≥3 months since last docetaxel dose 0.75 (0.51–1.11) 1 2 0.5 1.5 1 2 0.5 1.5

61 Secondary Endpoints Response Rates and Time to Progression (TTP)
TROPIC slide deck. Slide24,25,26 MP (n=377) CBZP (n=378) Hazard ratio (95% CI) P-value Tumor assessment Response rate* (%) 4.4 14.4 – .0005 Median TTP (months) 5.4 8.8 0.61 (0.49–0.76) <.0001 PSA assessment 17.8 39.2 .0002 3.1 6.4 0.75 (0.63–0.90) .0010 Pain assessment 7.7 9.2 .6286 NR 11.1 0.91 (0.69–1.19) .5192 NR: Not reached. *Determined only for subjects with pain or PSA ≥20 or measurable disease at baseline, respectively. NR=Not reached.

62 Most Frequent Grade ≥3 Treatment-Emergent AEs* Safety Population
TROPIC slide deck. Slide34 MP (n=371) CBZP (n=371) All grades (%) Grade ≥3 (%) Any adverse event 88.4 39.4 95.7 57.4 Febrile neutropenia 1.3 7.5 Diarrhea 10.5 0.3 46.6 6.2 Fatigue 27.5 3 36.7 4.9 Asthenia 12.4 2.4 20.5 4.6 Back pain 12.1 16.2 3.8 Nausea 22.9 34.2 1.9 Vomiting 10.2 22.6 Hematuria 0.5 16.7 Abdominal pain 3.5 11.6 *Sorted by decreasing frequency of events grade ≥3 in the CBZP arm.

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

64 Abiraterona (COU-AA-301) Orteronel (TAK-700)
Inibidor seletivo da biossíntese de androgênio que bloqueia a CYP17 Abiraterona Orteronel (TAK-700) Colesterol CYP17 CYP17 17-OH pregnenolona DHEA Pregnenolona A Abiraterona foi recentemente aprovada pelo FDA para tratamento de pacientes com câncer de próstata refratários a castração. A Abiraterona e o Orteronel (ou TAK-700) são inibidores da CYP-17 e bloqueiam a produção de androgênios na adrenal. A CYP-17 é responsável pela conversão de pregnenolona e progesterona em DHEA e androstenediona, e consequentemente testosterona e DHT. No entando, devido à redução de cortisol, ocorre um aumento da produção de ACTH na hipófise e esta hiper-estimulação acaba levando a aumento da produção de aldosterona, ocasionando um hiper-aldosteronismo. Devido a este fato que os pacientes são também tradados com Prednisona quando estão recebendo Abiraterona. CYP17 CYP17 Androstenediona 17-OH progesterona Progesterona Testosterona 11-Deoxicortisol Deoxicorticosterona DHT Cortisol Corticosterona Aldosterona

65 Abiraterona (COU-AA-301) Orteronel (TAK-700)
Inibidor seletivo da biossíntese de androgênio que bloqueia a CYP17 Abiraterona Colesterol CYP17 CYP17 17-OH pregnenolona DHEA Pregnenolona A Abiraterona foi recentemente aprovada pelo FDA para tratamento de pacientes com câncer de próstata refratários a castração. A Abiraterona e o Orteronel (ou TAK-700) são inibidores da CYP-17 e bloqueiam a produção de androgênios na adrenal. A CYP-17 é responsável pela conversão de pregnenolona e progesterona em DHEA e androstenediona, e consequentemente testosterona e DHT. No entando, devido à redução de cortisol, ocorre um aumento da produção de ACTH na hipófise e esta hiper-estimulação acaba levando a aumento da produção de aldosterona, ocasionando um hiper-aldosteronismo. Devido a este fato que os pacientes são também tradados com Prednisona quando estão recebendo Abiraterona. CYP17 CYP17 Androstenediona 17-OH progesterona Progesterona Testosterona 11-Deoxicortisol Deoxicorticosterona DHT Cortisol Corticosterona Aldosterona

66 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): 66

67 (147 sites in 13 countries; USA, Europe, Australia, Canada)
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 [present]) Prior chemotherapy (1 vs. 2) Type of progression (PSA only vs. radiographic progression with or without PSA progression) Abiraterone acetate 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):

68 Overall Survival – Interim Analysis
AA 797 736 657 520 282 68 2 Placebo 398 355 306 210 105 30 3 21 Hazard ratio = 0.65 ( ) P < 0.001 Placebo: 10.9 months (95% CI, ) Abiraterone acetate: 14.8 months (95% CI, ) 100 80 60 40 20 Survival (%) 6 9 12 15 18 Time to Death (Months) Overall survival was 14.8 months in the abiraterone acetate (AA) + prednisone (P) group and 10.9 months in the placebo + P group Treatment with AA + P resulted in a 35.4% reduction in the risk of death compared with placebo + P (HR = 0.646; 95% CI, ; P < ) de Bono et al. N Engl J Med 2011; 346(21):

69 Updated Overall Survival Data

70 Updated Analysis (775 Events): OS Benefit of AA Increased From 3
Updated Analysis (775 Events): OS Benefit of AA Increased From 3.9 to 4.6 Months HR (95% CI): 0.74 ( ) p < AA median OS (95% CI): 15.8 months ( ) Placebo median OS (95% CI): months ( ) 100 80 60 40 20 Survival (%) 6 12 18 24 797 398 657 306 473 183 273 15 Time to Death (Months) 30 AA Placebo Median duration of follow-up: 20.2 months Median duration of treatment: 8 months with AA vs. 4 months with placebo Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

71 Survival Benefit Observed With AA Is Consistent for Majority of Subgroups
0.5 0.75 1 1.5 Region Baseline ALK-P above median Baseline LDH above median Baseline PSA above median Visceral disease at entry Age, years Type of progression No. prior chemo regimens Baseline BPI Baseline ECOG All subjects Other N.A. NO YES ≥ 75 ≥ 65 < 65 Radiographic PSA only 2 ≥ 4 < 4 0-1 ALL 15.1 16.4 19.5 12.4 20.8 10.4 18.2 13.6 17.1 12.9 15.6 16.2 15 14.8 18.3 14.2 13.3 18.4 7.3 17 15.8 11.5 11.1 18 8.1 8 15.3 8.8 12.3 8.3 9.3 11.2 10.5 11.7 13.9 7 0.80 0.68 0.88 0.60 0.77 0.79 0.65 0.69 0.64 0.76 0.78 0.63 0.71 0.74 ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Variable Subgroup Median (months) AA Placebo HR 95% CI Favors AA Favors Placebo Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

72 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 20 6 12 18 24 715 353 608 281 452 174 263 97 14 AA Placebo Time to Death (Months) Survival (%) 30 ECOG 2 (10% of patients) 100 80 60 40 82 45 49 25 21 9 10 3 1 Abiraterone: 7.3 months 17 months Placebo: 7 months 12.3 months Median OS – AA vs. Placebo ECOG 0-1: 17 vs months (HR=0.74; 95% CI: ) ECOG 2: 7.3 vs. 7 months (HR=0.77; 95% CI: ) Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

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

74 1 Prior Line of Chemotherapy 2 Prior Lines of Chemotherapy
Survival Benefit Observed With AA for Subgroups with 1 or 2 Prior Lines of Chemotherapy at Study Entry 1 Prior Line of Chemotherapy 100 80 60 40 20 6 12 18 24 557 275 467 214 348 130 210 72 9 5 AA Placebo Time to Death (Months) Survival (%) 30 2 Prior Lines of Chemotherapy 240 123 190 92 125 53 63 28 1 Abiraterone: 17.1 months Placebo: 11.7 months 14.2 months 10.4 months Median OS – AA vs. Placebo 1 prior line of chemotherapy: 17.1 vs months (HR=0.71; 95% CI: ) 2 prior lines of chemotherapy: 14.2 vs months (HR=0.80; 95% CI: ) Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

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

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

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

78 Radiographic PFS and Time to PSA Progression Favored AA
100 80 60 40 20 6 12 18 24 797 398 371 138 199 52 74 1 AA Placebo Time to Death (Months) Survival (%) 30 293 59 125 42 8 2 Radiographic PFS Abiraterone: 5.6 months Placebo: 3.6 months 8.5 months 6.6 months HR (95% CI): 0.66 ( ) p < HR (95% CI): 0.63 ( ) Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

79 All Secondary End Points Achieved Statistical Significance
AA (n = 797) Placebo (n = 398) HR 95% CI P Value TTPP (months) 10.2 6.6 0.58 (0.46, 0.73) < 0.001 rPFS (months) 5.6 3.6 0.67 (0.58, 0.78) PSA response rate Total 38.0% 10.1% - Confirmed 29.1% 5.5% Objective response (RECIST) 14.0% 2.8% de Bono et al. N Engl J Med 2011; 346(21):

80 Summary of AEs AA (n = 791) Placebo (n = 394) All Grades Grades 3/4
All treatment-emergent AEs 98.9% 54.5% 99.0% 58.4% Serious AEs 37.5% 32.1% 41.4% 35.3% AEs leading to discontinuation 18.7% 10.5% 22.8% 13.5% AEs leading to death 11.6% 14.7% Deaths within 30 days of last dose 13.2% Underlying disease 7.5% 9.9% Other specified cause 2.9% 3.3% de Bono et al. Ann Oncol 2010: Abstract LBA5 (Oral presentation at ESMO)

81 AEs of Special Interest
AA (n = 791) Placebo (n = 394) All Grades Grade 3 Grade 4 Fluid retention and edema 31% 2% <1% 22% 1% Hypokalemia 17% 3% 8% Cardiac disorders 13% 11% LFT abnormalities 10% Hypertension The AEs of interest were more common in the AA arm. Fluid retention 30.5% AA vs 22.3% placebo, hypokalemia 17.1% AA vs 8.4% placebo, and cardiac disorders 12.5% AA vs 10.4% placebo were observed. Grade 3 and 4 hypokalaemia was observed in 3.8% of the AA group vs 0.8% of the placebo group. Grade 3 and 4 hypertension was observed in 1.3% of the AA vs 0.3 of the placebo group. de Bono et al. N Engl J Med 2011; 346(21):

82 Pain and Time to Skeletal Events

83 Symptomatic Improvement - Pain Intensity Palliation
155/349 (44.4%) 44/163 (27.0%) This figure compares improvement in patient reported pain intensity (based on the single item of the BPI questionnaire called "worst pain over the last 24 hours”) between AA and placebo Shown is the proportion of patients in both study arms who experienced clinically meaningful palliation (for at least 2 cycles, as per prospective definitions) at any time during the study Not shown: The cumulative proportion of patients with a change (vs baseline) in pain intensity was consistently in favor of AA. (See backup slide.) Logothetis et al. J Clin Oncol 2011; 29 (Suppl): Abstract 4520 (oral presentation)

84 Patient Reported Outcomes (PROs)

85 AA Was Associated With Higher FACT-P Responses
* p = 0.284 † 70 40 30 10 Total Score Patients With Improvement (%) 20 60 50 * p < 0.001 † p < 0.05 Physical WB Social/Family WB Emotional WB Functional WB FACT-G PCS Placebo + prednisone (n = 398) TOI AA + prednisone (n = 797) 48 32 46 28 54 39 41 58 25 44 33 Improvement was assessed in eligible patients only! Note: The Social/Family WB subscale would not be expected to change much in response to drug therapy, due to the nature of the items (they refer largely to the patient’s perception of support from family and friends) Harland et al. ECCO 2011: Abstract 7001 (oral presentation)

86 Câncer de Próstata Androgênio Resistente Da Literatura para o “Campo de Batalha”

87 Estratégia Terapêutica CPAI
Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-androgênio (retirada) Anti-androgênio Quimioterapia Análogo LHRH

88 Estratégia Terapêutica CPAI
Dediferenciação Tumoral ~ Ca Pequenas Células PSA baixo com alto volume de doença Comprometimento visceral não-ósseo Sintomas constitucionais relevantes Altos valores de DHL Gleason  8-9 Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-androgênio (retirada) Anti-androgênio Quimioterapia Análogo LHRH

89 Estratégia Terapêutica CPAI
Dediferenciação Tumoral ~ Ca Pequenas Células PSA baixo com alto volume de doença Comprometimento visceral não-ósseo Sintomas constitucionais relevantes Altos valores de DHL Gleason  8-9 Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-androgênio (retirada) Anti-androgênio Quimioterapia Abiraterona Análogo LHRH

90 Estratégia Terapêutica CPAI
Dediferenciação Tumoral ~ Ca Pequenas Células PSA baixo com alto volume de doença Comprometimento visceral não-ósseo Sintomas constitucionais relevantes Altos valores de DHL Gleason  8-9 Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-androgênio (retirada) Anti-androgênio Quimioterapia Abiraterona Análogo LHRH

91 Estratégia Terapêutica CPAI
Dediferenciação Tumoral ~ Ca Pequenas Células PSA baixo com alto volume de doença Comprometimento visceral não-ósseo Sintomas constitucionais relevantes Altos valores de DHL Gleason  8-9 Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-androgênio (retirada) Anti-androgênio Abiraterona Análogo LHRH Quimioterapia

92 Estratégia Terapêutica CPAI
Dediferenciação Tumoral ~ Ca Pequenas Células PSA baixo com alto volume de doença Comprometimento visceral não-ósseo Sintomas constitucionais relevantes Altos valores de DHL Gleason  8-9 Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-androgênio (retirada) Anti-androgênio Docetaxel-Prednisona Mitoxantrona-Prednisona Sintomas KPS Análogo LHRH Quimioterapia

93 AbirateronaCabazitaxel
Estratégia Terapêutica CPAI Dediferenciação Tumoral ~ Ca Pequenas Células PSA baixo com alto volume de doença Comprometimento visceral não-ósseo Sintomas constitucionais relevantes Altos valores de DHL Gleason  8-9 Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-androgênio (retirada) Anti-androgênio AbirateronaCabazitaxel Docetaxel-Prednisona Radiofármaco Mitoxantrona-Prednisona Sintomas KPS Análogo LHRH Quimioterapia

94 Estratégia Terapêutica CPAI
Sintomas Ósseos Relevantes Sintomas Constitucionais Relevantes Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-androgênio (retirada) Anti-androgênio Quimioterapia Análogo LHRH

95 Estratégia Terapêutica CPAI
Sintomas Ósseos Relevantes Sintomas Constitucionais Relevantes Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-androgênio (retirada) Anti-androgênio Quimioterapia Abiraterona Análogo LHRH

96 Estratégia Terapêutica CPAI
Sintomas Ósseos Relevantes Sintomas Constitucionais Relevantes Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-androgênio (retirada) Anti-androgênio Quimioterapia Abiraterona Análogo LHRH

97 Estratégia Terapêutica CPAI
Sintomas Ósseos Relevantes Sintomas Constitucionais Relevantes Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-androgênio (retirada) Anti-androgênio Abiraterona Análogo LHRH Quimioterapia

98 Estratégia Terapêutica CPAI
Sintomas Ósseos Relevantes Sintomas Constitucionais Relevantes Docetaxel-Prednisona Mitoxantrona-Prednisona Sintomas KPS Análogo LHRH Quimioterapia

99 Estratégia Terapêutica CPAI
Sintomas Ósseos Relevantes Sintomas Constitucionais Relevantes Docetaxel-Prednisona Mitoxantrona-Prednisona Sintomas KPS Zolendronato Análogo LHRH Quimioterapia

100 Estratégia Terapêutica CPAI
Sintomas Ósseos Relevantes Sintomas Constitucionais Relevantes Docetaxel-Prednisona Radiofármaco Mitoxantrona-Prednisona Sintomas KPS Zolendronato Análogo LHRH Quimioterapia

101 Estratégia Terapêutica CPAI
Sintomas Ósseos Relevantes Sintomas Constitucionais Relevantes Nomograma Docetaxel-Prednisona Mitoxantrona-Prednisona Sintomas KPS Zolendronato Análogo LHRH Quimioterapia

102 AbirateronaCabazitaxel
Estratégia Terapêutica CPAI Sintomas Ósseos Relevantes Sintomas Constitucionais Relevantes AbirateronaCabazitaxel Docetaxel-Prednisona Radiofármaco Mitoxantrona-Prednisona Sintomas KPS Zolendronato Análogo LHRH Quimioterapia

103 Estratégia Terapêutica CPAI
Ausência de sintomas Doença óssea muito extensa ! Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-androgênio (retirada) Anti-androgênio Quimioterapia Análogo LHRH

104 Estratégia Terapêutica CPAI
Ausência de sintomas Doença óssea muito extensa ! Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-androgênio (retirada) Anti-androgênio Quimioterapia Abiraterona Análogo LHRH

105 Estratégia Terapêutica CPAI
Ausência de sintomas Doença óssea muito extensa ! Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-androgênio (retirada) Anti-androgênio Quimioterapia Abiraterona Análogo LHRH

106 Estratégia Terapêutica CPAI
Ausência de sintomas Doença óssea muito extensa ! Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-androgênio (retirada) Anti-androgênio Abiraterona Análogo LHRH Quimioterapia

107 Estratégia Terapêutica CPAI
Ausência de sintomas Doença óssea muito extensa ! Docetaxel-Prednisona Mitoxantrona-Prednisona Sintomas KPS Análogo LHRH Quimioterapia

108 Estratégia Terapêutica CPAI
Ausência de sintomas Doença óssea muito extensa ! Docetaxel-Prednisona Mitoxantrona-Prednisona Sintomas KPS Zolendronato Análogo LHRH Quimioterapia

109 Estratégia Terapêutica CPAI
Ausência de sintomas Doença óssea muito extensa ! Docetaxel-Prednisona Mitoxantrona-Prednisona Sintomas KPS Zolendronato Análogo LHRH Quimioterapia

110 AbirateronaCabazitaxel
Estratégia Terapêutica CPAI Ausência de sintomas Doença óssea muito extensa ! AbirateronaCabazitaxel Docetaxel-Prednisona Mitoxantrona-Prednisona Sintomas KPS Zolendronato Análogo LHRH Quimioterapia

111 Câncer de Próstata Androgênio Resistente após Falha a Quimioterapia Novos Agentes e Novos Resultados

112 Overall Survival Benefit of Radium-223 Chloride (Alpharadin) in the Treatment of Patients With Symptomatic Bone Metastases in Castration-Resistant Prostate Cancer (CRPC): A Phase III Randomised Trial (ALSYMPCA) C. Parker,1 D. Heinrich,2 J.M. O’Sullivan,3 S. Fosså,4 A. Chodacki,5 T. Demkow,6 A. Cross,7 B. Bolstad,8 J. Garcia-Vargas,9 and O. Sartor,10 on behalf of the ALSYMPCA Investigators 1The Royal Marsden Hospital, Surrey, UK; 2Haukeland Univ Hospital, Bergen, Norway; 3Centre for Cancer Research and Cell Biology, Queen’s Univ, Belfast, Northern Ireland; 4Radiumhospitalet, Oslo, Norway; 5Hospital Kochova, Chomutov, Czech Republic; 6Centrum Onkologii – Instytut im Sklodowskiej-Curie, Warsaw, Poland; 7PharmaNet, Hemel Hempstead, UK; 8Algeta ASA, Oslo Norway; 9Bayer HealthCare Pharmaceuticals, Montville, NJ, USA; 10Tulane Cancer Center, New Orleans, LA, USA

113 Disclosures C. Parker has served in a consultant or advisory role for Algeta ASA (uncompensated) and Bayer D. Heinrich and O. Sartor have served in consultant or advisory roles for Algeta ASA B. Bolstad has an ownership interest in and was employed by Algeta ASA until December 2010 J. Garcia-Vargas is an employee of Bayer HealthCare Pharmaceuticals J.M. O’Sullivan, S. Fosså, A. Chodacki, T. Demkow, and A. Cross have nothing to disclose

114 Acknowledgments All patients who participated in the study, and their caregivers Investigators from 19 countries: Massimo Aglietta Dino Amadori Enrique Aranda Javier Arbizu Amit Bahl Vladimir Balaz Pilar Bello Rami Ben-Yosef Ignace Billiet David Bottomley Jan Breza Michael Brown Walter Cabral Micheal Cano Joan Carles Prabir Chakraborti Piotr Chlosta Ales Chodacki Rob Coleman Marian Cvik David Dalley Marcos Dall'Oglio Ronaldo Damiao Marinus de Goeij Graeme Dickie Sanjay Dixit Jesus Garcia Donas Anthony Dowling Ygael Dror Lionel Duck Monstserrat Estorch Ursula Falkmer David Feltl Sophie Dorothea Fosså Ann-Sofie Fransson Lars Franzen Stephanie Gibbs John Graham Alexander Haese Christian Hampel Rosemary Harrup Catherine Heath Daniel Heinrich Svein Inge Helle Milan Hora Peter Hoskin Gary Hudes Michael Jackson Nick D James Barbara Jarzab Piotr Jarzemski Dag Clement Johannessen Walter José Koff Unn-Miriam Kasti Christian Keil Jon Kindblom Olbjorn Klepp Robert Klijer Jan Kliment Laurence Klotz Ivo Kocak Andrzej Kolodziejczyk Markus Kuczyk Philip Kwong Magnus Lagerlund Kari Margrethe Larsen Angus Leung Eugene Leung Roberto Llarena John Logue Rafael López Jarad Martin Gavin M Marx Begoña Mellado Wilmosh Mermershtain Caterina Messina Jeff Michalski Andrew Miller Ivan Mincik Julian Money-Kyrle Alain Monnier Andre Moraes Andre Murad Chee Kwan Ng Carsten Nieder Sten Nilsson Joe O'Sullivan Christopher Parker Sarah Pascoe Samir Patel Alain Pecking Jaroslav Pernicka Ken Pittman Frank Priou Prakash Ramachandra Robert Reid Angus Robinson Ton Roeleveld Claudio Rossetti Alberto Sáenz-Cusí Diana Salvo Carlos Sampaio Howard Sandler Alton Oliver Sartor Andres Jan Schrader Jan Schraml Christopher Scrase Mihalj Seke Avishay Sella Sergio Vicente Serrano Mark Sidhom Arne Solberg Anna Sowa-Staszczak John Staffurth Andrew Stockdale Arne Strauss Santhanam Sundar Peter Swift Isabel Syndikus Miah Hiang Tay Michael Tomblyn Michel Toubeau Michael Carsten Truss Penny Vande Streek Subramaniam Vasanthan Henk Vergunst Paul Verhagen Nicholas Vogelzang Wolfgang von Pokrzywnitzki Steffen Alexander Wedel Anders Widmark Pawel Jan Wiechno Sibylle Böhmer Henry Woo Tsz Kok Yau Kwok Keung Yuen Roman Zachoval Romuald Zdrojowy ALSYMPCA was sponsored by Algeta ASA and Bayer Healthcare Pharmaceuticals.

115 Background and Rationale
> 90% of patients with metastatic CRPC have radiologic evidence of bone metastases1 Skeletal-related events (SREs) include spinal cord compression, pathological fracture, and need for surgery or EBRT2 Bone metastases are a major cause of death, disability, decreased quality of life, and increased treatment cost3 Current bone-targeted therapies have not been shown to improve survival Tannock et al. N Engl J Med. 2004;351: Lipton. Semin Oncol. 2010;37:S15-S29. Lange and Vasella. Cancer Metastasis Rev. 1999;17:

116 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 Ca Ra

117 Radium-223 Targets Bone Metastases
Range of alpha-particle Radium-223 Bone surface Alpha-particles induce double-strand DNA breaks in adjacent tumour cells1 Short penetration of alpha emitters (2-10 cell diameters) = highly localised tumour cell killing and minimal damage to surrounding normal tissue 1. Perez et al. Principles and Practice of Radiation Oncology. 5th ed. Lippincott Williams & Wilkins; 2007:103.

118 Radium-223 Improved Overall Survival in the Placebo-Controlled Phase II Study in CRPC
HR: 0.48; 95% CI: P = 0.017 100 75 Radium-223, n = 33 % 50 Placebo, n = 31 25 Week 20 40 60 80 100 120 % change from baseline Radium-223 Placebo P Value PSA –24% +45% 0.003 Total ALP –46% +31% < PINP –63% +38% N reported Radium-223 Placebo AEs 155 174 SAEs 12 19 Nilsson. Lancet Oncol. 2007;8:

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

120 ALSYMPCA Study Endpoints
Primary Endpoint Overall survival Secondary Endpoints Time to first SRE Time to total ALP progression Total ALP response Total ALP normalisation Time to PSA progression Safety Quality of life

121 ALSYMPCA Statistical Design
Statistical assumption 90% power HR = 0.76 0.05 two-sided alpha Planned Interim Analysis Final Analysis Events 320 640 Alpha 0.05

122 ALSYMPCA Planned Interim Analysis
314 events from 809 patients randomised at the time of the interim analysis Improvement in OS met the predetermined boundary for stopping the trial On June 3, 2011, the Independent Data Monitoring Committee (IDMC) recommended stopping the trial early due to evidence of a significant treatment benefit Q Q Q Q Q Q Q Q Q Q Q Q Q Q Q FPFV DATA CUTOFF LPFV IDMC

123 ALSYMPCA Patient Demographics and Baseline Characteristics (ITT; N = 809)
Parameter Radium-223 (n = 541) Placebo (n = 268) Age, y Mean 70.2 70.7 Race, n (%) Caucasian 507 (94) 252 (94) Baseline ECOG score, n (%) ≤ 1 2 467 (86) 71 (13) 229 (85) 37 (14) Extent of disease, n (%) < 6 metastases 6-20 metastases > 20 metastases/superscan 88 (16) 235 (44) 217 (40) 33 (12) 129 (48) 106 (40) WHO ladder, cancer pain index ≥ 2, n (%) 294 (54) 142 (53)

124 ALSYMPCA Patient Baseline Characteristics, cont (ITT; N = 809)
Parameter Median (min, max) Radium-223 (n = 541) Placebo (n = 268) Haemoglobin, g/dL 12.2 ( ) 12.1 ( ) Albumin, g/L 40 (24-53) 40 (23-50) Total ALP, µg/L 213 ( ) 224 ( ) LDH, U/L 317 ( ) 328 ( ) PSA, µg/L 159 ( ) 195 ( )

125 ALSYMPCA Study Drug Treatment Received*
% Number of Injections *Based on the number of injections patients had received at the time of the interim analysis. Treatment ongoing in 107 (21%) patients on radium-223 and 49 (19%) on placebo.

126 ALSYMPCA Overall Survival
100 HR 0.695; 95% CI, P = 90 80 70 60 Radium-223, n = 541 Median OS: 14.0 months % 50 40 30 Placebo, n = 268 Median OS: 11.2 months 20 10 Month 3 6 9 12 15 18 21 24 27 Radium- 223 541 450 330 213 120 72 30 Placebo 268 218 147 89 49 28 7

127 ALSYMPCA Time to First Skeletal-Related Event
100 HR 0.610; 95% CI, P = 90 80 70 Radium-223, n = 541 Median: 13.6 months 60 % Without SRE 50 40 Placebo, n = 268 Median: 8.4 months 30 20 10 Month 3 6 9 12 15 18 21 Radium-223 541 379 214 111 51 22 Placebo 268 159 74 30 7 2

128 ALSYMPCA Secondary Endpoints: ALP and PSA
Hazard ratio 95% CI P-value Time to Total ALP progression (0.121 – 0.221) < Time to PSA progression (0.546 – 0.826) Radium-223 n (%) Placebo n (%) P-value Total ALP response (30% reduction) 165 (43) 4 (3) < 0.001 Total ALP normalisation* 83 (33) 1 (1) *In patients who had elevated total ALP at baseline.

129 Survival Benefit Across Patient Subgroups
Note: Patients who did not experience an event are censored at the last date known to be alive. Note: The 95% CI is taken from the log rank test (stratified by total ALP, current use of bisphosphonates and prior use of Docetaxel, except for subgroups marked with ‘#’). Note: The hazard ratio (Alpharadin:placebo) is from a Cox proportional hazards model (adjusted for total ALP, current use of bisphosphonates and prior use of Docetaxel, except for subgroups marked with ‘#’). Note: Size of circle represents relative value of N.

130 ALSYMPCA Summary of Patients With Adverse Events: Safety Population
ALSYMPCA Summary of Patients With Adverse Events: Safety Population* (N = 762) Patients With Adverse Events (AEs), n (%) Radium-223 (n = 509) Placebo (n = 253) All grade AEs 450 (88) 237 (94) Grade 3 or 4 AEs 257 (51) 150 (59) Serious AEs (SAEs) 220 (43) 139 (55) Discontinuation due to AEs 68 (13) 51 (20) *Patients who received at least 1 injection.

131 ALSYMPCA Adverse Events of Interest
All Grades Grades 3 or 4 Radium-223 (n = 509) n (%) Placebo (n = 253) Haematologic Anaemia 136 (27) 69 (27) 54 (11) 29 (12) Neutropenia 20 (4) 2 (1) 9 (2) Thrombocytopenia 42 (8) 14 (6) 22 (4) 4 (2) Non-Haematologic Bone pain 217 (43) 147 (58) 89 (18) 59 (23) Diarrhoea 112 (22) 34 (13) 6 (1) 3 (1) Nausea 174 (34) 80 (32) 8 (2) Vomiting 88 (17) 32 (13) 10 (2) 6 (2) Constipation 46 (18)

132 Conclusions In CRPC patients with bone metastases:
Radium-223 significantly prolonged OS P value = ; HR = 0.695; 95% CI, Radium-223 significantly prolonged time to first SRE P value = ; HR = 0.610; 95% CI, Radium-223 was very well tolerated Radium-223, a novel alpha-pharmaceutical, may provide a new standard of care for the treatment of CRPC patients with bone metastases

133 Phase 3 Trial (AFFIRM) of Enzalutamide (MDV3100), an Androgen Receptor Signaling Inhibitor: Primary, Secondary, and Quality-of-Life Endpoint Results Johann De Bono MBChB FRCP MSc PhD The Institute of Cancer Research and Royal Marsden, London, UK Karim Fizazi, Fred Saad, Mary-Ellen Taplin, Cora N. Sternberg, Kurt Miller, Peter Mulders, Kim N. Chi, Andrew J. Armstrong, Mohammad Hirmand, Brian Selby, Howard I. Scher, for the AFFIRM Investigators ASCO June 2012

134 Financial Disclosures
J de Bono — Medivation, Astellas, J&J H Scher Medivation (u), J&J, Aragon (u), Millenium P Mulders Astellas, GSK, AstraZeneca, Pfizer K Fizazi Medivation, Astellas, J&J, Amgen, Sanofi Aventis F Saad Medivation, Astellas, J&J, Sanofi Aventis ME Taplin Medivation, J&J, Sanofi Aventis, Tokai C Sternberg J&J, Astellas, Sanofi-Aventis K Miller Medivation, Astellas M Hirmand Medivation employee B Selby A Armstrong Medivation, J&J, sanofi-aventis, Amgen, Dendreon, Active Biotech/Ipsen K Chi Enzalutamide is being co-developed by Medivation, Inc. and Astellas Portions of this presentation were previously presented at ASCO-GU 2012 u, uncompensated ASCO June 2012

135 Enzalutamide (MDV3100) An oral investigational drug rationally designed to target AR signaling, a key driver of prostate cancer growth. No agonist effects in pre-clinical models. T T Enzalutamide Inhibits Binding of Androgens to AR 1 AR Cell cytoplasm Inhibits Nuclear Translocation of AR 2 Cell nucleus Tumor Death AR Inhibits Association Of AR with DNA 3 Tran et al. Science 2009;324:787–90. ASCO June 2012

136 AFFIRM: Enzalutamide vs Placebo in Post-Chemotherapy Castration-Resistant Prostate Cancer (CRPC)
R A N D O M I Z E D 2:1 Primary Endpoint: Overall Survival Enzalutamide 160 mg daily n = 800 Placebo n = 399 Patient Population*: 1199 patients with progressive CRPC ** Failed docetaxel chemotherapy *Stratification variables: ECOG Performance Status (0-1, 2) Mean Brief Pain Inventory Q#3 Score (<4, ≥ 4) **Glucocorticoids were allowed but not required ASCO June 2012

137 AFFIRM Study Design Enrollment: 156 centers
N. America, Europe, Australia, S. America, and S. Africa September 2009 through November 2010 Statistical Design: Cumulative alpha, 0.05, 2-sided Power: 90% to detect a 24% reduction in mortality (Target HR = 0.76) One planned interim analysis at 520 events ASCO June 2012

138 Secondary Efficacy Endpoints
Response Indicators PSA Response Soft Tissue Objective Response FACT-P Quality of Life Response Pain Palliation Circulating Tumor Cells Progression Indicators Time to PSA Progression Radiographic Progression-free Survival Time to First Skeletal-Related Event ASCO June 2012

139 Prior Hormonal and Chemotherapy Treatments
Enzalutamide (n = 800) Placebo (n = 399) Prior Lines of Hormonal Drug Therapy 1 2 ≥ 3 8.2% 42.3% 49.1% 8.8% 37.9% 53.1% Number of Prior Chemotherapy Regimens 72.4% 24.5% 3.1% 74.2% 23.8% 2.0% Median Number of Prior Docetaxel Cycles 8.5 8.0 ASCO June 2012

140 Baseline Patient Characteristics
Enzalutamide (n = 800) Placebo (n = 399) Age (median in yrs, range) 69 (41−92) 69 (49−89) ECOG – Performance Status - 2 8.8% 8.0% Mean Brief Pain Inventory Score ≥ on Question 3 28.3% 28.8% Bone Disease 91.3% 91.2% Soft Tissue Disease 70.9% 68.9% Visceral Liver 11.6% 8.5% Visceral Lung 15.4% 14.8% ASCO June 2012

141 Enzalutamide Prolonged Survival, Reducing Risk of Death
HR = (0.529, 0.752) P <0.0001 37% reduction in risk of death Enzalutamide: 18.4 months (95% CI: 17.3, NYR) Placebo: 13.6 months (95% CI: 11.3, 15.8) Enzalutamide 800 775 701 627 400 211 72 7 Placebo 399 376 317 263 167 81 33 3 ASCO June 2012

142 Survival Benefit Seen Across All Subgroups
Hazard Ratio for Death (95% CI) Overall Survival median (mo) Enzalutamide / Placebo Favors Enzalutamide* Favors Placebo* *Based on data analysis cutoff date for the planned interim analysis. ASCO June 2012

143 Patients on Remained on Enzalutamide Longer than on Placebo
Patients treated (n) 800 399 Median duration of treatment (months) 8.3 3.0 Treatment ongoing (%) 28.9 4.8 Median duration of follow up was 14.4 months ASCO June 2012

144 Enzalutamide had a high PSA Response Rate
50% confirmed response rates: Enza 54% ; Placebo 2% (p<0.0001) 90% confirmed response rates: Enza 25%; Placebo 1% (p<0.0001) Placebo Enzalutamide Best PSA Response ASCO June 2012

145 Enzalutamide Delayed Time to PSA Progression by a Median of 5.3 Months
HR = P <0.0001 Enzalutamide: 8.3 months (95% CI: 5.8, 8.3) Placebo: 3.0 months (95% CI: 2.9, 3.7) Enzalutamide 800 603 287 145 68 27 7 1 Placebo 399 107 12 5 2 145 ASCO June 2012 PSA progression defined by PCWG2 criteria

146 Enzalutamide RECIST Response Rate
Placebo P-value Objective Response (CR +PR) 28.9% 3.8% < Best Overall Response for Study Complete response (CR) 1.0% Partial response (PR) 25.1% 2.9% Stable disease 39.2% 29.3% Response categories defined by RECIST 1.1 ASCO June 2012 ASCO June 2012

147 Enzalutamide Prolonged Duration of rPFS by a Median of 5.4 Months
Enzalutamide: 8.3 months (95% CI: 8.2, 9.1) Placebo: 2.9 months (95% CI: 2.8, 3.4) HR = P <0.0001 rProgression Free Survival, % Change Y axis to rPFS Enzalutamide 800 583 447 287 140 58 13 1 Placebo 399 176 86 46 20 7 3 rPFS defined by RECIST 1.1 for soft tissue and PCGW2 for bone disease ASCO June 2012

148 Enzalutamide Prolonged Time to First SRE by a Median of 3.4 Months
HR = P <0.0001 Enzalutamide: 16.7 months (95% CI: 14.6, 19.1) Placebo: 13.3 months (95% CI: 5.5, NYR) Enzalutamide 800 676 548 379 209 87 19 2 Placebo 399 278 196 128 68 33 11 ASCO June 2012

149 Enzalutamide Improved Quality-of-Life Response as Measured by FACT-P
* p < ^ p=0.006 * * * * * * * ^ Analysis includes all patients with baseline and post-baseline values WB= Well-being PCS = Prostate Cancer Subscale TOI = Trial Outcome Index ASCO June 2012

150 Summary of Adverse Events
All Grades Grades >3* Enzalutamide (n = 800) Placebo (n = 399) AEs 98.1% 97.7% 45.3% 53.1% Serious AEs 33.5% 38.6% 28.4% 33.6% Discontinuations due to AEs 7.6% 9.8% 4.6% 7.0% AEs leading to death 2.9% 3.5% * AEs graded for severity with grades 1 and 2 being milder and grades 3-5 being more severe ASCO June 2012

151 Adverse Events of Special Interest
All Grades Grade ≥ 3 Events Enzalutamide (n = 800) Placebo (n = 399) Fatigue 33.6% 29.1% 6.3% 7.3% Cardiac Disorders 6.1% 7.5% 0.9% 2.0% Myocardial Infarction 0.3% 0.5% LFT Abnormalities* 1.0% 1.5% 0.4% 0.8% Seizure 0.6% 0.0% *Includes terms hyperbilirubinaemia, AST increased, ALT increased, LFT abnormal, transaminases increased, and blood bilirubin increased. ASCO June 2012

152 Overall Survival Benefit in Recent CRPC Trials
Agent/ Date Approved Mechanism Comparator Survival (months) Hazard Ratio P-value AFFIRM Enzalutamide Androgen Receptor Signaling Inhibitor Placebo 18.4 vs. 13.6 0.631 <0.0001 COU-AA-301 Abiraterone + prednisone 2011 CYP17 Inhibitor Placebo + prednisone 14.8 vs. 10.9 0.646 TROPIC Cabazitaxel + prednisone 2010 Cytotoxic Mitoxantrone + prednisone 15.1 vs. 12.7 0.70 Alpharadin* Alpha-particle emitting radionuclide 14.9 vs 11.3 0.69 0.0018 * Only 60% of these patients were post-docetaxel patients ASCO June 2012

153 A Large Proportion of Patients Received Post-Trial Anticancer Therapy
Enzalutamide (n = 800) Placebo (n = 399) Patients with ≥1 post-treatment anticancer therapy 41.1% 58.4% Most common post-protocol treatment Abiraterone 20.9% 24.3% Cabazitaxel 9.8% 13.8% Docetaxel 8.5% 14.3% Mitoxantrone 2.6% 11.0% ASCO June 2012

154 Conclusions Enzalutamide, a once a day oral Androgen Receptor Signaling Inhibitor, is well tolerated and prolongs survival in men with CRPC by almost 5 months. Enzalutamide improved secondary measures of antitumor activity including health-related quality of life, response, time to SRE and time to disease progression. The androgen receptor remains a valid therapeutic target for treating CRPC following chemotherapy; enzalutamide is now being studied in chemotherapy naïve patients. ASCO June 2012

155 Câncer de Próstata Androgênio Resistente
O passado

156 Câncer de Próstata Androgênio Resistente
O passado O presente

157 Câncer de Próstata Androgênio Resistente
O passado O presente O futuro

158 Agentes Relacionados a Ganho de SG no Câncer de Próstata Resistente a HT Pré Docetaxel
Estudo/Data de Aprovação Mecanismo Comparação Sobrevida (meses) P Value Sipuleucel –T 2009 Imunoterapia (PAP-GMCSF) Placebo 25.8 vs 21.7 0.03 COU-AA-302 Abiraterona + Prednisona 2011 Inibidor CYP17 Placebo + Prednisona NA vs 27.2 0.009 Alfaradin 2011* Radiofármaco emissor de partícula alfa 14.9 vs 11.3 0.0018 * 40% dos pacientes não haviam recebido docetaxel

159 Agentes Relacionados a Ganho de SG no Câncer de Próstata Resistente a HT e com Falha a Docetaxel
Estudo/Data de Aprovação Mecanismo Comparação Sobrevida (meses) P Value AFFIRM – Enzalutamida 2012 Inibidor do Sinal do Receptor de Andrógeno Placebo 18.4 vs 13.6 < COU-AA-301 Abiraterona + Prednisona 2011 Inibidor CYP17 Placebo + Prednisona 14.8 vs 10.9 TROPIC – Cabazitaxel 20102 Inibidor do microtúbulo Mitoxantrona + Prednisona 15.1 vs 12.7 Alfaradin 2011 * Radiofármaco emissor de partícula alfa 14.9 vs 11.3 0.0018 * Somente 60% dos pacientes haviam recebido docetaxel

160 Ganho de Sobrevida em Câncer de Próstata Resistente a Castração
Ponto de largada

161 Ganho de Sobrevida em Câncer de Próstata Resistente a Castração
Ponto de largada Docetaxel (2.9 m)

162 Ganho de Sobrevida em Câncer de Próstata Resistente a Castração
Sipuleucel T (4.1 m) Ponto de largada Docetaxel (2.9 m)

163 Ganho de Sobrevida em Câncer de Próstata Resistente a Castração
Alfaradin (3.6m) Sipuleucel T (4.1 m) Ponto de largada Docetaxel (2.9 m)

164 Ganho de Sobrevida em Câncer de Próstata Resistente a Castração
Cabazitaxel (2.4 m) Alfaradin (3.6m) Sipuleucel T (4.1 m) Ponto de largada Docetaxel (2.9 m)

165 Ganho de Sobrevida em Câncer de Próstata Resistente a Castração
Cabazitaxel (2.4 m) Ponto de largada Abiraterona (4.6 m) Alfaradin (3.6m) Sipuleucel T (4.1 m) Ponto de largada Docetaxel (2.9 m)

166 Ganho de Sobrevida em Câncer de Próstata Resistente a Castração
Enzalutamida (4.8 m) Cabazitaxel (2.4 m) Abiraterona (4.6 m) Ponto de largada Alfaradin (3.6m) Sipuleucel T (4.1 m) Ponto de largada Docetaxel (2.9 m)

167 Ganho de Sobrevida em Câncer de Próstata Resistente a Castração
Enzalutamida (4.8 m) Cabazitaxel (2.4 m) Abiraterona (4.6 m) Ponto de largada Ganho: 22.4 m (km) Alfaradin (3.6m) Sipuleucel T (4.1 m) Ponto de largada Docetaxel (2.9 m)

168 Ganho de Sobrevida em Câncer de Próstata Resistente a Castração
Enzalutamida (4.8 m) Cabazitaxel (2.4 m) Abiraterona (4.6 m) Ponto de largada Nunca em um tumor sólido houve tantas drogas aprovadas em um década Alfaradin (3.6m) Alfaradin (3.6m) Sipuleucel T (4.1 m) Ponto de largada Docetaxel (2.9 m)

169 Ganho de Sobrevida em Câncer de Próstata Resistente a Castração
Enzalutamida (4.8 m) Cabazitaxel (2.4 m) Abiraterona (4.6 m) Ponto de largada E pela primeira vez..... Alfaradin (3.6m) Alfaradin (3.6m) Sipuleucel T (4.1 m) Ponto de largada Docetaxel (2.9 m)

170 Ganho de Sobrevida em Câncer de Próstata Resistente a Castração
Enzalutamida (4.8 m) Cabazitaxel (2.4 m) Abiraterona (4.6 m) Ponto de largada Alfaradin (3.6m) Antes de 2004 Sipuleucel T (4.1 m) Ponto de largada Docetaxel (2.9 m)

171 Ganho de Sobrevida em Câncer de Próstata Resistente a Castração
Maior longevidade e Melhor qualidade de vida 2012 ! Enzalutamida (4.8 m) Enzalutamida (4.8 m) Cabazitaxel (2.4 m) Abiraterona (4.6 m) Ponto de largada Alfaradin (3.6m) Antes de 2004 Sipuleucel T (4.1 m) Ponto de largada Docetaxel (2.9 m)

172

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174 Obrigado