Experiencia y Futuro del tratamiento con Enzalutamida

Desarrollo clínico en cáncer próstata PSA Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive Non-metastatic Castration resistant Castration sensitive First-line hormonal therapy/ castration Docetaxel + prednisone Local therapy Second-line hormonal therapies Bicalutamide, flutamide, nilutamide, etc. Cabazitaxel + prednisone Enzalutamide Abiraterone acetate + prednisone Sipuleucel-T AFFIRM TERRAIN: estudio (en) fase II aleatorizado para valorar (sobre) la seguridad y eficacia de enzalutamida frente a bicalutamida en pacientes con mCP(M)RC. Los pacientes (n=370) se aleatorizaron al grupo de 160 mg/día de enzalutamida o al grupo de bicalutamida. La variable principal del estudio es la SLP Estudio en monoterapia: estudio (en) fase II, abierto, de un solo brazo (grupo), para valorar (sobre) la seguridad y eficacia de enzalutamida en pacientes con cáncer de próstata que no han recibido antes terapia de DA. Los pacientes (n=400) se aleatorizaron al grupo de 160 mg/día de enzalutamida. La variable principal del estudio es la respuesta del PSA, definida como una reducción ≥80 % en la semana 25. Neoadyuvante a la prostatectomía radical: estudio aleatorizado (en) fase II, abierto, sobre enzalutamida como tratamiento neoadyuvante para pacientes candidatos a prostatectomía radical. Los pacientes (n=50) se aleatorizarán a una combinación triple (160 mg de enzalutamida, 0,5 mg de dutasteride(a) y 22,5 mg de acetato de leuprorelina o a 160 mg de enzalutamida únicamente. La variable principal del estudio es la tasa de RC patológica. Time 2 2

Uso Expandido 2012: HSCSP + Htal Asturias. T progresión por PSA Supervivencia libre de enfermedad Progresión por PSA: aumento >25% sobre nadir Mediana 5.25 m 3

Acceso Expandido: Htal Asturias + HSCSP: Respuesta PSA 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40

Perfil de PSA en el tiempo. % sobre el basal Semanas

Fase I/II: Inhibición del AR y farmacocinética Farmacocinética de monodosis Farmacocinética de dosis múltiples ug/ml de MDV3100 Días después de la monodosis de 150 mg/día de MDV3100 Conc. pre-dosis (Cmín) *FDHT: 16β-18F-fluoro-5α-dihidrotestosterona Scher HI, et al. Lancet. 375:1437, 2010

Respuesta precoz y supervivencia? Caffo et al. Fut Oncol 2014; 985

Desarrollo clínico en cáncer próstata PSA Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive Non-metastatic Castration resistant Castration sensitive First-line hormonal therapy/ castration Docetaxel + prednisone Local therapy Second-line hormonal therapies Bicalutamide, flutamide, nilutamide, etc. Cabazitaxel + prednisone Enzalutamide Abiraterone acetate + prednisone Sipuleucel-T AFFIRM ABIRATERONA ---- ENZALUTAMIDA TERRAIN: estudio (en) fase II aleatorizado para valorar (sobre) la seguridad y eficacia de enzalutamida frente a bicalutamida en pacientes con mCP(M)RC. Los pacientes (n=370) se aleatorizaron al grupo de 160 mg/día de enzalutamida o al grupo de bicalutamida. La variable principal del estudio es la SLP Estudio en monoterapia: estudio (en) fase II, abierto, de un solo brazo (grupo), para valorar (sobre) la seguridad y eficacia de enzalutamida en pacientes con cáncer de próstata que no han recibido antes terapia de DA. Los pacientes (n=400) se aleatorizaron al grupo de 160 mg/día de enzalutamida. La variable principal del estudio es la respuesta del PSA, definida como una reducción ≥80 % en la semana 25. Neoadyuvante a la prostatectomía radical: estudio aleatorizado (en) fase II, abierto, sobre enzalutamida como tratamiento neoadyuvante para pacientes candidatos a prostatectomía radical. Los pacientes (n=50) se aleatorizarán a una combinación triple (160 mg de enzalutamida, 0,5 mg de dutasteride(a) y 22,5 mg de acetato de leuprorelina o a 160 mg de enzalutamida únicamente. La variable principal del estudio es la tasa de RC patológica. Time 9 9

Median duration of Rx: 4 months Enza tras Abi N=137 Median duration of Rx: 4 months

Enzalutamide in progressive mCRPC previously treated with abiraterone Ongoing trials Enzalutamide in progressive mCRPC previously treated with abiraterone A Phase 4 multicentre, single-arm study Primary endpoint: rPFS Planned evaluations rPFS OS PSA response Time to PSA progression Safety Objective response rate QoL Time to start other antineoplastic therapy Enzalutamide (160 mg QD) n=200 Progressive mCRPC Testosterone ≤50 ng/dL Ongoing ADT ≥6 months prior treatment with abiraterone Asymptomatic/mildly symptomatic ECOG PS 0–1 ADT=androgen-deprivation therapy; ECOG PS=Eastern Cooperative Oncology Group performance status; mCRPC=metastatic castration-resistant prostate cancer; OS=overall survival; PFS=progression-free survival; PSA=prostate-specific antigen; QoL=quality of life; rPFS=radiographic PFS. EudraCT 2013-002271-17. Available at https://www.clinicaltrialsregister.eu. Last accessed: April 2014. 1111 11

Desarrollo clínico en cáncer próstata PSA Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive Non-metastatic Castration resistant Castration sensitive First-line hormonal therapy/ castration Docetaxel + prednisone Local therapy Second-line hormonal therapies Bicalutamide, flutamide, nilutamide, etc. Cabazitaxel + prednisone Enzalutamide Abiraterone acetate + prednisone Sipuleucel-T PREVAIL AFFIRM TERRAIN: estudio (en) fase II aleatorizado para valorar (sobre) la seguridad y eficacia de enzalutamida frente a bicalutamida en pacientes con mCP(M)RC. Los pacientes (n=370) se aleatorizaron al grupo de 160 mg/día de enzalutamida o al grupo de bicalutamida. La variable principal del estudio es la SLP Estudio en monoterapia: estudio (en) fase II, abierto, de un solo brazo (grupo), para valorar (sobre) la seguridad y eficacia de enzalutamida en pacientes con cáncer de próstata que no han recibido antes terapia de DA. Los pacientes (n=400) se aleatorizaron al grupo de 160 mg/día de enzalutamida. La variable principal del estudio es la respuesta del PSA, definida como una reducción ≥80 % en la semana 25. Neoadyuvante a la prostatectomía radical: estudio aleatorizado (en) fase II, abierto, sobre enzalutamida como tratamiento neoadyuvante para pacientes candidatos a prostatectomía radical. Los pacientes (n=50) se aleatorizarán a una combinación triple (160 mg de enzalutamida, 0,5 mg de dutasteride(a) y 22,5 mg de acetato de leuprorelina o a 160 mg de enzalutamida únicamente. La variable principal del estudio es la tasa de RC patológica. Time *Phase 1b; †Phase 2; ‡Phase 3. 12 12

PREVAIL Objetivos Co-primarios: Enzalutamida SG rPFS Placebo CPRC metastásico NO: Quimioterapia, ketoconazole, o abiraterone ECOG 0-1 BPI (Brief Pain Inventory): Asintomático (0- 1) o casi asintomático (2-3) Metástasis viscerales permitidas Pacientes NYHA I-II NO riesgo de convulsión pero SÎ con medicaciones que bajen el dintel convulsivo Corticoides permitidos Objetivos Co-primarios: SG rPFS Enzalutamida 160 mg/día (capsulas) n=872 Placebo n=845 R A N D O M I Z A D O 1:1 CRPCm=Cáncer de Próstata resistente a castración metastásico SG=Supervivencia Global; rPFS=Supervivencia Libre de Progresión Radiográfica. Beer TM, et al. ASCO-GU 2014; Oral presentation; ClinicalTrials.gov identifier: NCT01212991. 13

Dolor al inicio 0–1 BPI-SF 66.2% 67.5% Uso de corticoides al inicio Características Enzalutamida (n=872) Placebo (n=845) Edad, mediana (rango), a 72 (43−93) 71 (42−93) PSA, mediana, ng/mL 54.1 44.2 Gleason ≥8 50.6% 52.4% Puntuación ECOG = 0 67.0% 69.2% Dolor al inicio 0–1 BPI-SF 66.2% 67.5% Uso de corticoides al inicio 4.0% 4.3% Enfermedad ósea 85.0% 81.7% Enfermedad de tejidos blandos 59.3% 59.6% Enfermedad visceral (hepática y/o pulmonar) 11.2% 12.5% Beer TM, et al. ASCO-GU 2014; Oral presentation.

RECIST Enzalutamida (n=872) Placebo (n=845) Valor P Pacientes con enfemedad de tejidos blandos medibles al inicio 396 381 Respuesta Objetiva (RC + RP) 58.8% 5.0% <0.0001 Best overall response RC 19.7% 1.0% RP 39.1% 3.9% Categorías de respuesta según criterios RECIST 1.1. RC=respuesta completa; RP=Respuesta parcial; RECIST=Response Evaluation Criteria in Solid Tumors. Beer TM, et al. ASCO-GU 2014; Oral presentation.

Supervivencia libre de Progresión Radiográfica 3 6 15 18 21 12 100 80 60 40 20 rPFS (%) Meses 9 514 256 5 1 34 832 128 Enzalutamida, n 305 79 801 Placebo, n Placebo Enzalutamida HR=0.186 (95% CI: 0.15–0.23); p<0.0001 Estimated Mediana estimada de rPFS, meses (95% IC): Enzalutamida: NYR (13.8, NYR); Placebo: 3.9 (3.7, 5.4) Beer TM, et al. ASCO-GU 2014; Oral presentation.

SLPr: Análisis de subgrupos Nº de pacientes enzalutamida /  placebo Hazard ratio (95% IC) Todos los pacientes 832 / 801 0.19 (0.15–0.23) ECOG performance status at baseline = 0 557 / 549 0.15 (0.11–0.20) ECOG performance status at baseline = 1 275 / 252 0.27 (0.19–0.37) Edad <75 529 / 517 0.20 (0.15–0.26) Edad ≥75 303 / 284 0.17 (0.12–0.24) Región geográfica – North America 214 / 204 0.17 (0.12–0.25) Región geográfica – Europe 456 / 435 0.21 (0.15–0.28) Región geográfica – Rest of world 162 / 162 0.14 (0.08–0.25) Enfermedad visceral (hepática y/o pulmonar) al screening– Sí 97 / 101 0.28 (0.16–0.49) Enfermedad visceral (hepática y/o pulmonar) al screening– No 735 / 700 0.17 (0.14–0.22) 0.5 1.0 1.5 A favor enzalutamida A favor placebo ECOG=European Co-operative Group. Beer TM, et al. ASCO-GU 2014; Oral presentation.

Enzalutamida Placebo (n=872) (n=845) Tratamiento: Duración media (m) 16.6 4.6 Duración ≥ 12 ms 67.9% 18.0% Tratamiento activo al corte 42.1% 7.2% % con al menos 1 tratamiento posterior que prolonga la vida 40.3% 70.3% % de pacientes que recibieron tratamientos posteriores Docetaxel 32.8% 56.7% Abiraterona 20.5% 45.6% Cabazitaxel 5.8% 13.0% Enzalutamida 1.0% 4.4% Sipuleucel-T 1.4% 1.2% Beer TM, et al. ASCO-GU 2014; Oral presentation.

Supervivencia Global HR=0.706 (95% CI: 0.60–0.84); p<0.0001 3 6 30 33 36 12 100 80 60 40 20 Supervivencia (%) Meses 9 863 850 2 797 872 824 Enzalutamida, n 835 781 27 701 845 744 Placebo, n Placebo Enzalutamida HR=0.706 (95% CI: 0.60–0.84); p<0.0001 15 745 644 18 566 484 21 395 328 24 244 213 128 102 Mediana estimada de SG, meses (95% IC): Enzalutamida: 32.4 (30.1, NYR); Placebo: 30.2 (28.0, NYR) Beer TM, et al. ASCO-GU 2014; Oral presentation.

T a progresión por PSA Respuesta PSA Enzalutamida (n=854) Placebo ≥ 50% ≥ 90% 78.0% 46.8% 3.5% 1.2%

Otros beneficios asociados al tratamiento.... T a inicio de Quimioterapia HR=0.35 (95% CI: 0.30–0.40); p<0.0001

Acontecimientos Grado ≥3 (%) Toxicidad Todos los Grados (%) Acontecimientos Grado ≥3 (%) Enzalutamida (n=871) Placebo (n=844) Fatiga 35.6 25.8 1.8 1.9 Dolor de espalda 27.0 22.2 2.5 3.0 Estreñimiento 17.2 0.5 0.4 Artralgia 20.3 16.0 1.4 1.1 Eventos Cardiacos 10.1 7.8 2.8 2.1 Hipertensión 13.4 4.1 6.8 2.3 Aumento ALT 0.9 0.6 0.2 0.1 Convulsiones 0.0† 0.0 *Al menos 20% en enzalutamida y ≥2% más que en placebo; † Unaconvulsión ocurió después de la fecha de cutoff. ALT=alanina aminotransferasa. Beer TM, et al. ASCO-GU 2014; Presentación Oral.

Desarrollo clínico en cáncer próstata PSA Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive Non-metastatic Castration resistant Castration sensitive First-line hormonal therapy/ castration Docetaxel + prednisone Local therapy Second-line hormonal therapies Bicalutamide, flutamide, nilutamide, etc. Cabazitaxel + prednisone Enzalutamide Abiraterone acetate + prednisone Sipuleucel-T Neoadjuvant† TERRAIN† Monotherapy† STRIVE† M0 CRPC ‡ PREVAIL Enzalutamide post abiraterone† AFFIRM UPWARD ALLIANCE PRESIDE PREMIERE PLATO TERRAIN: estudio (en) fase II aleatorizado para valorar (sobre) la seguridad y eficacia de enzalutamida frente a bicalutamida en pacientes con mCP(M)RC. Los pacientes (n=370) se aleatorizaron al grupo de 160 mg/día de enzalutamida o al grupo de bicalutamida. La variable principal del estudio es la SLP Estudio en monoterapia: estudio (en) fase II, abierto, de un solo brazo (grupo), para valorar (sobre) la seguridad y eficacia de enzalutamida en pacientes con cáncer de próstata que no han recibido antes terapia de DA. Los pacientes (n=400) se aleatorizaron al grupo de 160 mg/día de enzalutamida. La variable principal del estudio es la respuesta del PSA, definida como una reducción ≥80 % en la semana 25. Neoadyuvante a la prostatectomía radical: estudio aleatorizado (en) fase II, abierto, sobre enzalutamida como tratamiento neoadyuvante para pacientes candidatos a prostatectomía radical. Los pacientes (n=50) se aleatorizarán a una combinación triple (160 mg de enzalutamida, 0,5 mg de dutasteride(a) y 22,5 mg de acetato de leuprorelina o a 160 mg de enzalutamida únicamente. La variable principal del estudio es la tasa de RC patológica. Time *Phase 1b; †Phase 2; ‡Phase 3. 23

Desarrollo clínico en cáncer próstata PSA Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive Non-metastatic Castration resistant Castration sensitive First-line hormonal therapy/ castration Docetaxel + prednisone Local therapy Second-line hormonal therapies Bicalutamide, flutamide, nilutamide, etc. Cabazitaxel + prednisone Enzalutamide Abiraterone acetate + prednisone Sipuleucel-T Neoadjuvant† TERRAIN† Monotherapy† STRIVE† M0 CRPC ‡ Enzalutamide post abiraterone† AFFIRM UPWARD ALLIANCE PRESIDE PREMIERE PLATO TERRAIN: estudio (en) fase II aleatorizado para valorar (sobre) la seguridad y eficacia de enzalutamida frente a bicalutamida en pacientes con mCP(M)RC. Los pacientes (n=370) se aleatorizaron al grupo de 160 mg/día de enzalutamida o al grupo de bicalutamida. La variable principal del estudio es la SLP Estudio en monoterapia: estudio (en) fase II, abierto, de un solo brazo (grupo), para valorar (sobre) la seguridad y eficacia de enzalutamida en pacientes con cáncer de próstata que no han recibido antes terapia de DA. Los pacientes (n=400) se aleatorizaron al grupo de 160 mg/día de enzalutamida. La variable principal del estudio es la respuesta del PSA, definida como una reducción ≥80 % en la semana 25. Neoadyuvante a la prostatectomía radical: estudio aleatorizado (en) fase II, abierto, sobre enzalutamida como tratamiento neoadyuvante para pacientes candidatos a prostatectomía radical. Los pacientes (n=50) se aleatorizarán a una combinación triple (160 mg de enzalutamida, 0,5 mg de dutasteride(a) y 22,5 mg de acetato de leuprorelina o a 160 mg de enzalutamida únicamente. La variable principal del estudio es la tasa de RC patológica. Time *Phase 1b; †Phase 2; ‡Phase 3. 24

PRESIDE: Continued enzalutamide treatment beyond progression in combination with docetaxel in chemotherapy-naïve mCRPC A Phase 3b randomised, double-blind placebo-controlled study Primary endpoint: PFS n=500 Chemotherapy-naïve mCRPC after ADT failure Testosterone ≤50 ng/dL Progressive disease with ongoing ADT Asymptomatic/ mildly symptomatic ECOG PS 0–1 Placebo QD + docetaxel 75 mg/m2/ 3 weeks + prednisone (5 mg BID) Open-label enzalutamide 160 mg QD R 1:1 Safety follow-up Enzalutamide (160 mg QD) + docetaxel 75 mg/m2/ 3 weeks + prednisone (5 mg BID) Planned evaluations rPFS, time to PSA progression, PSA response, objective response, time to pain progression, time to first SRE, QoL ADT=androgen-deprivation therapy; BID=twice daily; ECOG PS=Eastern Cooperative Oncology Group performance status; mCRPC=metastatic castration-resistant prostate cancer; PSA=prostate-specific antigen; QD=once daily; QoL=quality of life; R=randomisation; rPFS=radiographic progression-free survival. 2525 25

Ongoing trials PLATO: Continued enzalutamide treatment beyond progression in combination with abiraterone in chemotherapy-naïve mCRPC A Phase 4 randomised, double-blind placebo-controlled study Primary endpoint: PFS n=500 Chemotherapy- naïve mCRPC after ADT failure ECOG PS 0–1 Estimated life expectancy >12 months Placebo (QD) + abiraterone (1000 mg QD) + prednisone (5 mg BID) Open-label enzalutamide 160 mg QD R 1:1 PSA R I SE PROGRESS I ON Safety follow-up Enzalutamide (160 mg QD) + abiraterone (1000 mg QD) + prednisone (5 mg BID) Recruiting Planned evaluations PFS, time to PSA progression, PSA response, safety ADT=androgen-deprivation therapy; BID=twice daily; ECOG PS=Eastern Cooperative Oncology Group performance status; mCRPC=metastatic castration-resistant prostate cancer; PFS=progression-free survival; PSA=prostate-specific antigen; QD=once daily; R=randomisation. NCT01995513. Available at http://clinicaltrials.gov. Last accessed: April 2014. 2626 26

ALLIANCE: Study on enzalutamide with or without abiraterone in mCRPC Ongoing trials ALLIANCE: Study on enzalutamide with or without abiraterone in mCRPC A Phase 3 randomised, double-blind, placebo-controlled trial Primary endpoint: Metastatic-free survival Planned evaluations OS Safety, Grade ≥3 AEs Decline in PSA PFS Objective response rPFS Tumour burden and bone activity Timing Estimated primary completion December 2019 n=1224 Chemotherapy- naïve mCRPC No prior ketoconazole Progression after ADT ECOG PS 0–1 Enzalutamide (160 mg QD) Enzalutamide (160 mg QD) + abiraterone (1000 mg QD) + prednisone (5 mg BID) R 2:1 Recruiting ADT=androgen deprivation therapy; AE=adverse event; BID=twice daily; ECOG PS=Eastern Cooperative Oncology Group performance status; mCRPC=metastatic castration-resistant prostate cancer; OS=overall survival; PFS=progression-free survival; PSA=prostate-specific antigen; QD=once daily; R=randomisation; rPFS=radiographic PFS. NCT01949337. Available at http://clinicaltrials.gov. Last accessed: April 2014. 2727 27

Abiraterona + Enzalutamida

PEACE: EORTC: Comparing Radium-223 and Enzalutamide vs Enzalutamide Ongoing trials PEACE: EORTC: Comparing Radium-223 and Enzalutamide vs Enzalutamide A Phase 3 multicentre study Primary endpoint: sPFS 1 Planned evaluations Primary endpoint: sPFS 1 Secondary endpoints: PFS 2 ORR T1, T2 Predictive value bone markers and ADC (Diff coeff) Safety analysis At 25, 50, 100 patients At least two cycles or end of treatment Statistical analysis 233 events (Month 51) 90% power 9 month difference (17 vs. 26 months) 1-sided type 1 error 0.025 Enzalutamide (160 mg QD) + ADT n=510 Asymptomatic/mildly symptomatic Metastatic CRPC (≥2 bone mets) Visceral mets –ve Lymph node ±ve Maximum one line of treatment (chemo-naïve) BPI pain ≤4 (none to mild) Schedule for docetaxel, abi/P, enzalutamide ECOG 0–1 R Radium-223 50kBq/kg monthly, for 6 months + enzalutamide 160 mg QD + ADT Recruiting (subject to revision) FPI Q2/3 2014 Abi=abiraterone; ADC=apparent diffusion coefficient; ADT=androgen-deprivation therapy; BPI=Brief Pain Inventory; CRPC=castration-resistant prostate cancer; ECOG=Eastern Cooperative Oncology Group; FPI=first patient in; ORR=overall response rate; P=prednisone; PFS=progression-free survival; QD=once daily; R=randomisation. 30

Desarrollo clínico en cáncer próstata PSA Metastatic Symptoms Castration Resistant Non-Metastatic Asymptomatic Castration Sensitive Non-metastatic Castration resistant Castration sensitive First-line hormonal therapy/ castration Docetaxel + prednisone Local therapy Second-line hormonal therapies Bicalutamide, flutamide, nilutamide, etc. Cabazitaxel + prednisone Enzalutamide Abiraterone acetate + prednisone Sipuleucel-T Neoadjuvant† TERRAIN† Monotherapy† STRIVE† M0 CRPC ‡ PREVAIL Enzalutamide post abiraterone† AFFIRM UPWARD ALLIANCE PRESIDE PROSPER PLATO TERRAIN: estudio (en) fase II aleatorizado para valorar (sobre) la seguridad y eficacia de enzalutamida frente a bicalutamida en pacientes con mCP(M)RC. Los pacientes (n=370) se aleatorizaron al grupo de 160 mg/día de enzalutamida o al grupo de bicalutamida. La variable principal del estudio es la SLP Estudio en monoterapia: estudio (en) fase II, abierto, de un solo brazo (grupo), para valorar (sobre) la seguridad y eficacia de enzalutamida en pacientes con cáncer de próstata que no han recibido antes terapia de DA. Los pacientes (n=400) se aleatorizaron al grupo de 160 mg/día de enzalutamida. La variable principal del estudio es la respuesta del PSA, definida como una reducción ≥80 % en la semana 25. Neoadyuvante a la prostatectomía radical: estudio aleatorizado (en) fase II, abierto, sobre enzalutamida como tratamiento neoadyuvante para pacientes candidatos a prostatectomía radical. Los pacientes (n=50) se aleatorizarán a una combinación triple (160 mg de enzalutamida, 0,5 mg de dutasteride(a) y 22,5 mg de acetato de leuprorelina o a 160 mg de enzalutamida únicamente. La variable principal del estudio es la tasa de RC patológica. Time *Phase 1b; †Phase 2; ‡Phase 3. 31

Ongoing trials STRIVE: A study of Enzalutamide vs Bicalutamide in men with prostate cancer that failed primary ADT STRIVE is a Phase 2, randomised, double-blind, active-controlled trial Stratified by stage: M0N0, M0N1, or M1 Primary endpoint: PFS (biochemical or radiographic) Planned evaluations Biochemical or radiographic PFS Time to PSA progression PSA response (≥50% decline from baseline) Time to radiographic progression QoL (FACT-P) Safety Timing Estimated study completion June 2015 n=400 Progressive prostate cancer on first-line ADT* PSA ≥5 ng/mL or PSADT ≤10 months if PSA 2 to <5 ng/mL Enzalutamide 160 mg QD R 1:1 Bicalutamide 50 mg QD Enrolment complete ADT=androgen-deprivation therapy; FACT-P=Functional Assessment of Cancer Therapy-Prostate; PFS=progression-free survival; PSA=prostate-specific antigen; PSADT=PSA doubling time; QD=once daily; QoL=quality of life; R=randomisation. NCT01664923. Available at http://clinicaltrials.gov. Last accessed: April 2014. 3232 32

TERRAIN: A study of Enzalutamide vs Bicalutamide in castrate men with metastatic prostate cancer TERRAIN is a Phase 2, randomised, double-blind, active-controlled trial Primary endpoint: PFS Planned evaluations Radiographic PFS Time to first SRE Initiation of cytotoxic chemotherapy QoL (FACT-P, EQ-5D) PSA progression Pain palliation (BPI-SF) Safety (AEs, vital signs, physical exam, lab evaluations, ECG) PKs Timing Estimated study completion December 2014 n=370 mCRPC Asymptomatic or mildly symptomatic Progression after first-line ADT Enzalutamide 160 mg QD R 1:1 Bicalutamide 50 mg QD Enrolment complete 33

PROSPER: An efficacy and safety study of Enzalutamide in patients with non-metastatic CRPC M0 CRPC is a Phase 3, randomised, double-blind, placebo-controlled trial Primary endpoint: Metastatic-free survival Planned evaluations Metastatic-free survival OS Time to pain progression Time to opiate use for prostate cancer pain Time to first use of cytotoxic chemotherapy Time to first use of new antineoplastic therapy Time to PSA progression PSA response rates QoL Timing Estimated study completion August 2017 Enzalutamide 160 mg QD Placebo QD R 2:1 n=1560 Non-metastatic (M0) CRPC Testosterone ≤50 ng/dL Progressive disease with ongoing ADT Asymptomatic PSADT ≤10 months Recruiting ADT=androgen-deprivation therapy; CRPC=castration-resistant prostate cancer; EORTC=European Organisation for Research and Treatment of Cancer; FACT-P=Functional Assessment of Cancer Therapy-Prostate; OS=overall survival; PFS=progression-free survival; PSA=prostate-specific antigen; PSADT=PSA doubling time; QD=once daily; QLQ=Quality of Life Questionnaire; QoL=quality of life; R=randomisation. NCT02003924. Available at http://clinicaltrials.gov. Last accessed: April 2014. 3434 34

Enzalutamida en pacientes con cáncer de próstata sin tratamiento hormonal previo1,2 Estudio fase 2 que evalua la eficacia y seguridad de enzalutamida en monoterapia en pacientes con cáncer de próstata localizado, localmente avanzado o mestastásico que no hayan recibido previamente tratamientos hormonales o quimioterapia. Patient population Patients with hormone-naïve prostate cancer (all stages) Non-castrate levels of testosterone (≥230 ng/dL) PSA ≥2 ng/mL Rising PSA requiring ADT ECOG performance status 0 at screening Life expectancy ≥12 months (N=67)* Enzalutamide 160 mg QD for 25 weeks† Primary endpoint: PSA response (≥80% decline) at Week 52 Secondary endpoints: Enzalutamide PK PSA kinetics Changes in hormone levels Metabolic changes QoL Safety/tolerability *Patients must have an ECOG performance status of 0, life expectancy of >1 year. †If patients exhibited clinical benefit at Week 25, enzalutamide treatment was continued until disease progression or unacceptable toxicity. ADT=androgen-deprivation therapy; ECOG=Eastern Cooperative Oncology Group; mCRPC=metastatic castration-resistant prostate cancer; PK=pharmacokinetics; PSA=prostate-specific antigen; QD=once daily; QoL=quality of life. Tombal B, et al. ASCO-GU 2013; Poster presentation 18. Smith MR, et al. ECC 2013; Oral presentation 2852. 35

Maximum decline in PSA as percentage change from baseline Respuesta PSA semana 25 92.5% of patients (n=62*) experienced a PSA response† (95% CI: 86.2%–98.8%) Median decrease in PSA was 99.6% (range: –100 to –86.5%) 100 80 60 40 20 –20 –40 –60 –80 –100 Maximum decline in PSA as percentage change from baseline 1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58 61 64 67 Observations *Analysis was restricted to patients who completed the 25-week study period. Four patients who discontinued before Week 25 (for any reason) were considered non-responders; †≥80% decrease in PSA level. PSA=prostate-specific antigen. Tombal B, et al. ASCO-GU 2013; Poster presentation 18. 36

Cinética de la Respuesta por PSA

Cinética de las concetraciones séricas de LH y testosterona durante Enzalutamida Aumento medio de 185% en LH desde el basal a la semana 25 Aumento medio de 114% en la testosterona desde basal a la semana 25 450 400 350 300 250 200 150 100 50 LH Testosterone 185% (n=58) Concentration (%) 114% (n=63) 1 2 5 9 13 17 21 25 Time (weeks) LH=luteinising hormone. Tombal B, et al. ASCO-GU 2013; Poster presentation 18.

Neoadjuvant study: A study of Enzalutamide as a neoadjuvant therapy for patients undergoing prostatectomy for localised PC Phase 2, open-label, randomised study Stratified based on intermediate and high risk* Primary endpoint: Pathological CR rate Planned evaluations Pathological CR Downstage/surgical margins PSA, DHT, testosterone nadir, time to and duration of nadir Pharmacodynamic markers (proliferative index, apoptotic index, tumoural DHT, AR signalling markers, etc.) Safety and tolerability Timing Study completed 6 months of enzalutamide 160 mg QD + dutasteride 0.5 mg QD + leuprolide 22.5 mg SC Q3MOS prior to radical prostatectomy n=52 Intermediate to high risk prostate cancer* ≥3 positive cores ECOG PS 0–1 R 1:1 6 months of enzalutamide 160 mg QD prior to radical prostatectomy Completed *Intermediate risk: T2b or T2c clinical stage or PSA at screening 10–20 ng/mL or Gleason Score of 7; high risk: T3 clinical stage or PSA at screening >20 ng/mL or Gleason Score 8–10 AR=androgen receptor; CR=complete response; DHT=dihydrotestosterone; ECOG PS=Eastern Cooperative Oncology Group performance status; PSA=prostate-specific antigen; QD=once daily; Q3MOS=once every three months; R=randomisation; SC=subcutaneous. NCT01547299. Available at http://clinicaltrials.gov. Last accessed: April 2014. 3939 39

RESISTENCIA A ENZALUTAMIDA: LIGADA O NO AL RA Mechanisms of androgen independence. 1, amplification. Prostate cancer cells develop the ability to use low levels of androgen for survival by increased production of the androgen receptor (AR; usually by gene amplification), increased sensitivity of the androgen receptor to androgen, and by increased local conversion of testosterone to dihydrotestosterone by 5α-reductase (5αR). 2, promiscuous binding. Mutations of the androgen receptor broaden binding specificity allowing nonandrogenic steroid molecules normally present in the circulation as well as antiandrogens to bind and activate the androgen receptor. 3, outlaw pathway. Nonsteroid molecules activate the androgen receptor by ligand-dependent binding or activate downstream signaling of the androgen receptor by ligand-independent mechanisms [e.g., epidermal growth factor (EGF)]. 4, bypass pathway. Prostate cancer cells develop the ability of survive independent of the androgen receptor. The best known bypass pathway is through modulation of apoptosis by up-regulation of the molecule Bcl-2 by androgen-independent prostate cancer cells which protect them from apoptosis or programmed cell death when they are exposed to lack of testosterone. 5, coregulators. Alterations in the balance between coactivators and corepressors, which function as signaling intermediates between the androgen receptor and the transcriptional machinery, influence androgen receptor activation contributing to ability to respond to lower levels of androgen and alternative mechanisms of activation. 6, stem cell regeneration. Prostate cancer stem cells, which are not dependent on the androgen receptor for survival, continually resupply the tumor cell population despite therapy.

RESISTENCIA A ENZALUTAMIDA: LIGADA O NO AL RA Mechanisms of androgen independence. 1, amplification. Prostate cancer cells develop the ability to use low levels of androgen for survival by increased production of the androgen receptor (AR; usually by gene amplification), increased sensitivity of the androgen receptor to androgen, and by increased local conversion of testosterone to dihydrotestosterone by 5α-reductase (5αR). 2, promiscuous binding. Mutations of the androgen receptor broaden binding specificity allowing nonandrogenic steroid molecules normally present in the circulation as well as antiandrogens to bind and activate the androgen receptor. 3, outlaw pathway. Nonsteroid molecules activate the androgen receptor by ligand-dependent binding or activate downstream signaling of the androgen receptor by ligand-independent mechanisms [e.g., epidermal growth factor (EGF)]. 4, bypass pathway. Prostate cancer cells develop the ability of survive independent of the androgen receptor. The best known bypass pathway is through modulation of apoptosis by up-regulation of the molecule Bcl-2 by androgen-independent prostate cancer cells which protect them from apoptosis or programmed cell death when they are exposed to lack of testosterone. 5, coregulators. Alterations in the balance between coactivators and corepressors, which function as signaling intermediates between the androgen receptor and the transcriptional machinery, influence androgen receptor activation contributing to ability to respond to lower levels of androgen and alternative mechanisms of activation. 6, stem cell regeneration. Prostate cancer stem cells, which are not dependent on the androgen receptor for survival, continually resupply the tumor cell population despite therapy.

Mechanisms of androgen independence. 1, amplification Mechanisms of androgen independence. 1, amplification. Prostate cancer cells develop the ability to use low levels of androgen for survival by increased production of the androgen receptor (AR; usually by gene amplification), increased sensitivity of the androgen receptor to androgen, and by increased local conversion of testosterone to dihydrotestosterone by 5α-reductase (5αR). 2, promiscuous binding. Mutations of the androgen receptor broaden binding specificity allowing nonandrogenic steroid molecules normally present in the circulation as well as antiandrogens to bind and activate the androgen receptor. 3, outlaw pathway. Nonsteroid molecules activate the androgen receptor by ligand-dependent binding or activate downstream signaling of the androgen receptor by ligand-independent mechanisms [e.g., epidermal growth factor (EGF)]. 4, bypass pathway. Prostate cancer cells develop the ability of survive independent of the androgen receptor. The best known bypass pathway is through modulation of apoptosis by up-regulation of the molecule Bcl-2 by androgen-independent prostate cancer cells which protect them from apoptosis or programmed cell death when they are exposed to lack of testosterone. 5, coregulators. Alterations in the balance between coactivators and corepressors, which function as signaling intermediates between the androgen receptor and the transcriptional machinery, influence androgen receptor activation contributing to ability to respond to lower levels of androgen and alternative mechanisms of activation. 6, stem cell regeneration. Prostate cancer stem cells, which are not dependent on the androgen receptor for survival, continually resupply the tumor cell population despite therapy.

Mechanisms of androgen independence. 1, amplification Mechanisms of androgen independence. 1, amplification. Prostate cancer cells develop the ability to use low levels of androgen for survival by increased production of the androgen receptor (AR; usually by gene amplification), increased sensitivity of the androgen receptor to androgen, and by increased local conversion of testosterone to dihydrotestosterone by 5α-reductase (5αR). 2, promiscuous binding. Mutations of the androgen receptor broaden binding specificity allowing nonandrogenic steroid molecules normally present in the circulation as well as antiandrogens to bind and activate the androgen receptor. 3, outlaw pathway. Nonsteroid molecules activate the androgen receptor by ligand-dependent binding or activate downstream signaling of the androgen receptor by ligand-independent mechanisms [e.g., epidermal growth factor (EGF)]. 4, bypass pathway. Prostate cancer cells develop the ability of survive independent of the androgen receptor. The best known bypass pathway is through modulation of apoptosis by up-regulation of the molecule Bcl-2 by androgen-independent prostate cancer cells which protect them from apoptosis or programmed cell death when they are exposed to lack of testosterone. 5, coregulators. Alterations in the balance between coactivators and corepressors, which function as signaling intermediates between the androgen receptor and the transcriptional machinery, influence androgen receptor activation contributing to ability to respond to lower levels of androgen and alternative mechanisms of activation. 6, stem cell regeneration. Prostate cancer stem cells, which are not dependent on the androgen receptor for survival, continually resupply the tumor cell population despite therapy.

Mechanisms of androgen independence. 1, amplification Mechanisms of androgen independence. 1, amplification. Prostate cancer cells develop the ability to use low levels of androgen for survival by increased production of the androgen receptor (AR; usually by gene amplification), increased sensitivity of the androgen receptor to androgen, and by increased local conversion of testosterone to dihydrotestosterone by 5α-reductase (5αR). 2, promiscuous binding. Mutations of the androgen receptor broaden binding specificity allowing nonandrogenic steroid molecules normally present in the circulation as well as antiandrogens to bind and activate the androgen receptor. 3, outlaw pathway. Nonsteroid molecules activate the androgen receptor by ligand-dependent binding or activate downstream signaling of the androgen receptor by ligand-independent mechanisms [e.g., epidermal growth factor (EGF)]. 4, bypass pathway. Prostate cancer cells develop the ability of survive independent of the androgen receptor. The best known bypass pathway is through modulation of apoptosis by up-regulation of the molecule Bcl-2 by androgen-independent prostate cancer cells which protect them from apoptosis or programmed cell death when they are exposed to lack of testosterone. 5, coregulators. Alterations in the balance between coactivators and corepressors, which function as signaling intermediates between the androgen receptor and the transcriptional machinery, influence androgen receptor activation contributing to ability to respond to lower levels of androgen and alternative mechanisms of activation. 6, stem cell regeneration. Prostate cancer stem cells, which are not dependent on the androgen receptor for survival, continually resupply the tumor cell population despite therapy.

Enzalutamida es hoy una parte fundamental en el manejo del CPRC Conclusiones Enzalutamida es hoy una parte fundamental en el manejo del CPRC Enzalutamida, por su perfil de toxicidad, mínimo, lo hace idóneo para su aplicación en fases precoces de la enfermedad y en combinación Además de su incorporación a fases precoces de la enfermedad, optimizar la duración del tratamiento profundizando en los mecanismos de resistencia

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