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Fernando Cotait Maluf Diretor do Departamento de Oncologia Clínica Hospital São José-Beneficência Portuguesa Doutor em Urologia FMUSP Médico Integrante.

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Apresentação em tema: "Fernando Cotait Maluf Diretor do Departamento de Oncologia Clínica Hospital São José-Beneficência Portuguesa Doutor em Urologia FMUSP Médico Integrante."— Transcrição da apresentação:

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

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

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

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

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

6 Câncer de Próstata Hormone-Sensível Progressão após Tratamento Hormônio - Sensível SupressãoTestosterona Hormônio-Sensível Refratário Hormônio- Refratário Tx Hormonal 2 nd linha Tx 1 0 linha

7 Câncer de Próstata Doença Androgênio Resistente HormônioterapiaHormônioterapia -Segunda linha -Manutenção da castração QuimioterapiaQuimioterapia -Manutenção da castração BisfosfonadosBisfosfonados Radioterapia PaliativaRadioterapia Paliativa –Externa –Radiofármacos

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

9 Respostas Clínica Manipulação Hormonal de Segunda-linha Retirada de Anti-androgênio15-30% Bicalutamida 25% Nilutamida 25% (?) DES 30-55% PC-SPES 40-50% Ketoconazole (+ corticóide) 20-60% Glucocorticóide 20-80% Acetato Megestrol 15%

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

11 V1.0 COU-AA-302 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)

12 V1.0 COU-AA-302 Persistent Unmet Need in mCRPC Current Therapies Have Limitations: 1. Restricted to Post-Chemotherapy Setting 2. OS Benefit in Chemo-Naïve Setting Without Objective Response or Impact on How a Patient Feels or Functions 3. 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 V1.0 COU-AA-302 Abiraterone Acetate Is an Androgen Biosynthesis Inhibitor Pregnenolone DHEA AndrostenedioneTestosterone DHT 17OH- Pregnenolone Cortisol Aldosterone Androgens Cholesterol Abiraterone Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

14 V1.0 COU-AA-302 Abiraterone Acetate: OS Benefit Shown in Post-Chemotherapy mCRPC Patients Median Survival was 14.8 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 V1.0 COU-AA-302 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 months Adapted from Halabi S. J Clin Oncol. 2009;27: Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

16 V1.0 COU-AA-302 Overall Study Design of COU-AA-302 Phase 3 multicenter, randomized, double-blind, placebo-controlled study conducted at 151 sites in 12 countries; USA, Europe, Australia, Canada Stratification by ECOG performance status 0 vs. 1 AA 1000 mg daily Prednisone 5 mg BID (Actual n = 546) AA 1000 mg daily Prednisone 5 mg BID (Actual n = 546) Co-Primary: rPFS by central review OS Secondary: Time to opiate use (cancer-related pain) Time to initiation of chemotherapy Time to ECOG-PS deterioration TTPP Efficacy end points Placebo daily Prednisone 5 mg BID (Actual n = 542) Placebo daily Prednisone 5 mg BID (Actual n = 542) R A N D O M I Z E D 1:1 R A N D O M I Z E D 1:1 Progressive chemo- naïve mCRPC patients (Planned N = 1088) Asymptomatic or mildly symptomatic Patients Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

17 V1.0 COU-AA-302 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 V1.0 COU-AA-302 COU-AA-302 Statistical Plan IA = interim analysis. H o, HR=1.0. Overall AssumptionrPFSOS α Power91%85% HR Expected events IA3 (55% OS events) 425 Events = IA2 (40% OS Events) 311 Events = Planned OS Analysis IA1 (~15% OS Events) 116 Events < Q102Q103Q104Q101Q112Q113Q114Q111Q122Q123Q124Q12 Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

19 V1.0 COU-AA-302 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) Median PSA (ng/mL) Median testosterone (ng/dL)4.0 Median alkaline phosphatase (IU/L) Median hemoglobin (g/dL) Median lactate dehydrogenase (IU/L) Gleason score (8) at initial diagnosis54%50% Extent of disease Bone metastases >10 bone lesions Soft tissue or node 83% 48% 49% 80% 47% 50% Pain (BPI Short Form) % 32% 64% 33% Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

20 V1.0 COU-AA-302 Treatment Duration and Discontinuation *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) AA+P (n=540) Placebo + P (n=542) Median duration of follow up22.3 months Median No. of cycles of therapy, range15 (1-33)9 (1-31) Treatment discontinued69%84% Reasons for Discontinuation Radiographic progression only21%30% Unequivocal clinical progression* only21%25% Radiographic and unequivocal clinical progression 11%10% Adverse event7%5% Withdrew consent6%9% Other4%5%

21 V1.0 COU-AA-302 Statistically Significant Improvement in rPFS Primary End Point Data cutoff 20/12/ Progression-Free (%) AA PL 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:< Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

22 V1.0 COU-AA-302 rPFS Benefit Demonstrated Across Full Spectrum of Patient Subgroups VariableSubgroup Median (months) AAPlacebo HR95% CI Favors AA Favors Placebo NE 13.7 NE 11.1 NE NE 11.9 NE 11.5 NE 11.5 ALL YES NO < YES NO YES NO YES NO N.A. Other 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 ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

23 V1.0 COU-AA-302 Strong Trend in OS Primary End Point Pre-specified significance level by OBrien-Fleming Boundary = Survival (%) Time to Death (Months) 33 AA + P PL + P AA PL AA + P (median, mos):NR PL + P (median, mos):27.2 HR (95% CI):0.75 ( ) P value: Data cutoff 20/12/2011 Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

24 V1.0 COU-AA-302 Point Estimates for OS Favor AA in All Patient Subgroups VariableSubgroup Median (months) AAPlacebo HR95% CI Favors AA Favors Placebo NE 25.5 NE 26.9 NE 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 ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) NE NE NE NE ALL YES NO < YES NO YES NO YES NO N.A. Other Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

25 V1.0 COU-AA-302 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) Docetaxel207 (37.9)287 (53.0) Cabazitaxel45 (8.2)52 (9.6) Ketoconazole39 (7.1)63 (11.6) Sipuleucel-T27 (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 V1.0 COU-AA-302 Serologic and Clinical Responses AA + P (n = 546) Placebo + P (n = 542) RR (95% CI)P Value PSA decline 50%62%24%NA< N=220N=218 RECIST: Defined objective response Complete response Partial response Stable disease Progressive disease 36% 11% 25% 61% 2% 16% 4% 12% 69% 15% (1.591, 3.247) < Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

27 V1.0 COU-AA-302 Statistically Significant Improvement in All Secondary End Points AA + PPlacebo + P Median (months) HR (95% CI)P Value Time to opiate use (cancer related pain) NR (0.57, 0.83) Time to chemotherapy initiation (0.49, 0.69) < Time to ECOG PS deterioration (0.71, 0.94) Time to PSA progression (0.42, 0.57) < Data cut off 20/12/2011 Patient Reported Outcomes favored AA +P vs. Placebo +P Full data to be reported Note: All secondary end points remain significant after adjusting for multiplicity testing Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

28 V1.0 COU-AA-302 No New Safety Concerns Identified with Longer AA Treatment than in 301 Study AA + P (n = 542) % Placebo + P (n = 540) % All GradesGrades 3/4All GradesGrades 3/4 Fatigue Fluid retention Hypokalemia Hypertension Cardiac disorders Atrial fibrillation ALT increased AST increased Most ALT and AST increases occurred during the first 3 months of treatment Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

29 V1.0 COU-AA-302 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 V1.0 COU-AA-302 Landmarks of Disease Progression in mCRPC Adapted from Halabi S. J Clin Oncol. 2009;27: Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation) Baseline PSA Progression Tumor/Bone Progression Pain Death Chemotherapy ECOG PS Decline Primary Endpoints: rPFS and OS Secondary Endpoints months p = 0.001p < p = p < p =

31 V1.0 COU-AA-302 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 Ref.: Ryan CJ et al. J Clin Oncol 30, 2012 (suppl; abstr LBA4518) Abiraterona no Câncer de Próstata Metastático, Resistente a HT, e sem QT prévia

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

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

35 Ref.: Ryan CJ et al. J Clin Oncol 30, 2012 (suppl; abstr LBA4518) 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 (0.57, 0.83) Tempo para Início de Quimioterapia (meses) (0.49, 0.69) < Resposta por PSA Total62.0%24.0%-< Resposta Objetiva (RECIST) 36.0%16.0% 2.27 (1.59, 3.24)< 0.001

36 Câncer de Próstata Hormone-Sensível Progressão após Tratamento Hormônio - Sensível SupressãoTestosterona Hormônio-Sensível Refratário Hormônio- Refratário Tx Hormonal 2 nd linha Tx 1 0 linha

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

38 Estudo Europeu 134 pts HFRT 134 pts HFRT Prednisona 5mg 2 x dia Prednisona 5mg 2 x dia Prednisona 5mg 2 x dia Prednisona 5mg 2 x dia + Docetaxel 30mg/m 2 d1,8,15,22,29 (cada 6 semanas x 6 ciclos) (cada 6 semanas x 6 ciclos) Objetivo Primário: Objetivo Primário: - Resposta PSA 6 semanas: esperado 40%-D/P vs 20%-P Objetivos Secundários: Objetivos Secundários: - SVG, SLP, toxicidade, qualidade de vida - Forç estatística 80%, p=0.05

39 Fossa et al. Prostate ASCO, 2006 Estudo Europeu Eficácia DCT/P (57 pts) P 52 (pts) p RR PSA57%26%.01 Diminuição Dor50%15%.01 Melhora Qualidade Vida32%25%.01

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

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

42 TAX pts HFRT (supressão de testosterona) Docetaxel 75mg/m 2 Docetaxel 30mg/m 2 Mitoxantrona 12mg/m 2 (cada 3 semanas) (5 sem/ cada 6 sem) (cada 3 semanas) (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 PPP

43 TAX 327 Eficácia DCT 3 sem (335 pts) DCT sem (334 pts) M 3 sem (337 pts) p SVG média18,9 m17,4 m16,5 m0.009 HR Morte 0,76 (0,62 – 0,94) 0,91 (0,75 – 1,11) RR PSA45%48%32% RR mens.12%8%7%0.1 RR Dor35%31%22%0.01

44 TAX 327 Eficácia DCT 3 sem (335 pts) DCT sem (334 pts) M 3 sem (337 pts) p SVG média18,9 m17,4 m16,5 m0.009 HR Morte 0,76 (0,62 – 0,94) 0,91 (0,75 – 1,11) Todos os Grupos RR PSA45%48%32% RR mens.12%8%7%0.1 RR Dor35%31%22%0.01

45 Sobrevida Global Sobrevida Global TAX 327 Eficácia

46 DCT 3 sem (335 pts) DCT sem (334 pts) M 3 sem (337 pts) p SVG média18,9 m17,4 m16,5 m0.009 HR Morte 0,76 (0,62 – 0,94) 0,91 (0,75 – 1,11) RR PSA45%48%32% RR mens.12%8%7%0.1 RR Dor35%31%22%0.01

47 TAX 327 Eficácia DCT 3 sem (335 pts) DCT sem (334 pts) M 3 sem (337 pts) p SVG média18,9 m17,4 m16,5 m0.009 HR Morte 0,76 (0,62 – 0,94) 0,91 (0,75 – 1,11) RR PSA45%48%32% RR mens.12%8%7%0.1 RR Dor35%31%22%0.01

48 > 16 pontos da FACT-P comparado com linha de base TAX 327 Eficácia DCT 3 sem (278 pts) DCT sem (270 pts) M 3 sem (267 pts) QOL22%23%13% p

49 Câncer de Próstata Androgênio Resistente Questões de Ordem Prática

50 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 Não Doença M1 Assintomática (doença extensa) ~18 m Sim Doença M1 Sintomática 9 – 16 m Sim

51 Quando iniciar/parar quimioterapia no câncer de próstata androgênio-resistente ? Considerações: TAX 327: 30 semanas e SWOG 99-16: 36 semanas (arbitrário)TAX 327: 30 semanas e SWOG 99-16: 36 semanas (arbitrário) Não se sabe quando interromper quimioterapia !Não se sabe quando interromper quimioterapia ! –Ciclos: 4-6 –Eficácia: até máxima resposta (± 2) –Efeitos colaterais: neuropatia/mielosupressão Re-tratamento em pacientes docetaxel-sensível: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 Férias de QT ÓtimaRRAusência RR Tratamento de Segunda-linha TaxanoNão-Taxano TaxanoRe-txEstudo Clínico

55 Férias de QT ÓtimaRRAusência RR Tratamento de Segunda-linha TaxanoNão-Taxano TaxanoRe-txCabazitaxel

56 Cabazitaxel Foi Selecionado para Superar a Resistência à Quimioterapia Atividade demonstrada em modelos de tumor insensíveis à quimioterapia, incluindo docetaxel 1,2 Dados pré-clínicos mostram que o cabazitaxel é 3,4 : –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

57 57 TROPIC: Phase III Registration Study 146 Sites in 26 Countries 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 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. Stratification factors ECOG PS (0, 1 vs. 2) Measurable vs. non-measurable disease mCRPC patients who progressed during and after treatment with a docetaxel-based regimen (N=755)

58 58 Number at risk Proportion of PFS (%) months3 months9 months15 months18 months21 months6 months12 months Progression-Free Survival (PFS) Results PFS composite endpoint: PSA progression, pain progression, tumor progression, symptom deterioration, or death Median PFS (months) 0.64–0.8695% CI <.0001 P-value 0.74Hazard Ratio CBZPMP CBZP

59 59 Primary Endpoint: Overall Survival (ITT Analysis) MP CBZP Number at risk Proportion of OS (%) months 6 months12 months18 months24 months30 months Median OS (months) 0.59–0.8395% CI <.0001 P-value 0.70 Hazard Ratio CBZPMP

60 60 Subgroup Overall Survival Analysis Factor Hazard ratio (95% CI) f a v o r s C B Z P | f a v o r s M P All patients0.70 (0.59–0.83) ECOG status: 0,10.68 (0.57–0.82) ECOG status: (0.48–1.38) Measurable disease: No0.72 (0.55–0.93) Measurable disease: Yes0.68 (0.54–0.85) No. of prior chemo: (0.55–0.83) No. of prior chemo: (0.55–1.02) Age: < (0.61–1.08) Age: (0.50–0.78) Rising PSA: No0.88 (0.61–1.26) Rising PSA: Yes0.65 (0.53–0.80) Total docetaxel dose: <225 mg/m²0.96 (0.49–1.86) Total docetaxel dose: 225 to 450 mg/m²0.60 (0.43–0.84) Total docetaxel dose: 450 to 675 mg/m²0.83 (0.60–1.16) Total docetaxel dose: 675 to 900 mg/m²0.73 (0.48–1.10) Total docetaxel dose: 900 mg/m²0.51 (0.33–0.79) Progression: During last docetaxel treatment0.65 (0.47–0.90) Progression: <3 months since last docetaxel dose0.70 (0.55–0.91) Progression: 3 months since last docetaxel dose0.75 (0.51–1.11)

61 61 Secondary Endpoints Response Rates and Time to Progression (TTP) * Determined only for subjects with pain or PSA 20 or measurable disease at baseline, respectively. NR=Not reached. NR: Not reached. MP (n=377) CBZP (n=378)Hazard ratio (95% CI)P-value Tumor assessment Response rate * (%) –.0005 Median TTP (months) (0.49–0.76)<.0001 PSA assessment Response rate * (%) –.0002 Median TTP (months) (0.63–0.90).0010 Pain assessment Response rate * (%) –.6286 Median TTP (months)NR (0.69–1.19).5192

62 62 Most Frequent Grade 3 Treatment-Emergent AEs * Safety Population MP (n=371) CBZP (n=371) All grades (%)Grade 3 (%) All grades (%)Grade 3 (%) Any adverse event Febrile neutropenia Diarrhea Fatigue Asthenia Back pain Nausea Vomiting Hematuria Abdominal pain * Sorted by decreasing frequency of events grade 3 in the CBZP arm.

63 Férias de QT ÓtimaRRAusência RR Tratamento de Segunda-linha TaxanoNão-Taxano TaxanoRe-txAbiraterona

64 Orteronel (TAK-700) CYP17 DHEA Androstenediona Testosterona DHT 17-OH pregnenolona 17-OH progesterona 11-DeoxicortisolCortisolColesterolPregnenolonaProgesteronaDeoxicorticosteronaCorticosteronaAldosterona Abiraterona (COU-AA-301) Orteronel (TAK-700) Inibidor seletivo da biossíntese de androgênio que bloqueia a CYP17

65 Abiraterona CYP17 DHEA Androstenediona Testosterona DHT 17-OH pregnenolona 17-OH progesterona 11-DeoxicortisolCortisolColesterolPregnenolonaProgesteronaDeoxicorticosteronaCorticosteronaAldosterona Abiraterona (COU-AA-301) Orteronel (TAK-700) Inibidor seletivo da biossíntese de androgênio que bloqueia a CYP17

66 V2.0 COU-AA-301 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):

67 V2.0 COU-AA-301 COU-AA-301 Study Design Abiraterone acetate 1000 mg daily Placebo daily Phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled study (147 sites in 13 countries; USA, Europe, Australia, Canada) OS (25% improvement; HR 0.8) Primary endpoint: 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) 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) TREATUNTILPROGRESSIONTREATUNTILPROGRESSION TREATUNTILPROGRESSIONTREATUNTILPROGRESSION Prednisone 5mg twice daily de Bono et al. N Engl J Med 2011; 346(21):

68 V2.0 COU-AA-301 Overall Survival – Interim Analysis AA Placebo Hazard ratio = 0.65 ( ) P < Placebo: 10.9 months (95% CI, ) Abiraterone acetate: 14.8 months (95% CI, ) Survival (%) Placebo AA Time to Death (Months) de Bono et al. N Engl J Med 2011; 346(21):

69 V2.0 COU-AA-301 Updated Overall Survival Data

70 V2.0 COU-AA-301 Updated Analysis (775 Events): OS Benefit of AA Increased From 3.9 to 4.6 Months Median duration of follow-up: 20.2 months Median duration of treatment: 8 months with AA vs. 4 months with placebo HR (95% CI): 0.74 ( ) p < AA median OS (95% CI): 15.8 months ( ) Placebo median OS (95% CI): 11.2 months ( ) Survival (%) Time to Death (Months) AA Placebo AA Placebo Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

71 V2.0 COU-AA-301 Survival Benefit Observed With AA Is Consistent for Majority of Subgroups Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

72 V2.0 COU-AA-301 Survival by Baseline ECOG Status Favors AA for ECOG 0-1, but not for ECOG 2; May be Attributed by the Small Sample Size 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: ) ECOG AA Placebo Time to Death (Months) Survival (%) ECOG 2 (10% of patients) AA Placebo Time to Death (Months) Survival (%) Abiraterone: 7.3 months Abiraterone: 17 months Placebo: 7 months Placebo: 12.3 months Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

73 V2.0 COU-AA-301 Survival Benefit Observed With AA for Subgroups With and Without Pain at Study Entry 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: ) Pain (0-3 [absent]) AA Placebo Time to Death (Months) Survival (%) AA Placebo Time to Death (Months) Survival (%) Pain (4-10 [present]) Abiraterone: 18.4 months Placebo: 13.9 months Abiraterone: 13.3 months Placebo: 9.3 months Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

74 V2.0 COU-AA-301 Survival Benefit Observed With AA for Subgroups with 1 or 2 Prior Lines of Chemotherapy at Study Entry 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: ) 1 Prior Line of Chemotherapy AA Placebo Time to Death (Months) Survival (%) Prior Lines of Chemotherapy AA Placebo Time to Death (Months) Survival (%) Abiraterone: 17.1 months Placebo: 11.7 months Abiraterone: 14.2 months Placebo: 10.4 months Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

75 V2.0 COU-AA-301 Survival Benefit Observed With AA for Subgroups With PSA Progression Only or Radiographic Progression at Study Entry 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: ) Radiographic AA Placebo Time to Death (Months) Survival (%) AA Placebo Time to Death (Months) Survival (%) PSA Only Abiraterone: 18.3 months Placebo: 13.6 months Abiraterone: 14.8 months Placebo: 10.5 months Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

76 V2.0 COU-AA-301 Survival Benefit Observed With AA Across All Age Groups 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 V2.0 COU-AA-301 Survival Benefit Observed With AA for Subgroups With and Without Visceral Disease at Study Entry 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: ) With Visceral Disease AA Placebo Time to Death (Months) Survival (%) AA Placebo Time to Death (Months) Survival (%) Without Visceral Disease Abiraterone: 17.1 months Placebo: 12.3 months Abiraterone: 12.9 months Placebo: 8.3 months Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

78 V2.0 COU-AA-301 Radiographic PFS and Time to PSA Progression Favored AA Time to PSA Progression AA Placebo Time to Death (Months) Survival (%) AA Placebo Time to Death (Months) Survival (%) Radiographic PFS Abiraterone: 5.6 months Placebo: 3.6 months Abiraterone: 8.5 months Placebo: 6.6 months HR (95% CI): 0.66 ( ) p < HR (95% CI): 0.63 ( ) p < Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

79 V2.0 COU-AA-301 All Secondary End Points Achieved Statistical Significance AA (n = 797) Placebo (n = 398) HR 95% CI P Value TTPP (months) (0.46, 0.73) < rPFS (months) (0.58, 0.78) < PSA response rate Total38.0%10.1%-< Confirmed29.1%5.5%-< Objective response (RECIST) 14.0%2.8%-< de Bono et al. N Engl J Med 2011; 346(21):

80 V2.0 COU-AA-301 Summary of AEs AA (n = 791) Placebo (n = 394) All GradesGrades 3/4All GradesGrades 3/4 All treatment-emergent AEs98.9%54.5%99.0%58.4% Serious AEs37.5%32.1%41.4%35.3% AEs leading to discontinuation18.7%10.5%22.8%13.5% AEs leading to death11.6%14.7% Deaths within 30 days of last dose 10.5%13.2% Underlying disease7.5%9.9% Other specified cause2.9%3.3% de Bono et al. Ann Oncol 2010: Abstract LBA5 (Oral presentation at ESMO)

81 V2.0 COU-AA-301 AEs of Special Interest de Bono et al. N Engl J Med 2011; 346(21): AA (n = 791) Placebo (n = 394) All Grades Grade 3Grade 4 All Grades Grade 3Grade 4 Fluid retention and edema 31%2%<1%22%1%0 Hypokalemia17%3%<1%8%1%0 Cardiac disorders13%3%1%11%2%<1% LFT abnormalities10%3%<1%8%3%<1% Hypertension10%1%08%<1%0

82 V2.0 COU-AA-301 Pain and Time to Skeletal Events

83 V2.0 COU-AA-301 Symptomatic Improvement - Pain Intensity Palliation Logothetis et al. J Clin Oncol 2011; 29 (Suppl): Abstract 4520 (oral presentation) 155/349 (44.4%) 44/163 (27.0%) P =

84 V2.0 COU-AA-301 Patient Reported Outcomes (PROs)

85 V2.0 COU-AA-301 AA Was Associated With Higher FACT-P Responses * * * * p = * Total Score Patients With Improvement (%) * p < p < 0.05 Physical WB Social/Family WB Emotional WB Functional WB FACT-G PCS Placebo + prednisone (n = 398) TOI AA + prednisone (n = 797) 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 Análogo LHRH Quimioterapia

88 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 Análogo LHRH Quimioterapia Estratégia Terapêutica CPAI

89 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 Análogo LHRH Quimioterapia Estratégia Terapêutica CPAI Abiraterona

90 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 Análogo LHRH Quimioterapia Estratégia Terapêutica CPAI Abiraterona

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

92 Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-androgênio (retirada) Anti-androgênio Quimioterapia 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 Análogo LHRH Estratégia Terapêutica CPAI Sintomas KPS Mitoxantrona- Prednisona Docetaxel- Prednisona

93 Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-androgênio (retirada) Anti-androgênio Quimioterapia 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 Análogo LHRH Estratégia Terapêutica CPAI Sintomas KPS Mitoxantrona- Prednisona Docetaxel- Prednisona Radiofármaco Abiraterona Cabazitaxel

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

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

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

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

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

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

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

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

102 Sintomas Ósseos Relevantes Sintomas Constitucionais Relevantes Estratégia Terapêutica CPAI QuimioterapiaAnálogo LHRH Sintomas KPS Mitoxantrona- Prednisona Docetaxel- Prednisona Zolendronato Radiofármaco Abiraterona Cabazitaxel

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

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

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

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

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

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

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

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

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. OSullivan, 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 1 The Royal Marsden Hospital, Surrey, UK; 2 Haukeland Univ Hospital, Bergen, Norway; 3 Centre for Cancer Research and Cell Biology, Queens Univ, Belfast, Northern Ireland; 4 Radiumhospitalet, Oslo, Norway; 5 Hospital Kochova, Chomutov, Czech Republic; 6 Centrum Onkologii – Instytut im Sklodowskiej-Curie, Warsaw, Poland; 7 PharmaNet, Hemel Hempstead, UK; 8 Algeta ASA, Oslo Norway; 9 Bayer HealthCare Pharmaceuticals, Montville, NJ, USA; 10 Tulane 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. OSullivan, S. Fosså, A. Chodacki, T. Demkow, and A. Cross have nothing to disclose

114 Acknowledgments 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 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 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 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 All patients who participated in the study, and their caregivers ALSYMPCA was sponsored by Algeta ASA and Bayer Healthcare Pharmaceuticals. Investigators from 19 countries:

115 Background and Rationale > 90% of patients with metastatic CRPC have radiologic evidence of bone metastases 1 Skeletal-related events (SREs) include spinal cord compression, pathological fracture, and need for surgery or EBRT 2 Bone metastases are a major cause of death, disability, decreased quality of life, and increased treatment cost 3 Current bone-targeted therapies have not been shown to improve survival 1.Tannock et al. N Engl J Med. 2004;351: Lipton. Semin Oncol. 2010;37:S15-S29. 3.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 Ra Ca

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

118 Radium-223 Improved Overall Survival in the Placebo-Controlled Phase II Study in CRPC HR: 0.48; 95% CI: P = Week0120 Radium-223, n = 33 Placebo, n = 31 % % change from baseline Radium-223PlaceboP Value PSA–24%+45% Total ALP–46%+31% < PINP–63%+38% < N reportedRadium-223Placebo AEs SAEs1219 Nilsson. Lancet Oncol. 2007;8:

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

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 Alpha

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 DATA CUTOFF LPFVIDMCFPFV

123 ALSYMPCA Patient Demographics and Baseline Characteristics (ITT; N = 809) Parameter Radium-223 (n = 541) Placebo (n = 268) Age, y Mean Race, n (%) Caucasian507 (94)252 (94) Baseline ECOG score, n (%) (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 Month Radium Placebo ALSYMPCA Overall Survival % Radium-223, n = 541 Median OS: 14.0 months Placebo, n = 268 Median OS: 11.2 months HR 0.695; 95% CI, P =

127 Month Radium Placebo ALSYMPCA Time to First Skeletal-Related Event % Without SRE HR 0.610; 95% CI, P = Radium-223, n = 541 Median: 13.6 months Placebo, n = 268 Median: 8.4 months

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

129 Survival Benefit Across Patient Subgroups

130 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 AEs450 (88)237 (94) Grade 3 or 4 AEs257 (51)150 (59) Serious AEs (SAEs)220 (43)139 (55) Discontinuation due to AEs68 (13)51 (20) *Patients who received at least 1 injection.

131 ALSYMPCA Adverse Events of Interest All GradesGrades 3 or 4 Radium-223 (n = 509) n (%) Placebo (n = 253) n (%) Radium-223 (n = 509) n (%) Placebo (n = 253) n (%) Haematologic Anaemia136 (27)69 (27)54 (11)29 (12) Neutropenia20 (4)2 (1)9 (2)2 (1) Thrombocytopenia42 (8)14 (6)22 (4)4 (2) Non-Haematologic Bone pain217 (43)147 (58)89 (18)59 (23) Diarrhoea112 (22)34 (13)6 (1)3 (1) Nausea174 (34)80 (32)8 (2)4 (2) Vomiting88 (17)32 (13)10 (2)6 (2) Constipation89 (18)46 (18)6 (1)2 (1)

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 133 ASCO June 2012

134 Financial Disclosures Enzalutamide is being co-developed by Medivation, Inc. and Astellas Portions of this presentation were previously presented at ASCO-GU 2012 u, uncompensated 134 J de BonoMedivation, Astellas, J&J H ScherMedivation (u), J&J, Aragon (u), Millenium P MuldersAstellas, GSK, AstraZeneca, Pfizer K FizaziMedivation, Astellas, J&J, Amgen, Sanofi Aventis F SaadMedivation, Astellas, J&J, Sanofi Aventis ME TaplinMedivation, J&J, Sanofi Aventis, Tokai C SternbergJ&J, Astellas, Sanofi-Aventis K MillerMedivation, Astellas M HirmandMedivation employee B SelbyMedivation employee A ArmstrongMedivation, J&J, sanofi-aventis, Amgen, Dendreon, Active Biotech/Ipsen K Chi 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. Enzalutamide 1 T AR T Cell nucleus Inhibits Binding of Androgens to AR Inhibits Nuclear Translocation of AR Inhibits Association Of AR with DNA AR Cell cytoplasm Tran et al. Science 2009;324:787– 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 R A N D O M I Z E D 2:1 Primary Endpoint: Overall Survival Enzalutamide 160 mg daily n = 800 Enzalutamide 160 mg daily n = 800 Placebo n = 399 Placebo n = 399 Patient Population*: 1199 patients with progressive CRPC ** Failed docetaxel chemotherapy **Glucocorticoids were allowed but not required 136ASCO June 2012 *Stratification variables: ECOG Performance Status (0-1, 2) Mean Brief Pain Inventory Q#3 Score (<4, 4)

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 137 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 138 ASCO June 2012

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

140 Baseline Patient Characteristics Enzalutamide (n = 800) Placebo (n = 399) Age (median in yrs, range) 69 (4192) 69 (4989) ECOG – Performance Status %8.0% Mean Brief Pain Inventory Score 4 on Question %28.8% Bone Disease91.3%91.2% Soft Tissue Disease70.9%68.9% Visceral Liver11.6%8.5% Visceral Lung15.4%14.8% 140 ASCO June 2012

141 Enzalutamide Prolonged Survival, Reducing Risk of Death HR = (0.529, 0.752) P < % 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 Placebo ASCO June 2012

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

143 Patients on Remained on Enzalutamide Longer than on Placebo Median duration of follow up was 14.4 months EnzalutamidePlacebo Patients treated (n) Median duration of treatment (months) Treatment ongoing (%) ASCO June 2012

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

145 145 Enzalutamide Delayed Time to PSA Progression by a Median of 5.3 Months Enzalutamide Placebo HR = P < PSA progression defined by PCWG2 criteria Enzalutamide: 8.3 months (95% CI: 5.8, 8.3) Placebo: 3.0 months (95% CI: 2.9, 3.7) ASCO June 2012

146 Enzalutamide RECIST Response Rate ResponseEnzalutamidePlaceboP-value Objective Response (CR +PR)28.9%3.8%< Best Overall Response for Study Complete response (CR)3.8%1.0% Partial response (PR)25.1%2.9% Stable disease39.2%29.3% 146ASCO June 2012 Response categories defined by RECIST 1.1 ASCO June 2012

147 147 Enzalutamide Prolonged Duration of rPFS by a Median of 5.4 Months Enzalutamide Placebo Enzalutamide: 8.3 months (95% CI: 8.2, 9.1) Placebo: 2.9 months (95% CI: 2.8, 3.4) HR = P < rPFS defined by RECIST 1.1 for soft tissue and PCGW2 for bone disease ASCO June 2012 rProgression Free Survival, %

148 Enzalutamide Prolonged Time to First SRE by a Median of 3.4 Months HR = P < Enzalutamide: 16.7 months (95% CI: 14.6, 19.1) Placebo: 13.3 months (95% CI: 5.5, NYR) Enzalutamid e Placebo ASCO June 2012

149 Enzalutamide Improved Quality-of- Life Response as Measured by FACT- P ASCO June * * * * * * * ^ * p <0.001 ^ p=0.006 Analysis includes all patients with baseline and post-baseline valuesWB= Well-being PCS = Prostate Cancer Subscale TOI = Trial Outcome Index

150 Summary of Adverse Events All GradesGrades >3* Enzalutamide (n = 800) Placebo (n = 399) Enzalutamide (n = 800) Placebo (n = 399) AEs98.1%97.7%45.3%53.1% Serious AEs33.5%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%2.9%3.5% * AEs graded for severity with grades 1 and 2 being milder and grades 3-5 being more severe 150 ASCO June 2012

151 Adverse Events of Special Interest *Includes terms hyperbilirubinaemia, AST increased, ALT increased, LFT abnormal, transaminases increased, and blood bilirubin increased. All GradesGrade 3 Events Enzalutamide (n = 800) Placebo (n = 399) Enzalutamide (n = 800) Placebo (n = 399) Fatigue33.6%29.1%6.3%7.3% Cardiac Disorders6.1%7.5%0.9%2.0% Myocardial Infarction 0.3%0.5%0.3%0.5% LFT Abnormalities*1.0%1.5%0.4%0.8% Seizure0.6%0.0%0.6%0.0% 151 ASCO June 2012

152 Overall Survival Benefit in Recent CRPC Trials Trial/ Agent/ Date Approved MechanismComparator Survival (months) Hazard Ratio P-value AFFIRM Enzalutamide Androgen Receptor Signaling Inhibitor Placebo18.4 vs < COU-AA-301 Abiraterone + prednisone 2011 CYP17 Inhibitor Placebo + prednisone 14.8 vs < TROPIC Cabazitaxel + prednisone 2010 Cytotoxic Mitoxantrone + prednisone 15.1 vs < Alpharadin* Alpha-particle emitting radionuclide Placebo14.9 vs * 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 Abiraterone20.9%24.3% Cabazitaxel9.8%13.8% Docetaxel8.5%14.3% Mitoxantrone2.6%11.0% 153 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. 154 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 * 40% dos pacientes não haviam recebido docetaxel Agentes Relacionados a Ganho de SG no Câncer de Próstata Resistente a HT Pré Docetaxel Estudo/Data de Aprovação MecanismoComparaçãoSobrevida (meses)P Value Sipuleucel –T 2009Imunoterapia (PAP-GMCSF) Placebo25.8 vs COU-AA-302 Abiraterona + Prednisona 2011 Inibidor CYP17Placebo + Prednisona NA vs Alfaradin 2011* Radiofármaco emissor de partícula alfa Placebo14.9 vs

159 * Somente 60% dos pacientes haviam recebido docetaxel Agentes Relacionados a Ganho de SG no Câncer de Próstata Resistente a HT e com Falha a Docetaxel Estudo/Data de Aprovação MecanismoComparaçãoSobrevida (meses)P Value AFFIRM – Enzalutamida 2012 Inibidor do Sinal do Receptor de Andrógeno Placebo18.4 vs 13.6 < COU-AA-301 Abiraterona + Prednisona 2011 Inibidor CYP17Placebo + Prednisona 14.8 vs 10.9< TROPIC – Cabazitaxel Inibidor do microtúbulo Mitoxantrona + Prednisona 15.1 vs 12.7< Alfaradin 2011 * Radiofármaco emissor de partícula alfa Placebo14.9 vs

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 Ponto de largada Docetaxel (2.9 m) Sipuleucel T (4.1 m)

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

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

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

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

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

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

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

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

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

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174 Obrigado


Carregar ppt "Fernando Cotait Maluf Diretor do Departamento de Oncologia Clínica Hospital São José-Beneficência Portuguesa Doutor em Urologia FMUSP Médico Integrante."

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