Uma Viagem ao Novo Mundo do Câncer de Próstata UPTODATE Brasília

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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. - PowerPoint PPT Presentation

Transcript of Uma Viagem ao Novo Mundo do Câncer de Próstata UPTODATE Brasília

  • Fernando Cotait Maluf

    Diretor do Departamento de Oncologia Clnica

    Hospital So Jos-Beneficncia Portuguesa Doutor em Urologia FMUSP

    Mdico Integrante Clnica Oncovida Uma Viagem ao Novo Mundo do Cncer de PrstataUPTODATE Braslia

  • Ref.: Hussain M et al. J Clin Oncol 30, 2012 (suppl; abstr 4)Deprivao Androgncia Intermitente versus Contnua no Cncer de Prstata Metasttico

  • Ref.: Hussain M et al. J Clin Oncol 30, 2012 (suppl; abstr 4)Deprivao Androgncia Intermitente versus Contnua no Cncer de Prstata Metasttico

  • Ref.: Hussain M et al. J Clin Oncol 30, 2012 (suppl; abstr 4)Deprivao Androgncia Intermitente versus Contnua no Cncer de Prstata Metasttico

  • Fernando Cotait Maluf

    Diretor do Departamento de Oncologia Clnica

    Centro de Oncologia-Hospital So Jos Doutor em Urologia FMUSP Tratamento da Doena Andrognio-resistente

  • Cncer de Prstata Hormone-Sensvel Progresso aps TratamentoHormnio -SensvelSupressoTestosteronaHormnio-SensvelHormnio-RefratrioHormnio-RefratrioTx Hormonal2nd linhaTx 10 linha

  • Cncer de PrstataDoena Andrognio ResistenteHormnioterapiaSegunda linhaManuteno da castrao

    QuimioterapiaManuteno da castraoBisfosfonados

    Radioterapia PaliativaExternaRadiofrmacos

  • Cncer de Prstata

    Doena Andrognio Resistente: Tratamentos Hormonais de 2nd-Linha

  • Respostas Clnica Manipulao Hormonal de Segunda-linhaRetirada de Anti-andrognio15-30%Bicalutamida 25%Nilutamida 25% (?)DES 30-55%PC-SPES 40-50%Ketoconazole (+ corticide) 20-60%Glucocorticide 20-80%Acetato Megestrol 15%

  • Manipulao Hormonal de Segunda-linha Questes / AspectosDurao mdia limitada (2-4 m)Impacto a longo prazo at 2012 ?

    V1.0COU-AA-302

    Interim Analysis Results of COU-AA-302, a Randomized, Phase 3 Study of Abiraterone Acetate (AA) in Chemotherapy-Nave Patients With Metastatic Castration-Resistant Prostate Cancer (mCRPC)Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

    V1.0COU-AA-302

    Persistent Unmet Need in mCRPCCurrent Therapies Have Limitations:

    Restricted to Post-Chemotherapy Setting

    OS Benefit in Chemo-Nave Setting Without Objective Response or Impact on How a Patient Feels or Functions

    Limited Penetrance of Chemotherapy

    NCCN prostate cancer guidelines Version 3.2012Kantoff P, N Engl J Med. 2011; 363:411-422Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

    V1.0COU-AA-302

    Abiraterone Acetate Is an Androgen Biosynthesis InhibitorPregnenoloneDHEAAndrostenedioneTestosteroneDHT17OH-PregnenoloneCortisolAldosteroneAndrogensCholesterolAbirateroneAbirateroneRyan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

    V1.0COU-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 armde Bono J, N Engl J Med. 2011; 364:1995-2005Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

    V1.0COU-AA-302

    Landmarks of Disease Progression in mCRPCAdapted from Halabi S. J Clin Oncol. 2009;27: 2766-2771Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

    V1.0COU-AA-302

    Overall Study Design of COU-AA-302Phase 3 multicenter, randomized, double-blind, placebo-controlled study conducted at 151 sites in 12 countries; USA, Europe, Australia, CanadaStratification by ECOG performance status 0 vs. 1

    Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

    V1.0COU-AA-302

    COU-AA-302: rPFS DefinitionProgressive disease (PD) by bone scan: Adapted Prostate Cancer Working Group 2 Consensus CriteriaBlinded 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 criteriaDeath from any causeRyan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

    V1.0COU-AA-302

    COU-AA-302 Statistical PlanIA = interim analysis. Ho, HR=1.0.IA3 (55% OS events)425 Events = 0.0034IA2 (40% OS Events)311 Events = 0.0005

    Planned OS AnalysisIA1 (~15% OS Events)116 Events < 0.0001

    1Q102Q103Q104Q101Q112Q113Q114Q111Q122Q123Q124Q12Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

    Overall AssumptionrPFSOS0.010.04Power91%85%HR0.670.80Expected events378773

    V1.0COU-AA-302

    Treatment Arms Evenly MatchedRyan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

    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) 5.55.1Median PSA (ng/mL)42.037.7Median testosterone (ng/dL)4.04.0Median alkaline phosphatase (IU/L)93.090.0Median hemoglobin (g/dL)13.013.1Median lactate dehydrogenase (IU/L)187.0184.0Gleason score (8) at initial diagnosis54%50%Extent of diseaseBone metastases>10 bone lesionsSoft tissue or node83%48%49%80%47%50%Pain (BPI Short Form)0-12-366%32%64%33%

    V1.0COU-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 monthsMedian No. of cycles of therapy, range15 (1-33)9 (1-31)Treatment discontinued69%84%Reasons for DiscontinuationRadiographic progression only21%30%Unequivocal clinical progression* only21%25%Radiographic and unequivocal clinical progression11%10%Adverse event7%5%Withdrew consent6%9%Other4%5%

    V1.0COU-AA-302

    Statistically Significant Improvement in rPFS Primary End PointData cutoff 20/12/2010Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

    AA + P (median, mos): NRPL + P (median, mos): 8.3HR (95% CI): 0.43 (0.35-0.52)P value: < 0.0001

    V1.0COU-AA-302

    rPFS Benefit Demonstrated Across Full Spectrum of Patient Subgroups0.20.7511.58.38.37.48.48.213.75.65.69.711.08.08.55.69.08.28.38.28.4VariableSubgroupMedian (months)AAPlaceboHR95% CIFavors AAFavors PlaceboNE13.7NENE11.1NE11.313.7NENE11.9NENENE11.5NENE11.5ALL010-12-3YESNO< 65 65 75YESNOYESNOYESNON.A.OtherAll subjectsBaseline ECOG

    Baseline BPI

    Bone metastasis only at entry

    Age

    Baseline PSA above median

    Baseline LDH above median

    Baseline ALK-P above median

    Region0.430.450.350.420.510.480.380.360.450.570.440.400.370.480.500.340.360.52(0.35-0.52)(0.36-0.57)(0.23-0.54)(0.32-0.54)(0.35-0.75)(0.34-0.69)(0.30-0.49) (0.25-0.53) (0.35-0.58) 0.39-0.83) (0.33-0.58)(0.29-0.54)(0.28-0.49)(0.36-0.65)(0.38-0.66)(0.25-0.47)(0.27-0.48)(0.39-0.69)Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

    V1.0COU-AA-302

    Strong Trend in OS Primary End PointPre-specified significance level by OBrien-Fleming Boundary = 0.0008Data cutoff 20/12/2011Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

    AA + P (median, mos): NRPL + P (median, mos): 27.2HR (95% CI): 0.75 (0.61-0.93)P value: 0.0097

    V1.0COU-AA-302

    Point Estimates for OS Favor AA in All Patient SubgroupsRyan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

    V1.0COU-AA-302

    Subsequent Therapy Was Common*Prior to unblinding (e.g. not per protocol)Ryan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

    AA + P(n = 546) n (%)Placebo + P(n = 542) n (%) No. with selected subsequent therapy for mCRPC242 (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)

    V1.0COU-AA-302

    Serologic and Clinical ResponsesRyan et al. ASCO 2012; Abstract LBA4518 (Oral Presentation)

    AA + P(n = 546)Placebo + P(n = 542)RR (95% CI)P ValuePSA decline 50%62%24%NA

  • Ref.: Ryan CJ et al. J Clin Oncol 30, 2012 (suppl; abstr LBA4518)Abiraterona no Cncer de Prstata Metasttico, Resistente a HT, e sem QT prvia

  • Ref.: Ryan CJ et al. J Clin Oncol 30, 2012 (suppl; abstr LBA4518)Abiraterona no Cncer de Prstata Metasttico, Resistente a HT, e sem QT prvia

  • Ref.: Ryan CJ et al. J Clin Oncol 30, 2012 (suppl; abstr LBA4518)Abiraterona no Cncer de Prstata Metasttico, Resistente a HT, e sem QT prvia

  • Ref.: Ryan CJ et al. J Clin Oncol 30, 2012 (suppl; abstr LBA4518)Abiraterona no Cncer de Prstata Metasttico, Resistente a HT, e sem QT prvia

    AA (n = 546)Placebo (n = 542)HR 95% CIP ValueTempo para Uso Opiide (meses)NR 23.7 0.69(0.57, 0.83) 0.0001Tempo para Incio de Quimioterapia (meses)25.8 16.2 0.59(0.49, 0.69)< 0.001Resposta por PSATotal 62.0%24.0%-< 0.0001Resposta Objetiva (RECIST)36.0%16.0%2.27(1.59, 3.24)< 0.001

  • Cncer de Prstata Hormone-Sensvel Progresso aps TratamentoHormnio -SensvelSupressoTestosteronaHormnio-SensvelHormnio-RefratrioHormnio-RefratrioTx Hormonal2nd linhaTx 10 linha

  • Cncer de Prstata Andrognio Resistente

    Quimioterapia

    Novos Agentes e Novos Resultados

  • 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 Primrio: Resposta PSA 6 semanas: esperado 40%-D/P vs 20%-P Objetivos Secundrios: SVG, SLP, toxicidade, qualidade de vida For estatstica 80%, p=0.05

  • Fossa et al. Prostate ASCO, 2006Estudo Europeu Eficcia

    DCT/P(57 pts)P52 (pts)pRR PSA57%26%.01Diminuio Dor50%15%.01Melhora Qualidade Vida32%25%.01

  • Estudo Europeu Qualidade de VidaFossa et al. Prostate ASCO, 2006

  • Estudo EuropeuSobrevida Fossa et al. Prostate ASCO, 2006

  • TAX 3271006 pts HFRT (supresso de testosterona) Docetaxel 75mg/m2 Docetaxel 30mg/m2 Mitoxantrona 12mg/m2 (cada 3 semanas) (5 sem/ cada 6 sem) (cada 3 semanas) Estratificao: KPS: 70 vs > 80 Grau de dor: PPI 2 ou AS 10 vs PPI < 2 ou AS < 10 Objetivos: * SVG (fora estatstica 90%, HR: 0,75, two-sided, 0.05) Resposta PSA, melhora de dor ssea, QOL, toxicidade PPP

  • TAX 327Eficcia

    DCT 3 sem(335 pts)DCT sem(334 pts)M 3 sem(337 pts)pSVG mdia18,9 m17,4 m16,5 m0.009HR Morte0,76(0,62 0,94)0,91(0,75 1,11)RR PSA45%48%32%0.0005RR mens.12%8%7%0.1RR Dor35%31%22%0.01

  • TAX 327 Eficcia

    DCT 3 sem(335 pts)DCT sem(334 pts)M 3 sem(337 pts)pSVG mdia18,9 m17,4 m16,5 m0.009HR Morte0,76(0,62 0,94)0,91(0,75 1,11)Todos os GruposRR PSA45%48%32%0.0005RR mens.12%8%7%0.1RR Dor35%31%22%0.01

  • Sobrevida GlobalTAX 327 Eficcia

  • TAX 327 Eficcia

    DCT 3 sem(335 pts)DCT sem(334 pts)M 3 sem(337 pts)pSVG mdia18,9 m17,4 m16,5 m0.009HR Morte0,76(0,62 0,94)0,91(0,75 1,11)RR PSA45%48%32%0.0005RR mens.12%8%7%0.1RR Dor35%31%22%0.01

  • TAX 327 Eficcia

    DCT 3 sem(335 pts)DCT sem(334 pts)M 3 sem(337 pts)pSVG mdia18,9 m17,4 m16,5 m0.009HR Morte0,76(0,62 0,94)0,91(0,75 1,11)RR PSA45%48%32%0.0005RR mens.12%8%7%0.1RR Dor35%31%22%0.01

  • > 16 pontos da FACT-P comparado com linha de baseTAX 327 Eficcia

    DCT 3 sem(278 pts)DCT sem(270 pts)M 3 sem(267 pts)QOL22%23%13%p0.0090.005

  • Cncer de Prstata Andrognio Resistente

    Questes de Ordem Prtica

  • Quando iniciar quimioterapia no cncer de prstata andrognio-resistente ?

    Volume de DoenaSobrevida MdiaQuimioterapia IndicadaAumento de PSA~ 4 aNoDoena M1 Assintomtica (doena limitada)18 24 mNoDoena M1 Assintomtica(doena extensa)~18 mSimDoena M1 Sintomtica9 16 mSim

  • Quando iniciar/parar quimioterapia no cncer de prstata andrognio-resistente ?Consideraes:TAX 327: 30 semanas e SWOG 99-16: 36 semanas (arbitrrio)No se sabe quando interromper quimioterapia !Ciclos: 4-6Eficcia: at mxima resposta ( 2)Efeitos colaterais: neuropatia/mielosupressoRe-tratamento em pacientes docetaxel-sensvel:Resposta a tratamento prvio: simTolerncia ao tratamento prvio: timaTempo at progresso: 3-6 meses

  • Tratamento de Segunda-linhaPerodo de Frias (do Oncologista e da Quimioterapia)

  • Cncer de Prstata

    Tratamento de Segunda-linha aps falha a Docetaxel

  • Frias de QTtimaRRAusncia RRTratamento de Segunda-linhaTaxanoNo-TaxanoTaxanoRe-txEstudo Clnico

  • Frias de QTtimaRRAusncia RRTratamento de Segunda-linhaTaxanoNo-TaxanoTaxanoRe-txCabazitaxel

  • Cabazitaxel Foi Selecionado para Superar a Resistncia QuimioterapiaAtividade demonstrada em modelos de tumor insensveis quimioterapia, incluindo docetaxel1,2 Dados pr-clnicos mostram que o cabazitaxel 3,4:Mais citotxico in vitro que o docetaxel em clulas tumorais expressando o gene 1 (mdr-1) de mltipla resistncia drogas, assim como em linhagens celulares com resistncia adquirida doxorrubicina, vincristina, vimblastina e paclitaxelAtivo in vivo em modelos de tumor pouco sensveis, insensveis e resistentes ao docetaxel e ixabepilonaCapaz de cruzar a barreira hematoenceflica in vivoDados pr-clnicos sustentam o desenvolvimento clnico no CPCRm aps tratamento com docetaxel 1. Bissery MC, et al. Proc Am Assoc Cancer Res. 2000;41:214. Abstract 1364. 2. Dados em arquivo. Relatrio de estudo clnico. EFC6193 (TROPIC). 3. Bissery MC, et al. Proc Am Assoc Cancer Res. 1995;36:316. Abstract 1882. 4. Informaes para prescrio do cabazitaxel nos EUA. Bridgewater, NJ: sanofi-aventis EUA LLC; junho de 2010. 12

  • *TROPIC: Phase III Registration Study 146 Sites in 26 CountriesPrimary endpoint: OSSecondary endpoints: Progression-free survival (PFS), response rate, and safetyInclusion: Patients with measurable disease must have progressed by RECIST; otherwise must have had new lesions or PSA progression cabazitaxel 25 mg/m q 3 wk + prednisone* for 10 cycles(n=378)mitoxantrone 12 mg/m q 3 wk + prednisone* for 10 cycles(n=377)*Oral prednisone/prednisolone: 10 mg daily.Stratification factorsECOG PS (0, 1 vs. 2) Measurable vs. non-measurable diseasemCRPC patients who progressed during and after treatment with a docetaxel-based regimen (N=755)

  • *Number at riskProportion of PFS (%)8060402001000 months3 months9 months15 months18 months21 months6 months12 monthsProgression-Free Survival (PFS) Results

    MP37711552279642 CBZP378168905215400

  • *Primary Endpoint: Overall Survival (ITT Analysis)Number at riskProportion of OS (%)

    MP37730018867111 CBZP37832123190284

  • *Subgroup Overall Survival Analysis

    FactorHazard ratio (95% CI) f a v o r s C B Z P | f a v o r s M P

    All patients0.70 (0.590.83)ECOG status: 0,10.68 (0.570.82)ECOG status: 20.81 (0.481.38)Measurable disease: No0.72 (0.550.93)Measurable disease: Yes0.68 (0.540.85)No. of prior chemo: 10.67 (0.550.83)No. of prior chemo: 20.75 (0.551.02)Age:

  • *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 assessmentResponse rate* (%)4.414.4.0005Median TTP (months)5.48.80.61 (0.490.76)

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

    MP (n=371)CBZP (n=371)All grades (%)Grade 3 (%)All grades (%)Grade 3 (%)

    Any adverse event88.439.495.757.4Febrile neutropenia1.31.37.57.5Diarrhea10.50.346.66.2Fatigue27.5336.74.9Asthenia12.42.420.54.6Back pain12.1316.23.8Nausea22.90.334.21.9Vomiting10.2022.61.9Hematuria3.80.516.71.9Abdominal pain3.5011.61.9

  • Frias de QTtimaRRAusncia RRTratamento de Segunda-linhaTaxanoNo-TaxanoTaxanoRe-txAbiraterona

  • AbirateronaOrteronel (TAK-700)Abiraterona (COU-AA-301)Orteronel (TAK-700) Inibidor seletivo da biossntese de andrognio que bloqueia a CYP17

  • AbirateronaAbiraterona (COU-AA-301)Orteronel (TAK-700) Inibidor seletivo da biossntese de andrognio que bloqueia a CYP17

    V2.0COU-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 studyde Bono et al. N Engl J Med 2011; 346(21): 1995-2005

    V2.0COU-AA-301

    COU-AA-301 Study DesignPhase 3, multinational, multicenter, randomized, double-blind, placebo-controlled study (147 sites in 13 countries; USA, Europe, Australia, Canada)de Bono et al. N Engl J Med 2011; 346(21): 1995-2005

    V2.0COU-AA-301

    Overall Survival Interim Analysisde Bono et al. N Engl J Med 2011; 346(21): 1995-2005

    V2.0COU-AA-301

    Updated Overall Survival Data

    V2.0COU-AA-301

    Updated Analysis (775 Events): OS Benefit of AA Increased From 3.9 to 4.6 MonthsMedian duration of follow-up: 20.2 monthsMedian duration of treatment: 8 months with AA vs. 4 months with placeboFizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

    V2.0COU-AA-301

    Survival Benefit Observed With AA Is Consistent for Majority of SubgroupsFizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

    V2.0COU-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 SizeMedian OS AA vs. Placebo ECOG 0-1: 17 vs. 12.3 months (HR=0.74; 95% CI: 0.63-0.86)ECOG 2: 7.3 vs. 7 months (HR=0.77; 95% CI: 0.50-1.17)Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

    V2.0COU-AA-301

    Survival Benefit Observed With AA for Subgroups With and Without Pain at Study EntryMedian OS AA vs. PlaceboPain absent: 18.4 vs. 13.9 months (HR=0.69; 95% CI: 0.56-0.85)Pain present: 13.3 vs. 9.3 months (HR=0.78; 95% CI: 0.63-0.96)

    Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

    V2.0COU-AA-301

    Survival Benefit Observed With AA for Subgroups with 1 or 2 Prior Lines of Chemotherapy at Study EntryMedian OS AA vs. Placebo 1 prior line of chemotherapy: 17.1 vs. 11.7 months (HR=0.71; 95% CI:0.59-0.85)2 prior lines of chemotherapy: 14.2 vs. 10.4 months (HR=0.80; 95% CI: 0.61-1.03)

    Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

    V2.0COU-AA-301

    Survival Benefit Observed With AA for Subgroups With PSA Progression Only or Radiographic Progression at Study EntryMedian OS AA vs. Placebo: PSA only: 18.3 vs. 13.6 months (HR=0.63; 95% CI: 0.47-0.84)Radiographic: 14.8 vs. 10.5 months (HR=0.78; 95% CI: 0.65-0.93)Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

    V2.0COU-AA-301

    Survival Benefit Observed With AA Across All Age GroupsMedian OS AA vs. Placebo: < 65 years: 15.0 vs. 11.2 months (HR=0.69; 95% CI: 0.53-0.91) 65 years: 16.2 vs. 11.1 months (HR=0.76; 95% CI: 0.63-0.90) 75 years: 15.6 vs. 9.3 months (HR=0.64; 95% CI: 0.48-0.85)

    Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

    V2.0COU-AA-301

    Survival Benefit Observed With AA for Subgroups With and Without Visceral Disease at Study EntryMedian OS AA vs. Placebo: Without visceral disease: 17.1 vs. 12.3 months (HR = 0.69; 95% CI: 0.58-0.82)With visceral disease: 12.9 vs. 8.3 months (HR = 0.79; 95% CI: 0.59-1.05)Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

    V2.0COU-AA-301

    Radiographic PFS and Time to PSA Progression Favored AAFizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

    V2.0COU-AA-301

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

    AA (n = 797)Placebo (n = 398)HR 95% CIP ValueTTPP (months)10.2 6.6 0.58(0.46, 0.73) < 0.001rPFS (months)5.6 3.6 0.67(0.58, 0.78)< 0.001PSA response rateTotal 38.0%10.1%-< 0.001Confirmed29.1%5.5%-< 0.001Objective response (RECIST)14.0%2.8%-< 0.001

    V2.0COU-AA-301

    Summary of AEsde Bono et al. Ann Oncol 2010: Abstract LBA5 (Oral presentation at ESMO)

    AA (n = 791)Placebo (n = 394)All GradesGrades 3/4All GradesGrades 3/4All 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 dose10.5%13.2%Underlying disease7.5%9.9%Other specified cause2.9%3.3%

    V2.0COU-AA-301

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

    AA (n = 791)Placebo (n = 394)All GradesGrade 3Grade 4All GradesGrade 3Grade 4Fluid retention and edema31%2%

  • Cncer de Prstata Andrognio Resistente

    Da Literatura para o Campo de Batalha

  • Estratgia Teraputica CPAI

    Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-andrognio (retirada) Anti-andrognioAnlogo LHRHQuimioterapia

  • Dediferenciao Tumoral ~ Ca Pequenas Clulas PSA baixo com alto volume de doena Comprometimento visceral no-sseo Sintomas constitucionais relevantes Altos valores de DHL Gleason 8-9

    Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-andrognio (retirada) Anti-andrognioAnlogo LHRHQuimioterapiaEstratgia Teraputica CPAI

  • Dediferenciao Tumoral ~ Ca Pequenas Clulas PSA baixo com alto volume de doena Comprometimento visceral no-sseo Sintomas constitucionais relevantes Altos valores de DHL Gleason 8-9

    Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-andrognio (retirada) Anti-andrognioAnlogo LHRHQuimioterapiaEstratgia Teraputica CPAIAbiraterona

  • Dediferenciao Tumoral ~ Ca Pequenas Clulas PSA baixo com alto volume de doena Comprometimento visceral no-sseo Sintomas constitucionais relevantes Altos valores de DHL Gleason 8-9

    Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-andrognio (retirada) Anti-andrognioAnlogo LHRHQuimioterapiaEstratgia Teraputica CPAIAbiraterona

  • QuimioterapiaDediferenciao Tumoral ~ Ca Pequenas Clulas PSA baixo com alto volume de doena Comprometimento visceral no-sseo Sintomas constitucionais relevantes Altos valores de DHL Gleason 8-9Anlogo LHRHEstratgia Teraputica CPAI

    Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-andrognio (retirada) Anti-andrognioAbiraterona

  • Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-andrognio (retirada) Anti-andrognioQuimioterapiaDediferenciao Tumoral ~ Ca Pequenas Clulas PSA baixo com alto volume de doena Comprometimento visceral no-sseo Sintomas constitucionais relevantes Altos valores de DHL Gleason 8-9Anlogo LHRHEstratgia Teraputica CPAISintomas KPSMitoxantrona-PrednisonaDocetaxel-Prednisona

  • Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-andrognio (retirada) Anti-andrognioQuimioterapiaDediferenciao Tumoral ~ Ca Pequenas Clulas PSA baixo com alto volume de doena Comprometimento visceral no-sseo Sintomas constitucionais relevantes Altos valores de DHL Gleason 8-9Anlogo LHRHEstratgia Teraputica CPAISintomas KPSMitoxantrona-PrednisonaDocetaxel-PrednisonaRadiofrmacoAbirateronaCabazitaxel

  • Sintomas sseos RelevantesSintomas Constitucionais Relevantes

    Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-andrognio (retirada) Anti-andrognioAnlogo LHRHQuimioterapiaEstratgia Teraputica CPAI

  • Sintomas sseos RelevantesSintomas Constitucionais Relevantes

    Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-andrognio (retirada) Anti-andrognioAnlogo LHRHQuimioterapiaEstratgia Teraputica CPAIAbiraterona

  • Sintomas sseos RelevantesSintomas Constitucionais Relevantes

    Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-andrognio (retirada) Anti-andrognioAnlogo LHRHQuimioterapiaEstratgia Teraputica CPAIAbiraterona

  • Sintomas sseos RelevantesSintomas Constitucionais RelevantesEstratgia Teraputica CPAIQuimioterapiaAnlogo LHRH

    Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-andrognio (retirada) Anti-andrognioAbiraterona

  • Sintomas sseos RelevantesSintomas Constitucionais RelevantesEstratgia Teraputica CPAIQuimioterapiaAnlogo LHRHSintomas KPSMitoxantrona-PrednisonaDocetaxel-Prednisona

  • Sintomas sseos RelevantesSintomas Constitucionais RelevantesEstratgia Teraputica CPAIQuimioterapiaAnlogo LHRHSintomas KPSMitoxantrona-PrednisonaDocetaxel-PrednisonaZolendronato

  • Sintomas sseos RelevantesSintomas Constitucionais RelevantesEstratgia Teraputica CPAIQuimioterapiaAnlogo LHRHSintomas KPSMitoxantrona-PrednisonaDocetaxel-PrednisonaZolendronatoRadiofrmaco

  • Sintomas sseos RelevantesSintomas Constitucionais RelevantesEstratgia Teraputica CPAIQuimioterapiaAnlogo LHRHSintomas KPSMitoxantrona-PrednisonaDocetaxel-PrednisonaZolendronatoNomograma

  • Sintomas sseos RelevantesSintomas Constitucionais RelevantesEstratgia Teraputica CPAIQuimioterapiaAnlogo LHRHSintomas KPSMitoxantrona-PrednisonaDocetaxel-PrednisonaZolendronatoRadiofrmacoAbirateronaCabazitaxel

  • Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-andrognio (retirada) Anti-andrognioAnlogo LHRHQuimioterapiaEstratgia Teraputica CPAIAusncia de sintomasDoena ssea muito extensa !

  • Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-andrognio (retirada) Anti-andrognioAnlogo LHRHQuimioterapiaEstratgia Teraputica CPAIAusncia de sintomasDoena ssea muito extensa !Abiraterona

  • Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-andrognio (retirada) Anti-andrognioAnlogo LHRHQuimioterapiaEstratgia Teraputica CPAIAusncia de sintomasDoena ssea muito extensa !Abiraterona

  • Cetoconazol + Predn. Dexametasona Dietilbestrol Anti-andrognio (retirada) Anti-andrognioAnlogo LHRHEstratgia Teraputica CPAIAusncia de sintomasDoena ssea muito extensa !QuimioterapiaAbiraterona

  • Anlogo LHRHEstratgia Teraputica CPAIAusncia de sintomasDoena ssea muito extensa !QuimioterapiaSintomas KPSMitoxantrona-PrednisonaDocetaxel-Prednisona

  • Anlogo LHRHEstratgia Teraputica CPAIAusncia de sintomasDoena ssea muito extensa !QuimioterapiaSintomas KPSMitoxantrona-PrednisonaDocetaxel-PrednisonaZolendronato

  • Anlogo LHRHEstratgia Teraputica CPAIAusncia de sintomasDoena ssea muito extensa !QuimioterapiaSintomas KPSMitoxantrona-PrednisonaDocetaxel-PrednisonaZolendronato

  • Anlogo LHRHEstratgia Teraputica CPAIAusncia de sintomasDoena ssea muito extensa !QuimioterapiaSintomas KPSMitoxantrona-PrednisonaDocetaxel-PrednisonaZolendronatoAbirateronaCabazitaxel

  • Cncer de Prstata Andrognio Resistente aps Falha a Quimioterapia

    Novos Agentes e Novos Resultados

  • 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. Foss,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, Queens 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

  • DisclosuresC. Parker has served in a consultant or advisory role for Algeta ASA (uncompensated) and BayerD. Heinrich and O. Sartor have served in consultant or advisory roles for Algeta ASAB. Bolstad has an ownership interest in and was employed by Algeta ASA until December 2010J. Garcia-Vargas is an employee of Bayer HealthCare PharmaceuticalsJ.M. OSullivan, S. Foss, A. Chodacki, T. Demkow, and A. Cross have nothing to disclose

  • AcknowledgmentsAlton Oliver SartorAndres Jan SchraderJan SchramlChristopher ScraseMihalj SekeAvishay SellaSergio Vicente SerranoMark SidhomArne SolbergAnna Sowa-StaszczakJohn StaffurthAndrew StockdaleArne StraussSanthanam SundarPeter SwiftIsabel SyndikusMiah Hiang TayMichael TomblynMichel ToubeauMichael Carsten TrussPenny Vande StreekSubramaniam VasanthanHenk VergunstPaul VerhagenNicholas VogelzangWolfgang von PokrzywnitzkiSteffen Alexander WedelAnders WidmarkPawel Jan WiechnoSibylle BhmerHenry WooTsz Kok YauKwok Keung YuenRoman ZachovalRomuald ZdrojowyAnn-Sofie FranssonLars FranzenStephanie GibbsJohn GrahamAlexander HaeseChristian HampelRosemary HarrupCatherine HeathDaniel HeinrichSvein Inge HelleMilan HoraPeter HoskinGary HudesMichael JacksonNick D JamesBarbara JarzabPiotr JarzemskiDag Clement JohannessenWalter Jos KoffUnn-Miriam KastiChristian KeilJon KindblomOlbjorn KleppRobert KlijerJan KlimentLaurence KlotzIvo KocakAndrzej KolodziejczykMarkus KuczykPhilip KwongMagnus LagerlundKari Margrethe LarsenAngus LeungEugene LeungRoberto LlarenaMassimo AgliettaDino AmadoriEnrique ArandaJavier ArbizuAmit BahlVladimir BalazPilar BelloRami Ben-YosefIgnace BillietDavid BottomleyJan BrezaMichael BrownWalter CabralMicheal CanoJoan CarlesPrabir ChakrabortiPiotr ChlostaAles ChodackiRob ColemanMarian CvikDavid DalleyMarcos Dall'OglioRonaldo DamiaoMarinus de GoeijGraeme DickieSanjay DixitJesus Garcia DonasAnthony DowlingYgael DrorLionel DuckMonstserrat EstorchUrsula FalkmerDavid FeltlSophie Dorothea FossJohn LogueRafael LpezJarad MartinGavin M MarxBegoa MelladoWilmosh MermershtainCaterina MessinaJeff MichalskiAndrew MillerIvan MincikJulian Money-KyrleAlain MonnierAndre MoraesAndre MuradChee Kwan NgCarsten NiederSten NilssonJoe O'SullivanChristopher ParkerSarah PascoeSamir PatelAlain PeckingJaroslav PernickaKen PittmanFrank PriouPrakash RamachandraRobert ReidAngus RobinsonTon RoeleveldClaudio RossettiAlberto Senz-CusDiana SalvoCarlos SampaioHoward SandlerAll patients who participated in the study, and their caregiversALSYMPCA was sponsored by Algeta ASA and Bayer Healthcare Pharmaceuticals.Investigators from 19 countries:

  • Background and Rationale> 90% of patients with metastatic CRPC have radiologic evidence of bone metastases1Skeletal-related events (SREs) include spinal cord compression, pathological fracture, and need for surgery or EBRT2Bone 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;351:1502-1512.Lipton. Semin Oncol. 2010;37:S15-S29.Lange and Vasella. Cancer Metastasis Rev. 1999;17:331-336.

  • Radium-223 Targets Bone MetastasesRadium-223 acts as a calcium mimic

    Naturally targets new bone growth in and around bone metastases

    Radium-223 is excreted by the small intestine

  • Radium-223 Targets Bone MetastasesAlpha-particles induce double-strand DNA breaks in adjacent tumour cells1Short penetration of alpha emitters (2-10 cell diameters) = highly localised tumour cell killing and minimal damage to surrounding normal tissueRange of alpha-particleRadium-223Bone surface1. Perez et al. Principles and Practice of Radiation Oncology. 5th ed. Lippincott Williams & Wilkins; 2007:103.

  • Radium-223 Improved Overall Survival in the Placebo-Controlled Phase II Study in CRPCHR: 0.48; 95% CI: 0.26-0.88 P = 0.017255075100204060801000 Week0120Radium-223, n = 33Placebo, n = 31%Nilsson. Lancet Oncol. 2007;8:587-594.

    % change from baselineRadium-223PlaceboP ValuePSA24%+45% 0.003Total ALP46%+31% < 0.0001PINP63%+38% < 0.0001

    N reportedRadium-223PlaceboAEs155174SAEs1219

  • TREATMENT 6 injections at 4-week intervalsRadium-223 (50 kBq/kg) + Best standard of carePlacebo (saline) + Best standard of careN = 922PATIENTSALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) Phase III Study DesignClinicaltrials.gov identifier: NCT00699751. Total ALP: < 220 U/L vs 220 U/L Bisphosphonate use: Yes vs No Prior docetaxel: Yes vs NoSTRATIFICATION

    Planned follow-up is 3 years

  • ALSYMPCA Study EndpointsPrimary EndpointOverall survival

    Secondary EndpointsTime to first SRETime to total ALP progressionTotal ALP responseTotal ALP normalisationTime to PSA progressionSafetyQuality of life

  • ALSYMPCA Statistical DesignStatistical assumption90% powerHR = 0.760.05 two-sided alpha

    Planned Interim AnalysisFinal AnalysisEvents320640Alpha 0.003060.05

  • ALSYMPCA Planned Interim Analysis314 events from 809 patients randomised at the time of the interim analysisImprovement in OS met the predetermined boundary for stopping the trialOn June 3, 2011, the Independent Data Monitoring Committee (IDMC) recommended stopping the trial early due to evidence of a significant treatment benefit

  • ALSYMPCA Patient Demographics and Baseline Characteristics (ITT; N = 809)

    ParameterRadium-223(n = 541)Placebo(n = 268)Age, y Mean70.270.7Race, n (%) Caucasian507 (94)252 (94)Baseline ECOG score, n (%) 1 2467 (86)71 (13)229 (85)37 (14)Extent of disease, n (%) < 6 metastases 6-20 metastases > 20 metastases/superscan88 (16)235 (44)217 (40)33 (12)129 (48)106 (40)WHO ladder, cancer pain index 2, n (%)294 (54)142 (53)

  • ALSYMPCA Patient BaselineCharacteristics, cont (ITT; N = 809)

    Parameter Median (min, max)Radium-223 (n = 541)Placebo (n = 268)Haemoglobin, g/dL12.2 (8.5-15.7)12.1 (8.4-16.4)Albumin, g/L40 (24-53)40 (23-50)Total ALP, g/L213 (32-4661)224 (29-3225)LDH, U/L317 (76-2171)328 (132-3856)PSA, g/L159 (3.78-6026)195 (1.5-14500)

  • 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.

  • ALSYMPCA Overall Survival0102030405060708090100 %Radium-223, n = 541Median OS: 14.0 monthsPlacebo, n = 268Median OS: 11.2 monthsHR 0.695; 95% CI, 0.552-0.875 P = 0.00185

    Month0369121518212427Radium- 22354145033021312072301530Placebo26821814789492815730

  • ALSYMPCA Time to First Skeletal-Related Event0102030405060708090100 % Without SREHR 0.610; 95% CI, 0.461-0.807 P = 0.00046Radium-223, n = 541Median: 13.6 monthsPlacebo, n = 268Median: 8.4 months

    Month036912151821Radium-223541379214111512260Placebo268159743015720

  • *In patients who had elevated total ALP at baseline.ALSYMPCA Secondary Endpoints: ALP and PSA

    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) < 0.001

    Hazard ratio 95% CI P-valueTime to Total ALP progression0.163 (0.121 0.221) < 0.00001 Time to PSA progression 0.671 (0.546 0.826) 0.00015

  • Survival Benefit Across Patient Subgroups

  • ALSYMPCA Summary of Patients With Adverse Events: Safety Population* (N = 762)*Patients who received at least 1 injection.

    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)

  • ALSYMPCA Adverse Events of Interest

    All GradesGrades 3 or 4Radium-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)

  • ConclusionsIn CRPC patients with bone metastases:Radium-223 significantly prolonged OSP value = 0.00185; HR = 0.695; 95% CI, 0.552-0.875Radium-223 significantly prolonged time to first SREP value = 0.00046; HR = 0.610; 95% CI, 0.461-0.807Radium-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

  • 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

    ASCO June 2012

  • Financial DisclosuresEnzalutamide is being co-developed by Medivation, Inc. and AstellasPortions of this presentation were previously presented at ASCO-GU 2012u, uncompensated

    *ASCO June 2012

    J de BonoMedivation, Astellas, J&JH Scher Medivation (u), J&J, Aragon (u), Millenium P Mulders Astellas, GSK, AstraZeneca, PfizerK FizaziMedivation, Astellas, J&J, Amgen, Sanofi AventisF Saad Medivation, Astellas, J&J, Sanofi AventisME Taplin Medivation, J&J, Sanofi Aventis, TokaiC Sternberg J&J, Astellas, Sanofi-AventisK Miller Medivation, AstellasM Hirmand Medivation employeeB SelbyMedivation employeeA ArmstrongMedivation, J&J, sanofi-aventis, Amgen, Dendreon, Active Biotech/IpsenK Chi

    ASCO June 2012

  • 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.EnzalutamideTTCell nucleusInhibits Binding of Androgens to ARInhibits Nuclear Translocation of ARInhibits AssociationOf AR with DNACell cytoplasmTran et al. Science 2009;324:78790. *ASCO June 2012

    ASCO June 2012

  • AFFIRM: Enzalutamide vs Placebo in Post-Chemotherapy Castration-Resistant Prostate Cancer (CRPC)**Glucocorticoids were allowed but not required*ASCO June 2012*Stratification variables:ECOG Performance Status (0-1, 2)Mean Brief Pain Inventory Q#3 Score (
  • AFFIRM Study Design

    Enrollment:156 centersN. America, Europe, Australia, S. America, and S. AfricaSeptember 2009 through November 2010Statistical Design:Cumulative alpha, 0.05, 2-sidedPower: 90% to detect a 24% reduction in mortality (Target HR = 0.76)One planned interim analysis at 520 events

    *ASCO June 2012

    ASCO June 2012

  • Secondary Efficacy EndpointsResponse IndicatorsPSA ResponseSoft Tissue Objective ResponseFACT-P Quality of Life ResponsePain Palliation Circulating Tumor CellsProgression IndicatorsTime to PSA ProgressionRadiographic Progression-free SurvivalTime to First Skeletal-Related Event *ASCO June 2012

    ASCO June 2012

  • Prior Hormonal and Chemotherapy Treatments*ASCO June 2012

    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 1 2 372.4%24.5% 3.1%74.2%23.8% 2.0%Median Number of Prior Docetaxel Cycles8.58.0

    ASCO June 2012

  • Baseline Patient Characteristics*ASCO June 2012

    Enzalutamide(n = 800)Placebo (n = 399)Age (median in yrs, range)69 (4192)69 (4989)ECOG Performance Status - 2 8.8%8.0%Mean Brief Pain Inventory Score 4 on Question 328.3%28.8%Bone Disease91.3%91.2%Soft Tissue Disease 70.9%68.9% Visceral Liver11.6%8.5% Visceral Lung15.4%14.8%

    ASCO June 2012

  • Enzalutamide Prolonged Survival, Reducing Risk of DeathHR = 0.631 (0.529, 0.752) P
  • Survival Benefit Seen Across All Subgroups*Based on data analysis cutoff date for the planned interim analysis.Overall Survival median (mo)Enzalutamide / PlaceboHazard Ratio for Death(95% CI)Favors Enzalutamide*Favors Placebo**ASCO June 2012

    ASCO June 2012

  • Patients on Remained on Enzalutamide Longer than on PlaceboMedian duration of follow up was 14.4 months *ASCO June 2012

    EnzalutamidePlaceboPatients treated (n)800399Median duration of treatment (months)8.33.0Treatment ongoing (%)28.94.8

    ASCO June 2012

  • Enzalutamide had a high PSA Response Rate *ASCO June 2012EnzalutamidePlaceboBest PSA Response90% confirmed response rates:Enza 25%; Placebo 1% (p
  • **Enzalutamide Delayed Time to PSA Progression by a Median of 5.3 Months HR = 0.248 P
  • Enzalutamide RECIST Response Rate *ASCO June 2012Response categories defined by RECIST 1.1ASCO June 2012

    ResponseEnzalutamidePlaceboP-valueObjective Response (CR +PR)28.9%3.8%< 0.0001Best Overall Response for Study Complete response (CR)3.8%1.0% Partial response (PR)25.1%2.9% Stable disease39.2%29.3%

    ASCO June 2012

  • *Enzalutamide Prolonged Duration of rPFS by a Median of 5.4 MonthsrPFS defined by RECIST 1.1 for soft tissue and PCGW2 for bone diseaseASCO June 2012rProgression Free Survival, %

    Enzalutamide800583447287140581310Placebo3991768646207300

    ASCO June 2012

  • Enzalutamide Prolonged Time to First SRE by a Median of 3.4 MonthsHR = 0.621 P
  • Enzalutamide Improved Quality-of-Life Response as Measured by FACT-PASCO June 2012********^* p
  • Summary of Adverse Events* AEs graded for severity with grades 1 and 2 being milder and grades 3-5 being more severe*ASCO June 2012

    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 AEs7.6%9.8%4.6%7.0%AEs leading to death2.9%3.5%2.9%3.5%

    ASCO June 2012

  • Adverse Events of Special Interest*Includes terms hyperbilirubinaemia, AST increased, ALT increased, LFT abnormal, transaminases increased, and blood bilirubin increased.*ASCO June 2012

    All GradesGrade 3 EventsEnzalutamide(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 Infarction0.3%0.5%0.3%0.5%LFT Abnormalities*1.0%1.5%0.4%0.8%Seizure0.6%0.0%0.6%0.0%

    ASCO June 2012

  • Overall Survival Benefit in Recent CRPC Trials** Only 60% of these patients were post-docetaxel patients ASCO June 2012

    Trial/Agent/ Date ApprovedMechanismComparatorSurvival(months)Hazard RatioP-valueAFFIRMEnzalutamide Androgen Receptor Signaling InhibitorPlacebo18.4 vs. 13.60.631

  • A Large Proportion of Patients Received Post-Trial Anticancer Therapy*ASCO June 2012

    Enzalutamide(n = 800)Placebo (n = 399)Patients with 1 post-treatment anticancer therapy41.1%58.4%Most common post-protocol treatmentAbiraterone20.9% 24.3% Cabazitaxel9.8%13.8%Docetaxel8.5%14.3%Mitoxantrone2.6%11.0%

    ASCO June 2012

  • ConclusionsEnzalutamide, 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 nave patients.*ASCO June 2012

    ASCO June 2012

  • Cncer de Prstata Andrognio Resistente

    O passado

  • Cncer de Prstata Andrognio Resistente

    O passadoO presente

  • Cncer de Prstata Andrognio Resistente

    O passadoO presenteO futuro

  • * 40% dos pacientes no haviam recebido docetaxelAgentes Relacionados a Ganho de SG no Cncer de Prstata Resistente a HT Pr Docetaxel

    Estudo/Data de AprovaoMecanismoComparaoSobrevida (meses)P ValueSipuleucel T 2009Imunoterapia (PAP-GMCSF)Placebo 25.8 vs 21.7 0.03COU-AA-302 Abiraterona + Prednisona 2011Inibidor CYP17 Placebo + PrednisonaNA vs 27.20.009Alfaradin 2011*Radiofrmaco emissor de partcula alfaPlacebo14.9 vs 11.3 0.0018

  • * Somente 60% dos pacientes haviam recebido docetaxelAgentes Relacionados a Ganho de SG no Cncer de Prstata Resistente a HT e com Falha a Docetaxel

    Estudo/Data de AprovaoMecanismoComparaoSobrevida (meses)P ValueAFFIRM Enzalutamida 2012Inibidor do Sinal do Receptor de Andrgeno Placebo 18.4 vs 13.6 < 0.0001COU-AA-301 Abiraterona + Prednisona 2011Inibidor CYP17 Placebo + Prednisona14.8 vs 10.9< 0.0001TROPIC Cabazitaxel 20102Inibidor do microtbuloMitoxantrona + Prednisona15.1 vs 12.7< 0.0001Alfaradin 2011 *Radiofrmaco emissor de partcula alfaPlacebo14.9 vs 11.3 0.0018

  • Ganho de Sobrevida em Cncer de Prstata Resistente a CastraoPonto de largada

  • Ganho de Sobrevida em Cncer de Prstata Resistente a CastraoPonto de largadaDocetaxel(2.9 m)

  • Ganho de Sobrevida em Cncer de Prstata Resistente a CastraoPonto de largadaDocetaxel(2.9 m)Sipuleucel T(4.1 m)

  • Ganho de Sobrevida em Cncer de Prstata Resistente a CastraoPonto de largadaDocetaxel(2.9 m)Sipuleucel T(4.1 m)Alfaradin(3.6m)

  • Ganho de Sobrevida em Cncer de Prstata Resistente a CastraoPonto de largadaDocetaxel(2.9 m)Sipuleucel T(4.1 m)Alfaradin(3.6m)Cabazitaxel (2.4 m)

  • Ganho de Sobrevida em Cncer de Prstata Resistente a CastraoPonto de largadaDocetaxel(2.9 m)Sipuleucel T(4.1 m)Alfaradin(3.6m)Cabazitaxel (2.4 m)

    Ponto de largadaAbiraterona (4.6 m)

  • Ganho de Sobrevida em Cncer de Prstata Resistente a CastraoPonto de largadaDocetaxel(2.9 m)Sipuleucel T(4.1 m)Alfaradin(3.6m)Cabazitaxel (2.4 m)

    Ponto de largadaAbiraterona (4.6 m)

    Enzalutamida (4.8 m)

  • Ganho de Sobrevida em Cncer de Prstata Resistente a CastraoPonto de largadaDocetaxel(2.9 m)Sipuleucel T(4.1 m)Alfaradin(3.6m)Cabazitaxel (2.4 m)

    Ponto de largadaAbiraterona (4.6 m)

    Enzalutamida (4.8 m)

    Ganho: 22.4 m (km)

  • Ganho de Sobrevida em Cncer de Prstata Resistente a CastraoPonto de largadaDocetaxel(2.9 m)Sipuleucel T(4.1 m)Alfaradin(3.6m)Cabazitaxel (2.4 m)

    Ponto de largadaAbiraterona (4.6 m)

    Enzalutamida (4.8 m)

    Alfaradin(3.6m) Nunca em um tumor slido houve tantas drogas aprovadas em um dcada

  • Ganho de Sobrevida em Cncer de Prstata Resistente a CastraoPonto de largadaDocetaxel(2.9 m)Sipuleucel T(4.1 m)Alfaradin(3.6m)Cabazitaxel (2.4 m)

    Ponto de largadaAbiraterona (4.6 m)

    Enzalutamida (4.8 m)

    Alfaradin(3.6m) E pela primeira vez.....

  • Ganho de Sobrevida em Cncer de Prstata Resistente a CastraoPonto de largadaDocetaxel(2.9 m)Sipuleucel T(4.1 m)Alfaradin(3.6m)Cabazitaxel (2.4 m)

    Ponto de largadaAbiraterona (4.6 m)

    Enzalutamida (4.8 m)

    Antes de 2004

  • Ganho de Sobrevida em Cncer de Prstata Resistente a CastraoPonto de largadaDocetaxel(2.9 m)Sipuleucel T(4.1 m)Alfaradin(3.6m)Cabazitaxel (2.4 m)

    Ponto de largadaAbiraterona (4.6 m)

    Enzalutamida (4.8 m)

    Antes de 2004Enzalutamida (4.8 m)

    Maior longevidade e Melhor qualidade de vida 2012 !

  • Obrigado

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    *********12*TROPIC slide deck. Slide6,10,13*TROPIC slide deck. Slide24*TROPIC slide deck. Slide21*TROPIC slide deck. Slide22*TROPIC slide deck. Slide24,25,26*TROPIC slide deck. Slide34A Abiraterona foi recentemente aprovada pelo FDA para tratamento de pacientes com cncer de prstata refratrios a castrao.

    A Abiraterona e o Orteronel (ou TAK-700) so inibidores da CYP-17 e bloqueiam a produo de andrognios na adrenal. A CYP-17 responsvel pela converso de pregnenolona e progesterona em DHEA e androstenediona, e consequentemente testosterona e DHT. No entando, devido reduo de cortisol, ocorre um aumento da produo de ACTH na hipfise e esta hiper-estimulao acaba levando a aumento da produo de aldosterona, ocasionando um hiper-aldosteronismo. Devido a este fato que os pacientes so tambm tradados com Prednisona quando esto recebendo Abiraterona.A Abiraterona foi recentemente aprovada pelo FDA para tratamento de pacientes com cncer de prstata refratrios a castrao.

    A Abiraterona e o Orteronel (ou TAK-700) so inibidores da CYP-17 e bloqueiam a produo de andrognios na adrenal. A CYP-17 responsvel pela converso de pregnenolona e progesterona em DHEA e androstenediona, e consequentemente testosterona e DHT. No entando, devido reduo de cortisol, ocorre um aumento da produo de ACTH na hipfise e esta hiper-estimulao acaba levando a aumento da produo de aldosterona, ocasionando um hiper-aldosteronismo. Devido a este fato que os pacientes so tambm tradados com Prednisona quando esto recebendo Abiraterona.**Overall survival was 14.8 months in the abiraterone acetate (AA) + prednisone (P) group and 10.9 months in the placebo + P groupTreatment with AA + P resulted in a 35.4% reduction in the risk of death compared with placebo + P (HR = 0.646; 95% CI, 0.543-0.768; P < 0.0001)**********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.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 placeboShown 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 studyNot shown: The cumulative proportion of patients with a change (vs baseline) in pain intensity was consistently in favor of AA. (See backup slide.) 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 patients perception of support from family and friends)

    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.**********Change Y axis to rPFS***