Actualización de la evidencia científica de Abiraterona en Prequimioterapia Joan Carles Jefe de Sección Director del Programa de GU, SNC y Sarcomas Hospital Universitario Vall d’Hebron Barcelona

HISTORIA NATURAL DEL CÁNCER DE PRÓSTATA Desde el punto de vista del tratamiento hormonal existen dos tipos de pacientes: Cáncer de próstata sensible a terapia hormonal Cáncer de próstata resistente a la castración ASINTOMÁTICO No metástasis Terapia local Deprivación de andrógenos Quimioterapia Postquimioterapia Death Sensible a la castración Resistente a la castración Sintomático Metástasis

GUIAS CLÍNICAS EUA 2010

OPCIONES TERAPÉUTICAS DE SEGUNDA LÍNEA La abstención terapéutica La supresión de Antiandrógeno La adición de otro Antiandrógeno Los compuestos con actividad Estrogénica Corticoides Los agentes Adrenolíticos ó inhibidores de CYP 17

RETIRADA DEL ANTIANDRÓGENO Ensayo Prospectivo de 210 enfermos 21% RO por PSA 0% RO radiológicas SLP 3 meses mSLP a 12 meses del 19% Sartor et al Cancer 2008;112:2393-2400

BJU Inter. 2012;110:E826-29

En pacientes CPRC sintomáticos el CONCLUSIÓN En pacientes CPRC sintomáticos el tratamiento con prednisona es similar a flutamida per con mejor calidad de vida Fosså S D et al. JCO 2001;19:62-71

CYP17 y síntesis de andrógenos CYP 17: codificado en cromosoma 10 (q24.3) Retículo Endoplasmático testículo-células de Leydig teca interna del ovario suprarrenal (zona fascicular y reticular) Cataliza dos reacciones Esteroideas 17α- Hidroxilasa 17-20 Liasa Haider SM et al. Molecular modeling on inhibitor complexes and active-site dynamics of cytochrome P450 C17, a target for prostate cancer therapy. J Mol Biol 2010;400(5):1078-98.

PERSISTENCIA DE ANDRÓGENOS A PESAR DE LA DEPRIVACIÓN ANDROGÉNICA Mostaghel et al. Urol Oncol 2009;27(3):251-7

¿Cómo se consigue el aumento de síntesis de andrógenos Intratumoral? Fuente de andrógenos Intratumoral Expresión enzimática de las principales enzimas esteroidogénicas en CPRC frente a tumor primario

RAA vs RAA + Ketoconazol 260 pacientes, Cáncer de próstata en progresión a BAC: Retirada de antiandrógeno + Ketoconazol -Prednisona Retirada de antiandrógeno Ketoconazol - Prednisona Cortesía Dr Cassinello Small et al. JCO 2004, 22: 1025-33

Supervivencia libre de enfermedad Supervivencia global PSA RR TTP PSA OR mOS RAA 11% 5.9 2% 15.3 RAA + KETO 27% 8.6 20% 16.7 La toxicidad no es baladí con ketoconazol Small et al. JCO 2004

TRATAMIENTO HORMONAL DE SEGUNDA LÍNEA % Respuestas Duración Retirada de antiandrógeno 20-35% 3-5 meses Flutamida 34-54% Bicalutamida altas dosis 20-24% Nilutamida 29-50% 11 meses Acetato de megestrol 8-12% Corticoides a bajas dosis 18-22% Aminoglutetimida 37% Ketoconazol 27-63% Estrogenos (DES) 26-66% NO MEJORIA DE LA SUPERVIVENCIA

Supervivencia en el CPRC según la intensidad del dolor Oudard S, et al. BJUI 2009

NOMOGRAMA 2014 Halabi S et al. JCO 2014;32:671-677

(A, B) Kaplan-Meier survival curves for the two risk groups in the testing and validation sets. (A, B) Kaplan-Meier survival curves for the two risk groups in the testing and validation sets. (C, D) Kaplan-Meier survival curves for the three risk groups in the testing and validation sets. Halabi S et al. JCO 2014;32:671-677

Survival distribution by the training, testing, and validation data sets. Halabi S et al. JCO 2014;32:671-677

Five New Agents with OS Benefits Approved Since Study Initiation Abiraterone acetate (Chemo-naïve-302) EU approvals Enzalutamide (Post-chemo) Abiraterone acetatea (Post-chemo-301) Sipuleucel-T Cabazitaxel Docetaxel Radium-223 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 Sipuleucel-T Enzalutamide (Chemo-naive) Docetaxel Cabazitaxel Abiraterone acetate (Post-chemo-301) Radium-223 Abiraterone acetate (Chemo-naïve-302) US approvals Enzalutamide (Post-chemo) aHereafter referred to as abiraterone FPI, first patient in; LPI, last patient in. 19

GUIAS CLÍNICAS EUA 2014

N .Eng J Med. 2013;368:138-48

Deoxy-corticosterona Abiraterona: Mecanismo de acción Colesterol ACTH Feedback positivo Hipopotasemia Hipertensión Retención de líquidos Desmolasa Renina Deoxy-corticosterona Pregnenolona Progesterona Corticosterona Aldosterona 17α-hydroxylasa 11β-Hydroxylase Abiraterona bloquea la producción de andrógenos, incluyendo la testosterona y DHT, a través de la inhibición selectiva y potente de la actividad enzimática de CYP171,2 17α-OH-pregnenolona 17α –OH-progesterona 11-Deoxy-cortisol Cortisol C17,20-lyasa 5α-reductasa DHEA Androstenediona Testosterona DHT CYP19: aromatasa Estradiol Ang JE, et al. Br J Cancer. 2009;100:671-675. Attard G, et al. J Clin Oncol. 2008;26:4563-4571.

Abiraterona: Mecanismo de acción Colesterol Desmolasa Renina Deoxy-corticosterona Pregnenolona Progesterona Corticosterona Aldosterona 17α-hydroxylasa 11β-Hydroxylase Prednisona 17α-OH-pregnenolona 17α –OH-progesterona 11-Deoxy-cortisol Cortisol ACTH C17,20-lyasa 5α-reductasa DHEA Androstenediona Testosterona DHT CYP19: aromatasa Estradiol Ang JE, et al. Br J Cancer. 2009;100:671-675. Attard G, et al. J Clin Oncol. 2008;26:4563-4571.

Final Overall Survival Analysis of COU-AA-302, a Randomized Phase 3 Study of Abiraterone Acetate in Metastatic Castration-Resistant Prostate Cancer Patients Without Prior Chemotherapy CJ Ryan,1 MR Smith,2 K Fizazi,3 K Miller,4 PFA Mulders,5 CN Sternberg,6 F Saad,7 T Griffin,8 EJ Small1, P De Porre,9 YC Park,10 J Li,10 T Kheoh,8 V Naini,8 A Molina,11 and DE Rathkopf12 1Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA; 2Harvard Medical School and Massachusetts General Hospital, Boston, MA, USA; 3Institut Gustave Roussy, University of Paris Sud, Villejuif, France; 4Department of Urology, Charité Berlin, Berlin, Germany; 5Radboud University Medical Centre, Nijmegen, The Netherlands; 6San Camillo and Forlanini Hospitals, Rome, Italy; 7University of Montréal, Montréal, QC, Canada; 8Janssen Research & Development, Los Angeles, CA, USA; 9Janssen Research & Development, Beerse, Belgium; 10Janssen Research & Development, Raritan, NJ, USA; 11Janssen Research & Development, Menlo Park, CA, USA; 12Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA

Ryan CJ, et al. Lancet Oncol. 2015 Jan 15. [Epub ahead of print]

Purpose of the Current Analysis To report prespecified final analysis of COU-AA-302 in chemotherapy-naïve mCRPC patients, including: Full evolution of OS Overall clinical benefit Long-term safety data . mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival.

Five New Agents with OS Benefits Approved Since Study Initiation Abiraterone acetate (Chemo-naïve-302) EU approvals Enzalutamide (Post-chemo) Abiraterone acetatea (Post-chemo-301) Sipuleucel-T Cabazitaxel Docetaxel Radium-223 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 Sipuleucel-T Enzalutamide (Chemo-naive) Docetaxel Cabazitaxel Abiraterone acetate (Post-chemo-301) Radium-223 Abiraterone acetate (Chemo-naïve-302) US approvals Enzalutamide (Post-chemo) aHereafter referred to as abiraterone FPI LPI COU-AA-302 FPI, first patient in; LPI, last patient in. 29

Challenges in Demonstrating OS Benefit in mCRPC Trials Multiple new treatments available with proven OS benefit Sequential use of 2 or more of these treatments common Chronicity and heterogeneity of mCRPC treatment sequencing may confound ability to measure OS benefit Requires larger and longer clinical studies

without prior chemotherapy; COU-AA-302: Study Design R A N D O M I Z E D 1:1a Patient Population Co-primary end points: rPFS (central review) OS Abiraterone 1000 mg daily + Prednisone 5 mg BID (actual n = 546) Progressive mCRPC without prior chemotherapy; Asymptomatic or mildly symptomatic Secondary end points: Time to opiate use Time to initiation of chemotherapy Time to ECOG PS deterioration Time to PSA progression Placebo daily + Prednisone 5 mg BID (actual n = 542) aStratification by ECOG PS 0 vs 1. IA3 Slide 7: With these factors in consideration, the design and timing of the 302 study are shown here. Eligible patients were required to have metastatic castration resistant prostate cancer and to be free of disease related symptoms that led to a requirement for opiate analgesic therapies. 1088 PATIENTS WERE randomized in a 1:1 fashion to receive abiraterone at a dose of 1000 mg daily with concurrent prednisone, 5 mg twice daily, or placebo plus prednisone. The study was powered to measure two Co-primary endpoints: radiographic progression free survival and Overall survival. ….As well as a variety of clinically relevant secondary endpoints – time to opiate use, time to the initiation of chemotherapy, performance status decline, as well as time to psa progression. The first patient entered the trial on APRIL 20 2009 and the last patient was randomized on APRIL 16 2010. The study was unblinded upon the recommendation of the independent data safety monitoring committee after the second interim analysis based on the significant difference in rPFS, as well as an emerging trend in OS favoring treatment with abiraterone. The current analysis incorporates survival and other data following the OBSERVATION OF 741 DEATHS, which represents 96 % of the deaths required for the completion of the final statistical analysis. Unblinding IA1 IA2 FPI LPI FA 2008 2009 2010 2011 2012 2013 2014 Final analysis: 96% of expected deaths, 741 actual deaths BID, twice daily; rPFS, radiographic progression-free survival; ECOG PS, Eastern Cooperative Oncology Group performance status; FA, final analysis; IA, interim analysis; PSA, prostate-specific antigen.

Treatment Arms Were Well Balanced at Baseline Abiraterone (n = 546) Prednisone (n = 542) Median age, years (range) 71 (44-95) 70 (44-90) Median time from initial diagnosis to first dose (years) 5.5 5.1 Median PSA (ng/mL) 42.0 37.7 Gleason score (≥ 8) at initial diagnosis 54% 50% Extent of disease Bone metastases 83% 80% > 10 bone metastases 49% 47% Soft tissuea Pain (BPI-SF) 0-1 66% 64% 2-3 32% 33% aExcludes visceral metastases. BPI-SF, Brief Pain Inventory-Short Form (scale 0-10).

Time to All Landmarks Significantly Improved With Abiraterone Secondary Endpoints Pain PSA Progression Tumor/Bone Progression ECOG PS Decline Death Baseline Chemotherapy Primary Endpoints: rPFS and OS Median Follow-Up of > 4 Years ECOG PS = Eastern Cooperative Oncology Group Performance Status. Adapted from Halabi S, J Clin Oncol 2009;27: 2766-2771.

Abiraterone Doubled Time to rPFS1 100 HR (95% CI): 0.52 (0.45-0.61) p Value: < 0.0001 80 Abiraterone, 16.5 mos 60 Progression-Free Survival (%) 40 Prednisone, 8.2 mos 20 3 6 9 12 15 18 21 24 27 30 33 36 Time to Progression or Death (Months) Abiraterone Prednisone 546 542 485 406 389 244 311 176 240 133 195 99 157 78 131 62 117 45 66 20 20 7 4 Third interim analysis data. rPFS assessed by investigator review at prespecified IA. Rathkopf DE, et al. Eur Urol. 2014 March 6 [Epub ahead of print].

Most Patients Discontinued Due to Progression Abiraterone (n = 542) Prednisone (n = 540) Median duration of follow-up 49.2 months Median no. of cycles of therapy, range 15.0 (1-62) 9.0 (1-54) Treatment discontinued 92.3% 100% Reasons for discontinuation Progression 68% 69% Radiographic only 30% 32% Unequivocal clinical onlya 26% Radiographic and clinical 13% 10% Adverse event 9% 6% Withdrew consent 8% Other aUnequivocal clinical progression is 1 or more of the following: pain requiring opiates, chemotherapy, palliative radiation therapy, decline in ECOG PS, surgical intervention. Ryan CJ, et al. Lancet Oncol. 2015 Jan 15. [Epub ahead of print]

Final OS Analysis Median follow-up of 49.2 mos 100 HR (95% CI): 0.81 (0.70-0.93) p Value: 0.0033 80 Abiraterone, 34.7 mos 60 Overall Survival (%) 40 Prednisone, 30.3 mos 20 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 Time to Death (Months) Abiraterone Prednisone 546 542 538 534 525 509 504 493 483 466 453 438 422 401 394 363 359 322 330 292 296 261 273 227 235 201 218 176 202 148 189 132 118 84 59 42 15 10 1 Median follow-up of 49.2 mos Abiraterone treatment effect more pronounced when adjusting for 44% of prednisone patients who received subsequent abiraterone (HR = 0.74) Ryan CJ, et al. Lancet Oncol. 2015 Jan 15. [Epub ahead of print]

Statistical Significance of OS Benefit Emerged Over Time 100 546 542 524 509 412 387 2 538 534 452 437 120 106 503 493 482 465 258 237 27 25 HR (95% CI): 0.75 (0.61-0.93) p Value: 0.0097 Prednisone, 27.2 mos Abiraterone, not reached 546 542 525 509 422 401 296 261 59 42 202 148 538 534 453 438 359 322 189 132 15 10 HR (95% CI): 0.81 (0.70-0.93) p Value: 0.0033 Prednisone, 30.3 mos Abiraterone, 34.7 mos 1 118 84 218 176 504 493 483 466 394 363 330 292 273 227 235 201 FA IA3 IA2 546 542 524 508 421 400 68 67 538 534 452 437 333 283 503 492 482 465 393 361 175 153 15 9 HR (95% CI): 0.79 (0.66-0.95) p Value: 0.0151 Prednisone, 30.1 mos Abiraterone, 35.3 mos 80 Overall Survival (%) 60 40 20 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 Time to Death (Months) Abiraterone Prednisone

Evolution of Statistical Significance Required p Value for Significance IA3 0.0035 FA 0.0384 IA1 <0.0001 IA2 0.0008 2009 2010 2011 2012 2013 2014 2015 IA1 0.6926 IA2 0.0097 IA3 0.0151 FA 0.0033 Actual p Value Observed 38

OS Benefit Observed Across All Patient Subgroups Ryan CJ, et al. Lancet Oncol. 2015 Jan 15. [Epub ahead of print]

Subsequent Therapy Was Common in Both Groups Abiraterone n (%) Prednisone No. with selected subsequent therapy for mCRPC 365 (67) 435 (80) 69 (13) 238 (44)a Cabazitaxel 100 (18) 105 (19) Docetaxel 311 (57) 331 (61) Enzalutamide 87 (16) 54 (10) Ketoconazole 42 (8) 68 (13) Radium-223 20 (4) 7 (1) Sipuleucel-T 45 (8) 32 (6) aIncludes 93 patients who received abiraterone per protocol amendments.

Subsequent Therapy Was Common in Both Groups Ryan CJ, et al. Lancet Oncol. 2015 Jan 15. [Epub ahead of print]

Patients Without Opiate Use (%) Time to Opiate Use (Months) Significant Improvement in Time to Opiate Use for Cancer-Related Pain in the Final Analysis 100 HR (95% CI): 0.72 (0.61-0.85) p Value:< 0.0001 80 Abiraterone, 33.4 mos 60 Patients Without Opiate Use (%) 40 Prednisone, 23.4 mos 20 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 Time to Opiate Use (Months) Abiraterone Prednisone 546 542 519 500 495 442 454 406 407 365 364 317 328 273 297 237 263 208 244 186 219 168 192 141 169 121 162 108 143 97 128 85 74 56 35 25 9 6 1 At the time of IA3, the median time to opiate use had not been reached for abiraterone All secondary end points showed significant improvement with abiraterone

Pre-Specified AEs of Special Interest: Profile Remains Favorable

Time to All Landmarks Significantly Improved With Abiraterone Secondary Endpoints p < 0.0001 p < 0.0001 p = 0.0002 p = 0.005 Pain PSA Progression Tumor/Bone Progression ECOG PS Decline Death Baseline Chemotherapy p < 0.0001 p = 0.0033 Primary Endpoints: rPFS and OS Median Follow-Up of > 4 Years ECOG PS = Eastern Cooperative Oncology Group Performance Status. Adapted from Halabi S, J Clin Oncol 2009;27: 2766-2771.

Conclusions Median follow-up of more than 4 years, Abiraterone improvement in overall survival was statistically significant 44% in the prednisone arm received Abiraterone Abiraterone delayed the need for opiate analgesics Tha safety profile of Abiraterona plus prednisona at this final analysis was consistent with that reported at the interim analyses. No new safety signals were observed Despite early unblinding, final survival data support continued data collection vs. early trial termination in clinical trial conduct