Manejo del cáncer de próstata metastásico en el 2014

Manejo del cáncer de próstata metastásico en el 2014 Dra. Aránzazu González del Alba Servicio de Oncología Médica Hospital Universitario Son Espases Palma de Mallorca Barcelona, 18 de marzo de 2014

Introducción 15% de pacientes diagnosticados de CaP fallecerán a causa de enfermedad avanzada La terapia de deprivación androgénica (TDA) es eficaz en la mayoría de casos, aunque la progresión es la norma al cabo de 1-2 años de la respuesta inicial. Segundas maniobras hormonales pueden ser una opción en algunos pacientes, aunque las respuestas son transitorias con agentes disponibles hasta la fecha y sin impacto en supervivencia.

Introducción II Denominamos cáncer de próstata resistente a la castración (CPRC) al cáncer de próstata que progresa a pesar de niveles séricos de castración (<50 ng/ml)

Evolución histórica del tratamiento del cáncer de próstata avanzado Sipuleucel-T* [8] Cabazitaxel* [7] Denosumab LHRH agonists* [1,2] Zoledronic Acid [4] [9] Abiraterone* [10] Mitoxantrone [3] Docetaxel* [5,6] Enzalutamida [11] Radium-223 [12] 1984-1989 1996 2002 2004... 2010 2011 Reversible AR blockers [1,2] * Approved agent for PCa However, this rapid change has left many unanswered questions, including the optimal selection and sequence of therapy 1. The Leuprolide Study Group. N Engl J Med. 1984;311:1281-1286. 2. Crawford ED, et al. N Engl J Med. 1989;321:419-424. 3. Tannock IF, et al. J Clin Oncol. 1996;14:1756-1764. 4. Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468. 5. Petrylak DP, et al. N Engl J Med. 2004;351:1513-1520. 6. Tannock IF, et al. N Engl J Med. 2004;351:1502-1512. 7. de Bono JS, et al. Lancet. 2010;376:1147-1154. 8. Kantoff PW, et al. N Engl J Med. 2010;363:411-422. 9. Fizazi K, et al. Lancet. 2011;377:813-822. 10. de Bono JS, et al. N Engl J Med. 2011;364:1995-2005. 11. Scher HI, et al. ASCO GU 2012. Abstract LBA1. 12. Parker C, et al. ASCO GU 2012. Abstract 8.

Revisar Terminología Cáncer de próstata hormono-refractario Cáncer de próstata andrógeno-independiente Cáncer de próstata resistente a castración Evidencia clara de que segundas maniobras hormonales (antiandrógenos, ketoconazol, estrógenos y nuevos agentes) consiguen respuesta clínica incluso en pacientes refractarios a TDA

Improvement in pain control No difference in survival The FDA approved mitoxantrone-prednisone as palliative treatment for patients with symptomatic HRPC

2004: Docetaxel improves OS vs mitoxantrone Docetaxel q3w Docetaxel q1w Mitoxantrone q3w Median survival (months) HR P 18.9 0.76 0.009 17.3 0.93 0.3 16.4 - - Docetaxel q3w (N=335) Docetaxel q1w (N=334) Mitoxantrone q3w (N=337) 3-year survival rate* 18.6% 16.8% 13.5% Tannock IF et al. N Engl J Med 2004;351:1502-12. Berthold D et al. J Clin Oncol 2008;26:242-5. * Data 2006 7

mcprc tratamiento de primera línea Docetaxel 75 mg/m 2 cada 3 semanas estándar en primera línea de CRPC metastático 1 Heidenreich A, et al. (2010 update) www.uroweb.org 2 Mohler J, et al. (2009 update) www.nccn.org 3 Basch EM, et al. J Clin Oncol 2007;25:1 6 4 Horwich A, et al. Ann Oncol 2009;20(Suppl 4):76 8

Distintas situaciones clínicas en CPRC ASINTOMATICO MINIMAMENTE SINTOMATICO SINTOMATICO PROGRESION PSA PROGRESION GGO PROGRESION VISCERAL BAJA CARGA TUMORAL ALTA CARGA TUMORAL

Criterios de progresión en CP Scher et al. J Clin Oncol 2008;26:1148-59

Metástasis hepáticas Nº localizaciones m1 (<2 vs >2) Dolor al inicio del tto. PS (<80 vs >80) Tipo de progresión Enfermedad medible Empeoramiento GGO Grado Gleason (<8 vs >8) PSA-DT (<55 vs >55 días) PSA basal F alcalina Hb

La vía de señal androgénica

Molecular states framework for androgen receptor (AR) activation in prostate cancer. Nelson P S JCO 2012 feb ;30:644-646

Evolución natural del cáncer de próstata Docetaxel Muerte ADT / Castración Terapias hormonales de 2 ª línea Bicalutamida Flutamida Nilutamida Sipuleucel T Abiraterona Enzalutamida Volumen tumoral Terapia local* Señalización AR continuada Cabazitaxel Abiraterona Rad 223 Enzalutamida Asintomático Síntomas No metastásico Sensible a hormonas *por ejemplo, cirugía, radioterapia Kohli & Tindall. Mayo Clin Proc 2010;85:77 86. Tiempo Metastásico Resistente a la castración RA, receptor de andrógenos

Atrasentan Zibotentan Sunitinib Sorafenib Bevacizumab Aflibercept Talidomida Lenalidomida Dasatinib 3/22/2014 SOGUG, Madrid Oblimersen AT-101 Custirsen

Since 2004, many attempts to further improve docetaxel efficacy have failed Negative studies Docetaxel-HD-Calcitriol 1 Docetaxel-Bevacizumab 2 Hasta la fecha ningún estudio fase III Docetaxel-GVAX de combinación 3 en primera línea ha conseguido mejorar la supervivencia Docetaxel-Oblimersen global del CPRC comparado con el tratamiento estándar 4 de Docetaxel-Lenalidomide docetaxel-prednisona Docetaxel-Atrasentan 5 Docetaxel-Aflibercept 6 Docetaxel-Zibotentan 7 1. Scher HI et al. J Clin Oncol 2010;28:15s (Abstract 4509). 2. Kelly WK et al. J Clin Oncol 2010;28:18s (Abstract LBA4511). 3. Small E et al. ASCO GU symposium 2009 (Abstract 7). 4. Sternberg C et al. Annals Oncol 2009;20:1264-69. 5. University of Michigan press release (April 2011). 6. Press release Sanofi-Regeneron 2012. 7. Nelson JB et al. J Clin Oncol 2011;29 (suppl 7):Abst 117.

Agents with overall survival benefit in mcrpc Cortesia Dr J.Carles

Sipuleucel T

Sipuleucel-T Pacientes asintomáticos o mínimamente sintomáticos Coste = $93,000 No aprobado en Europa

Cabazitaxel: selected to overcome taxane resistance Cabazitaxel: Poor affinity for the PgP efflux pump Greater penetration of the blood brain barrier compared with docetaxel and paclitaxel Active in vitro and in vivo on tumors resistant to Docetaxel R Taxane Docetaxel and paclitaxel have a strong affinity for the PgP pump If the PgP pump is overexpressed, it drives drug out of tumor cell H Mita AC et al, Clin Cancer Res. 2009, 15, 723-730

Second-line Cabazitaxel in mcrpc patients: TROPIC Study design 146 Sites in 26 Countries (North America, Europe, India, Latin America, Asia, South Africa) mcrpc patients who progressed during or after treatment with a docetaxel-based regimen (N=755) N=378 Stratification factors N=377 ECOG PS (0, 1) vs ECOG PS (2) Measurable vs non-measurable disease Cabazitaxel 25 mg/m 2 q3w + 10 mg oral prednisone * daily 10 cycles Mitoxantrone 12 mg/m 2 q3w + 10 mg oral prednisone * daily 10 cycles 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 de Bono JS et al. Lancet 2010;376:1147-54 * or prednisolone, when prednisone was unavailable 24

TROPIC trial: Pre-protocol treatments MP (n=377) CBZP (n=378) Total prior docetaxel dose (mg/m²) Median 529.2 576.6 Months from last docetaxel dose to progression Median 0.70 0.80 Number of patients progressed (%) During last docetaxel treatment 27.6 30.4 <3 months since last docetaxel dose 48.0 41.8 3 months since last docetaxel dose 24.0 27.0 Chemotherapy (%) 1 regimen 71.1 68.8 2 regimens 21.0 24.9 3 regimens 8.0 6.3 A heavily pretreated population who progressed rapidly after first line docetaxel De Bono J et al. Lancet, 2010, 376:1147-54

Beneficio SG en todos los subgrupos Factor Subgroup Hazard ratio (95% CI) Población ITT Todos los pacientes 0.70 (0.59 0.83) ECOG status 0, 1 0.68 (0.57 0.82) 2 0.81 (0.48 1.38) Enfermedad No 0.72 (0.55 0.93) medible Si 0.68 (0.54 0.85) No. tratamientos previos 1 0.67 (0.55 0.83) 2 0.75 (0.55 1.02) Edad <65 0.81 (0.61 1.08) 65 0.62 (0.50 0.78) Dolor basal No 0.57 (0.43 0.77) Si 0.76 (0.59 0.98) Aumento PSA No 0.88 (0.61 1.26) Si 0.65 (0.53 0.80) Dosis total docetaxel <225 mg/m² 0.96 (0.49 1.86) 225 to 450 mg/m² 0.60 (0.43 0.84) 450 to 675 mg/m² 0.83 (0.60 1.16) 675 to 900 mg/m² 0.73 (0.48 1.10) 900 mg/m² 0.51 (0.33 0.79) A Favor CBZP A Favor MP 0.25 0.5 1 1.5 2 Progresión Durante tto con docetaxel 0.65 (0.47 0.90) <3 meses desde la última dosis de DTX 0.70 (0.55 0.91) 3 meses desde la última dosis de DTX 0.75 (0.51 1.11) De Bono et al. The lancet 2010; 376: 1147-54 *El protocolo se enmendó tras los primeros 59 pacientes incluídos, para asegurar que los pacientes incluídos hubiesen recibido >225 mg/m² de docetaxel

Proportion of PFS (%) TROPIC Trial: Progression-free survival 100 80 60 40 20 MP CBZP Median PFS (months) 1.4 2.8 Hazard ratio 0.75 95% CI 0.65 0.87 P-value 0.0002 PFS composite endpoint: PSA progression, pain progression, tumor progression, symptom deterioration, or death. Censored MP CBZP 0 0 3 6 9 12 15 18 21 Combined median follow-up: 13.7 months Time (months) Number at Risk MP CBZP 377 378 117 168 55 92 30 55 12 18 25% reduction in risk of progression 9 6 6 1 4 1 De Bono J et al. Lancet, 2010, 376:1147-54 28

TROPIC Trial: Response rate and time to progression MP (n=377) CBZP (n=378) Hazard ratio (95% CI) P-value Tumor assessment Response rate* (%) 4.4 14.4 0.0005 Median TTP (months) 5.4 8.8 0.61 (0.49 0.76) <0.0001 PSA assessment Response rate* (%) 17.8 39.2 0.0002 Median TTP (months) Pain response rate (N patients) Response rate (%) 3.1 (168) 7.7 TTP: time to progression ; *50% decrease or more in PSA 6.4 (174) 9.2 0.75 (0.63 0.90) 0.91 (0.69-1.19) 0.001 0.63 De Bono J et al. Lancet, 2010, 376:1147-54 29

Most Frequent Treatment-Emergent Adverse Events* MP (n=371) CBZP (n=371) Grade 3/4 Grade 3/4 All grades (%) (%) All grades (%) (%) Any adverse event 88 39 96 57 Febrile neutropenia 1 1 8 8 Neutropenia* 88 58 94 82 Diarrhea 11 <1 47 6 Fatigue 27 3 37 5 Back pain 12 3 16 4 Nausea 23 <1 34 2 Vomiting 10 0 23 2 Hematuria 4 1 17 2 Abdominal pain 4 0 12 2 *Sorted by 2% incidence rate for grade 3 events in the cabazitaxel arm. Low rate of grade 3-4 peripheral neuropathy (1% in each group) De Bono J et al. Lancet, 2010, 376:1147-54 30

Síntesis de andrógenos Abiraterona Nacusi et al Nature Publishing Group 2011;8:378 384

COU-AA-301 Study Design Phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled study (147 sites in 13 countries; USA, Europe, Australia, Canada) 1195 patients with progressive, mcrpc Failed 1 or 2 chemotherapy regimens, one of which contained docetaxel Randomised 2:1 Stratification by: ECOG performance status (0-1 vs. 2) Worst pain over previous 24 hours (BPI short form; 0-3 [absent] vs. 4-10 [present]) Prior chemotherapy (1 vs. 2) Type of progression (PSA only vs. radiographic progression Primary endpoint: with or without PSA progression) Abiraterone acetate 1000 mg daily Prednisone 5mg twice daily Placebo daily Prednisone 5mg twice daily OS (25% improvement; HR 0.8) de Bono et al. N Engl J Med 2011; 346(21): 1995-2005 T R E A T U N T I L P R O G R E S S I O N

Updated Analysis (775 Events): OS Benefit of AA Increased From 3.9 to 4.6 Months Survival (%) 100 80 HR (95% CI): 0.74 (0.64-0.86) p < 0.0001 60 AA median OS (95% CI): 15.8 months (14.8-17.0) 40 20 0 0 Placebo median OS (95% CI): 11.2 months (10.4-13.1) AA Placebo 6 12 18 24 Time to Death (Months) 30 AA Placebo 797 398 657 306 473 183 273 100 15 6 0 0 Median duration of follow-up: 20.2 months Median duration of treatment: 8 months with AA vs. 4 months with placebo Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

Survival Benefit Observed With AA Is Consistent for Majority of Subgroups Median (months) Variable Subgroup AA Placebo HR 95% CI All subjects ALL 15.8 11.2 0.74 (0.64-0.86) Baseline ECOG 0-1 17 12.3 0.74 (0.63-0.86) 2 7.3 7 0.77 (0.50-1.17) Baseline BPI < 4 18.4 13.9 0.69 (0.56-0.85) 4 13.3 9.3 0.78 (0.63-0.96) No. prior chemo regimens 1 17.1 11.7 0.71 (0.59-0.85) Type of progression 2 PSA only 14.2 18.3 10.4 13.6 0.80 0.63 (0.61-1.03) (0.47-0.84) Radiographic 14.8 10.5 0.78 (0.65-0.93) Age, years < 65 15 11.2 0.69 (0.53-0.91) 65 16.2 11.1 0.76 (0.63-0.90) 75 15.6 9.3 0.64 (0.48-0.85) Visceral disease at entry YES 12.9 8.3 0.79 (0.59-1.05) NO 17.1 12.3 0.69 (0.58-0.82) Baseline PSA above median YES 13.6 8.8 0.65 (0.53-0.79) NO 18.2 15.3 0.79 (0.63-0.99) Baseline LDH above median YES 10.4 8 0.77 (0.63-0.93) NO 20.8 18 0.75 (0.59-0.96) Baseline ALK-P above median YES 12.4 8.1 0.60 (0.50-0.74) NO 19.5 18 0.88 (0.69-1.12) Region N.A. 16.4 11.1 0.68 (0.56-0.83) Other 15.1 11.5 0.80 (0.64-1.00) Favors AA 0.5 0.75 1 1.5 Favors Placebo Fizazi et al. ECCO 2011: Abstract 7000 (oral presentation)

AEs of Special Interest Fluid retention and edema AA (n = 791) All Grades Grade 3 Grade 4 All Grades Placebo (n = 394) Grade 3 Grade 4 31% 2% <1% 22% 1% 0 Hypokalemia 17% 3% <1% 8% 1% 0 Cardiac disorders 13% 3% 1% 11% 2% <1% LFT abnormalities 10% 3% <1% 8% 3% <1% Hypertension 10% 1% 0 8% <1% 0 de Bono et al. N Engl J Med 2011; 346(21): 1995-2005

Radionúclidos y tratamiento paliativo Hasta la fecha actual 3 radionúclidos habían sido aprobados para el tratamiento del dolor óseo: Radionúclidos de primera generación: Fósforo 32 Radionúclidos de segunda generación: Stroncio 89 Radionúclidos de tercera generación: Samario 153 Sr 89 demostró aumento del tiempo a recurrencia del dolor Sm 153: Alivio del dolor y disminución del consumo de analgésicos con menor toxicidad hematológica Climent MA, 2012 Crit Rev and Hematology

Radium Ra 223 Dichloride (Alpharadin) Metal alcalino térreo Afinidad ósea por su parecido al Calcio Emisor alfa 20 Ca 38 Sr 56 Ba 88 Ra 1. Bruland Ø, et al. Clin Cancer Res. 2006;12:6250s-6257s.

Características Físicas Rotura simple Reparables Baja letalidad Cortesía Dr Vallejo Rotura doble Apoptosis Alt. Mitótica Fase G0

Bone Targeted Localized Mechanism of Action α-pharmaceuticals Range of β-particle (large volume) Bone marrow Range of α-particle (small volume) Tumor Radionuclide Bone Bone surface Henriksen G, et al. Cancer Res. 2002;62:3120 25 42

ALSYMPCA Trial Design (Alpharadin in symptomatic PC) TREATMENT PHASE 6 injections at 4-week intervals FOLLOW-UP PHASE Assessments R 2:1 Radium Ra 223 dichloride a 50 kbq/kg Saline* (placebo) Stratification factors Total ALP < 220 U/L vs 220 U/L Bisphosphonate use (yes vs no) Prior docetaxel (yes vs no) Key inclusion criteria Confirmed symptomatic CRPC 2 bone metastases No known visceral metastases Post-docetaxel or unfit for docetaxel Monthe M0 M6 M8 M10 M12 M16 M20 M24 M28 M32 Primary endpoints: overall survival Secondary endpoints: time to first SRE, time to total ALP progression, total ALP response, total ALP normalization, time to PSA progression, safety, PS and HRQoL ALP, alkalinphosphatase; ALSYMPCA, ALpharadin in SYMptomatic Prostate Cancer; R, randomization a Plus best standard of care. M36 Parker C, et al. J Clin Oncol. 2012;30(suppl). Abstract LBA4512. Clinical Trials.gov identifier # NCT00699751.

Survival (%) ALSYMPCA: Radium Ra 223 Dichloride Significantly Prolonged Overall Survival Compared With Placebo 100 80 Radium 223 Placebo Median OS (months) 14.9 11.3 Hazard ratio 0.695 95% CI 0.581-0.832 P < 0.0001 60 40 20 Median OS Δ: 3.6 months Radium 223 Placebo 0 Month Radium 223 0 614 3 578 6 504 9 369 12 274 15 178 18 105 21 60 24 41 27 18 30 7 33 1 36 0 39 0 Placebo 307 288 228 157 103 67 39 24 14 7 4 2 1 0 ALSYMPCA, ALpharadin in SYMptomatic Prostate Cancer; CI, confidence interval; OS, overall survival. Parker C, et al. J Clin Oncol. 2012;30(suppl). Abstract LBA4512.

100 90 80 70 60 ALSYMPCA Updated Analysis OS by Stratification Variables: Prior Docetaxel Use Prior docetaxel use HR = 0.710 95% CI, 0.565, 0.891 P = 0.00307 100 90 80 70 60 NO prior docetaxel use HR = 0.745 95% CI, 0.562, 0.987 P = 0.03932 % 50 40 Radium-223, n = 352 Median: 14.4 months % 50 40 Radium-223, n = 262 Median: 16.1 months 30 30 20 10 Placebo, n = 174 Median: 11.3 months 20 10 Placebo, n = 133 Median: 11.5 months 0 Month 0 4 8 12 16 20 24 28 32 36 40 Radium-223 352 327 238 155 88 45 27 5 1 0 0 Placebo 174 152 104 61 35 15 5 4 1 1 0 0 Month 0 4 8 12 16 20 24 28 32 36 Radium-223 262 236 168 119 70 31 14 7 1 0 Placebo 133 113 74 42 24 14 9 3 1 0

ALSYMPCA Updated Analysis OS by Stratification Variables: Bisphosphonate Use 100 Current bisphosphonate use 90 80 70 HR = 0.699 95% CI, 0.525, 0.931 P = 0.01378 NO current bisphosphonate use 100 90 80 70 HR = 0.736 95% CI, 0.587, 0.923 P = 0.00775 60 % 50 % 40 30 Radium-223, n = 250 Median: 15.3 months 60 50 40 30 Radium-223, n = 364 Median: 14.5 months 20 10 Placebo, n = 124 Median: 11.5 months 20 10 Placebo, n = 183 Median: 11.0 months 0 Month 0 4 8 12 16 20 24 28 32 36 Radium-223 250 232 171 115 61 26 14 6 2 0 Placebo 124 110 76 45 26 13 4 1 0 0 0 Month 0 4 8 12 16 20 24 28 32 36 40 Radium-223 364 331 235 159 97 50 27 6 0 0 0 Placebo 183 155 102 58 33 16 10 6 2 1 0

ALSYMPCA Updated Analysis OS by Stratification Variables: Baseline ALP 100 90 80 70 Total ALP < 220 U/L HR = 0.825 95% CI, 0.635, 1.072 P = 0.14945 100 90 80 70 Total ALP 220 U/L HR = 0.619 95% CI, 0.486, 0.788 P = 0.00009 60 % 50 % 40 30 Radium-223, n = 348 Median: 17.0 months 60 50 40 30 Radium-223, n = 266 Median: 11.4 months 20 Placebo, n = 169 Median: 15.8 months 20 10 0 Month 0 4 8 12 16 20 24 28 32 36 adium-223 348 325 246 179 107 52 31 9 2 0 Placebo 169 151 115 75 44 20 11 5 1 0 10 Placebo, n = 138 Median: 8.1 months 0 Month 0 4 8 12 16 20 24 28 32 36 40 Radium-223 266 238 160 95 51 24 10 3 0 0 0 Placebo 138 114 63 28 15 9 3 2 1 1 0

ALSYMPCA: Adverse Events of Interest n (%) Hematologic Radium 223 (n = 600) All Grades Grades 3 or 4 Placebo (n = 301) Radium 223 (n = 600) Placebo (n = 301) Anemia 187 (31.2) 92 (31) 77 (13) 40 (13) Neutropenia 30 (5) 3 (1) 13 (2) 2 (1) Thrombocytopenia 69 (11.5) 17 (5.6) 38 (6.3) 6 (2) Nonhematologic Bone pain 300 (50) 187 (62) 125 (21) 77 (26) Diarrhea 151 (25) 45 (15) 9 (1.5) 5 (1.7) Nausea 213 (35.5) 104 (35) 10 (2) 5 (2) Vomiting 111 (18.5) 41 (14) 10 (2) 7 (2) Constipation 108 (18) 64 (21) 6 (1) 4 (1) ALSYMPCA, ALpharadin in SYMptomatic Prostate Cancer. Parker C, et al. J Clin Oncol. 2012;30(suppl.). Abstract LBA4512. Data on file. Wayne, NJ: Bayer HealthCare Pharmaceuticals. ClinicaTrials.gov identifier # NCT00699751.

Enzalutamide (MDV3100): Mechanism of action AR signalling inhibition at three levels: Blocks binding of testosterone to the AR Inhibits nuclear translocation of AR Inhibits binding of the AR to DNA 1 2 T Inhibits binding of androgens to AR T AR Inhibits nuclear translocation of AR Enzalutamide Cell cytoplasm Cell nucleus 3 Inhibits association of AR with DNA AR T, testosterone Tran C et al. Science 2009;324:787 790; Baskin-Bey ES et al. ASCO GU 2011 abstr 177; Watson PA et al. Proc Natl Acad Sci USA 2010;107:16759 65

Phase III: AFFIRM trial of enzalutamide in mcrpc patients post-chemotherapy AFFIRM is a phase III randomised, double-blind, placebocontrolled trial Primary endpoint: Overall survival n = 1199 mcrpc 1 2 prior chemotherapy regimens* R 2:1 Enzalutamide 160 mg qd (n = 800) Placebo per qd (n = 399) * 1 docetaxel (glucocorticoids were allowed but not required) Stratification variables: ECOG performance status (0 1 vs 2) Mean Brief Pain Inventory Q#3 score (<4, 4) Recruitment in 156 centres from 15 countries across 5 continents between September 2009 and November 2010 Scher et al. NEJM Aug 15. [Epub ahead of print] (2012). mcrpc, metastatic castrateresistant prostate cancer; qd, once per day; R, randomisation

Survival (%) AFFIRM: Overall survival 100 80 HR = 0.63 (95%CI: 0.53 0.75); p<0.001 37% reduction in risk of death Enzalutamide: 18.4 months (95% CI: 17.3 NYR) 60 40 20 Placebo: 13.6 months (95% CI: 11.3 15.8) 4.8 month difference in median overall survival N o at risk: Enzalutamide, n = Placebo, n = 0 0 3 6 9 12 15 18 21 24 Scher et al. NEJM Aug 15. [Epub ahead of print] (2012). Duration of overall survival (months) 800 775 701 627 400 211 72 7 0 399 376 317 263 167 81 33 3 0 CI, confidence interval; HR, hazard ratio; NYR, not yet reached

AFFIRM: Secondary endpoints Enzalutamide (n = 800) Placebo (n = 399) Hazard ratio p-value Confirmed PSA response rates 50% reduction from baseline (%) 54 2 p<0.001 90% reduction from baseline (%) 25 1 p<0.001 PSA progression Median time to PSA progression (months) 8.3 3.0 0.25 p<0.001 Soft tissue response* Soft tissue response rate (%) 29 4 p<0.001 Progression-free survival Radiographic progression-free survival (months) 8.3 2.9 0.40 p<0.001 Skeletal-related events Time to first skeletal-related event (months) 16.7 13.3 0.69 p<0.001 Health-related quality of life Functional Assessment of Cancer Therapy - Prostate (FACT-P) quality of life response rate (%) 43 18 p<0.001 Percentages relate to patients with baseline and postbaseline assessments *n=446 and n=208 for enzalutamide and placebo arms respectively Scher et al. NEJM Aug 15. [Epub ahead of print] (2012). PSA, prostate-specific antigen

AFFIRM: Overall survival Subgroup Hazard ratio for death (95% CI) Median overall survival (months) Enzalutamide/placebo All subjects 0.63 (0.53 0.75) 18.4/13.6 Age < 65 65 Baseline ECOG performance status 0 1 2 Baseline mean pain score on BPI-SF (question #3) < 4 4 Geographical region North America Other Number of prior chemotherapy regimens 1 2 Type of progression at study entry PSA progression only Radiographic progression PSA progression Baseline value > median PSA LDH 0.63 (0.46 0.87) 0.63 (0.51 0.78) 0.62 (0.52 0.75) 0.65 (0.39 1.07) 0.59 (0.47 0.74) 0.71 (0.54 0.94) 0.63 (0.47 0.83) 0.64 (0.51 0.80) 0.59 (0.48 0.73) 0.74 (0.54 1.03) 0.62 (0.46 0.83) 0.64 (0.52 0.80) 0.62 (0.50 0.78) 0.61 (0.50 0.76) /12.4 18.4/13.9 /14.2 10.5/7.2 /16.2 12.4/9.1 17.4/12.3 /14.4 /14.2 15.9/12.3 /19.5 17.3/13.0 15.3/10.3 12.4/8.5 The size of the circles is proportional to the size of the subgroup 0 0.5 1.0 1.5 2.0 Favours Enzalutamide Favours placebo Scher et al. NEJM Aug 15. [Epub ahead of print] (2012). BPI-SF, Brief Pain Inventory - short form; CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase; PSA, prostate-specific antigen

AFFIRM: resumen de AA Acontecimientos adversos, n (%) Acontecimientos totales (todos los grados) Enzalutamida (n = 800) Placebo (n = 399) AA, acontecimiento adverso; LFT, pruebas de función hepática *las anomalías en las LFT eran hiperbilirrubinemia y aumento de los niveles de aspartato aminotransferasa o alanina aminotransferasa El periodo de notificación de acontecimientos adversos para el grupo de enzalutamida fue más del doble que el correspondiente al grupo placebo Acontecimientos de grado 3 Enzalutamida (n = 800) Placebo (n = 399) 1 acontecimientos adversos 785 (98) 390 (98) 362 (45) 212 (53) Cualquier acontecimiento adverso grave Interrupciones debidas a acontecimientos adversos Acontecimientos causantes de muerte Acontecimientos adversos de interés, n (%) 268 (34) 154 (39) 227 (28) 134 (34) 61 (8) 39 (10) 37 (5) 28 (7) 23 (3) 14 (4) 23 (3) 14 (4) Cansancio 269 (34) 116 (29) 50 (6) 29 (7) Trastornos cardíacos (cualquiera) 49 (6) 30 (8) 7 (1) 8 (2) Infarto de miocardio 2 (<1) 2 (<1) 2 (<1) 2 (<1) Alteración transaminasas* 8 (1) 6 (2) 3 (<1) 3 (<1) Convulsiones 7 (<1) 0 5 (<1) 0 N Engl J Med 2012; 367: 1187 1197

Zoledronic Acid in Castration-Resistant Prostate Cancer Eligibility Criteria Patients with prostate cancer Castration resistant Bone metastases (N = 643) R A N D O M I Z E D Zoledronic acid 4 mg q3 wks (n = 214) Zoledronic acid 4 mg q3 wks (initially 8 mg) (n = 221) Placebo q3 wks (n = 208) Patients in 8-mg arm reduced to 4 mg owing to renal toxicity Primary outcome: proportion of patients having 1 SRE Secondary outcomes: time to first on-study SRE, proportion of patients with SREs, and time to disease progression Saad F, et al. J Natl Cancer Inst. 2002;94:1458-1468.

Study Design: International, Randomized, Double-Blind, Active-Controlled Study Key Inclusion Hormone-refractory (castrationresistant) prostate cancer and bone metastases Key Exclusion Current or previous IV bisphosphonate treatment Denosumab 120 mg SC and Placebo IV* q4 wks (n = 950) Zoledronic acid 4 mg IV* and Placebo SC q4 wks (n = 951) Calcium and vitamin D supplemented in both treatment groups Accrual period from May 2006 - December 2008 Analysis cutoff date: October 2009 *Per protocol and zoledronic acid label, IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine. No SC dose adjustments made due to increased serum creatinine. Fizazi K, et al. Lancet. 2011;377:813-822.

Proportion of Subjects Without SRE Time to First On-Study SRE 1.00 HR: 0.82 (95% CI: 0.71-0.95; P =.0002, noninferiority; P =.008, superiority) 18% Risk reduction 0.75 0.50 0.25 Denosumab Zoledronic acid KM Estimate of Median Mos 20.7 17.1 0 0 3 6 9 12 15 18 21 24 27 Pts at Risk, n Study Mo Zoledronic acid 951 733 544 407 299 207 140 93 64 47 Denosumab 950 758 582 472 361 259 168 115 70 39 Fizazi K, et al. Lancet. 2011;377:813-822.

Novel Study Design: Co-primary End Points Study COU-AA-302 Patient Population Progressive mcrpc without prior chemotherapy; Asymptomatic or mildly symptomatic R A N D O M I Z E D 1:1 a a Stratification by ECOG PS 0 vs 1. Abiraterone 1000 mg daily + Prednisone 5 mg BID (actual n = 546) Placebo daily + Prednisone 5 mg BID (actual n = 542) Co-primary end points: rpfs (central review) OS Secondary end points: Time to opiate use Time to initiation of chemotherapy Time to ECOG PS deterioration Time to PSA progression Exploratory end points: HR-QoL (FACT-P, BPI-SF) BID, twice daily; rpfs, radiographic progression free survival; OS, overall survival; HR-QoL, Health-related quality of life; FACT-P, Functional Assessment of Cancer Therapy-Prostate; BPI-SF, Brief Pain Inventory-Short Form; ECOG PS, Eastern Cooperative Oncology Group performance status; PSA, prostate-specific antigen. 5

Subjects Without Progression or Death (%) Abiraterone Doubled Time to rpfs 100 80 Abiraterone (median, mos): 16.5 Prednisone (median, mos): 8.3 HR (95% CI): 0.53 (0.45-0.62) p Value: < 0.0001 60 40 20 0 0 Abiraterone Prednisone 3 6 9 12 15 18 21 24 27 30 33 36 Months From Randomization 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 0 0 0 IA3 data. rpfs assessed by investigator review at prespecified IA.

Subjects Without Death (%) 13 OS Favors Abiraterone 100 Abiraterone (median, mos): 35.3 Prednisone (median, mos): 30.1 HR (95% CI): 0.79 (0.66-0.95) p Value a : 0.0151 80 60 40 20 0 0 Abiraterone Prednisone 3 6 9 12 15 18 21 24 27 30 33 36 Months From Randomization Abiraterone Prednisone 546 542 538 534 524 508 503 492 482 465 452 437 421 400 393 361 333 283 175 153 68 67 15 9 0 0 IA3 data. a Prespecified significance level by O Brien-Fleming Boundary = 0.0035.

IA3 data. Note: All secondary end points remain significant after adjusting for multiplicity testing. Improvement in All Clinical End Points Abiraterone Median (months) Prednisone Median (months) HR (95% CI) p Value Secondary end points Time to opiate use (cancer-related pain) Time to chemotherapy initiation Time to ECOG PS deterioration NR 23.7 0.71 (0.59-0.85) 0.0002 26.5 16.8 0.61 (0.51-0.72) < 0.0001 12.3 10.9 0.83 (0.72-0.94) 0.0052 Time to PSA progression 11.1 5.6 0.50 (0.43-0.58) < 0.0001 Exploratory end points Time to BPI-SF pain interference progression Time to degradation in FACT-P (total score) 10.3 7.4 0.80 (0.68-0.93) 0.0049 12.7 8.3 0.79 (0.67-0.93) 0.0046

PREVAIL: A Phase 3 trial of enzalutamide after progression on ADT in men with mcrpc Patient population: 1717 men with progressive mcrpc Asymptomatic/ mildly symptomatic Chemotherapy-naïve Steroids allowed but not required R A N D O M I Z E D 1:1 Enzalutamide 160 mg/day (capsules) n=872 Placebo n=845 OS rpfs Co-primary endpoints: ADT=androgen-deprivation therapy; mcrpc=metastatic castration-resistant prostate cancer; OS=overall survival; rpfs=radiographic progression-free survival. Beer TM, et al. ASCO-GU 2014; Oral presentation; ClinicalTrials.gov identifier: NCT01212991.

rpfs (%) Enzalutamide prolonged radiographic progression-free survival 100 HR=0.186 (95% CI: 0.15 0.23); p<0.0001 80 60 Enzalutamide 40 20 Placebo 0 0 3 6 9 12 15 18 21 Months Enzalutamide, n Placebo, n 832 514 256 128 34 5 1 0 801 305 79 20 5 0 0 0 Estimated median rpfs, months (95% CI): Enzalutamide: NYR (13.8, NYR); Placebo: 3.9 (3.7, 5.4) NYR = Not Yet Reached CI=confidence interval; HR=hazard ratio; rpfs=radiographic progression-free survival. Beer TM, et al. ASCO-GU 2014; Oral presentation.

Survival (%) Enzalutamide reduced the risk of death by 29% 100 HR=0.706 (95% CI: 0.60 0.84); p<0.0001 80 60 Placebo Enzalutamide 40 20 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months Enzalutamide, n Placebo, n 872 863 850 824 797 745 566 395 244 128 33 2 0 845 835 781 744 701 644 484 328 213 102 27 2 0 Estimated median OS, months (95% CI): Enzalutamide: 32.4 (30.1, NYR); Placebo: 30.2 (28.0, NYR) NYR = Not Yet Reached CI=confidence interval; HR=hazard ratio. Beer TM, et al. ASCO-GU 2014; Oral presentation.

Cytotoxic chemotherapy free (%) Enzalutamide delayed median time to chemotherapy by 17 months 100 HR=0.35 (95% CI: 0.30 0.40); p<0.0001 80 60 Enzalutamide: 28.0 months 40 20 Placebo: 10.8 months Enzalutamide, n Placebo, n 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months 872 854 799 751 665 575 388 252 158 78 21 2 0 845 734 518 415 324 257 165 103 64 25 9 0 0 CI=confidence interval; HR=hazard ratio. Beer TM, et al. ASCO-GU 2014; Oral presentation.

El CPRCm hasta 2010 Metastásico, sin quimioterapia previa, asintomático Metastásico, sin quimioterapia previa, sintomático Metastásico, Post-docetaxel Segunda línea hormonal Docetaxel Docetaxel Mitoxantrone Otros (CTX, VNB) Ácido zoledrónico

CPRCm en 2014 Metastásico, sin quimioterapia previa, asintomático Metastásico, sin quimioterapia previa, sintomático Metastásico, Post-docetaxel 2ª línea hormonal Docetaxel Sipuleucel (USA) Abiraterona Enzalutamida Docetaxel Rad 223 (EAP) Cabazitaxel Abiraterona Mitoxantrone Rad 223 (EAP) Enzalutamida Ácido zoledrónico Denosumab

Consideraciones finales En CPRC la vía de señal de AR continúa activa y promoviendo el crecimiento celular La quimioterapia consigue paliación y mejoría en supervivencia en CPRC (primera línea: docetaxel, segunda línea: cabazitaxel) (nivel evidencia 1) Abiraterona y Enzalutamida mejoran la supervivencia en pacientes que han progresado a docetaxel (nivel 1) y antes de la QT

Consideraciones finales La inmunoterapia con Sipuleucel-T mejora la supervivencia en pacientes asintomáticos o mínimamente sintomáticos (nivel 1) En pacientes con metástasis oseas sintomáticas Rad 223 mejora la supervivencia en pacientes no tratados con docetaxel y tras progresión al mismo Queda por definir la mejor secuencia terapéutica en el CPRCm La inclusión de pacientes en ensayo clínico sigue siendo primordial: facilita el acceso a fármacos y responde a preguntas relevantes en nuestra práctica clínica.

MUCHAS GRACIAS