CA NCER DE PRO STATA. OFRECIENDO UNA SECUENCIA O PTIMA DE TRATAMIENTO Enrique Gallardo egallardo@tauli.cat - @EnriqueGallar12
CONFLICTOS DE INTERÉS Consultant or Advisory Role: Sanofi, Janssen, Astellas, Pfizer, Bayer, Roche, Ipsen. Speaking: Astellas, Janssen, Sanofi, Bayer. Grant or travel support: Astellas, Janssen, Sanofi, Bayer. Participation in clinical trials: Sanofi, Astellas, Pfizer, Bayer, Ipsen, Bavarian-Nordic, Roche, Clovis.
CONSIDERACIONES INICIALES En los últimos años, y continúa, el panorama del cáncer de próstata ha experimentado importantes cambios en el conocimiento, los paradigmas y las secuencias de tratamiento. El mejor conocimiento de las características clínicas y sobre todo moleculares nos debería permitir mejorar la supervivencia y la calidad de vida de los pacientes.
WORLD CANCER INCIDENCE AND MORTALITY OF PROSTATE CANCER Ferlay J, et al. Int J Cancer 2015;136:E359-E386
PROSTATE CANCER LANDSCAPE Castration nmcrpc Clinically Localized Disease Rising PSA Noncastrate mcrpc: 1st line mcrpc: 2nd line mcrpc: n line Castration Clinical Metastases: Noncastrate Scher HI, et al. J Clin Oncol 2016;34:1402-1418
LAS CÉLULAS DEL CÁNCER DE PRÓSTATA SON SENSIBLES A LOS ANDRÓGENOS Premio Nobel 1966 Charles Huggins 1901-1997 Huggins C, Hodges CV. Cancer Res 1941;1(4):293-297
Nelson PS. N Engl J Med 2014;371(11):1067-9 VÍA DEL RECEPTOR ANDROGÉNICO
HR for death with intermittent therapy: 1.10 (90% CI, 0.99-1.23 Hussain M, et al. N Engl J Med 2013;368:1314-1325
Despite regressions of great magnitude, it is obvious that there are many failures of endocrine therapy to control the disease. Charles Huggins Nobel lecture December 13, 1966 LA RESISTENCIA PRIMARIA ES INTRÍNSECA A CUALQUIER MODALIDAD DE TRATAMIENTO HORMONAL
PROSTATE CANCER LANDSCAPE Castration nmcrpc Clinically Localized Disease Rising PSA Noncastrate mcrpc: 1st line mcrpc: 2nd line mcrpc: n line Castration Clinical Metastases: Noncastrate Scher HI, et al. J Clin Oncol 2016;34:1402-1418
DEFINITION OF CASTRATION-RESISTANT PROSTATE CANCER Castration serum testosterone < 50 ng/dl or 1.7 nmol/l + Biochemical progression Or Radiological progression Three consecutive rises in PSA 1 wk apart, resulting in two 50% increases over the nadir, and PSA >2 ng/ml. The appearance of new lesions: either two or more new bone lesions on bone scan or a soft tissue lesion using RECIST. Cornford P, et al. Eur Urol 2017;71(4):630-642
CPRC: ANTES DE 2004
CPRC 2004: DOCETAXEL
DOCETAXEL ES ESTÁNDAR EN PRIMERA LÍNEA DE QUIMIOTERAPIA EN CPRCm Tannock IF, et al. N Engl J Med 2004;351(15):1502-12 Petrylak D, et al. N Engl J Med 2004;351(15):1513-20
LOS TAXANOS BLOQUEAN LA TRASLOCACIÓN NUCLEAR DEL RECEPTOR ANDROGÉNICO Microtubules facilitate AR nuclear translocation and enhance downstream AR transcriptional activity - Taxanes block this pathway Zhu ML, et al. Cancer Res 2010;70:7992-8002 van Soest RJ, et al. Eur J Cancer 2013;49(18):3821-30
ENSAYOS NEGATIVOS EN COMBINACIÓN CON DOCETAXEL Docetaxel-HD Calcitriol 1 Docetaxel-Bevacizumab 2 Docetaxel-GVAX 3 Docetaxel-Oblimersen 4 Docetaxel-Lenalidomide 5 Docetaxel-Atrasentan 6 1. Scher HI, et al. J Clin Oncol. 2011;29(16):2191-8 2. Kelly WK, et al. J Clin Oncol. 2012;30(13):1534-40 3. Small EJ, et al. ASCO GU symposium 2009 (Abstract 7) 4. Sternberg CN, et al. Ann Oncol 2009;20:1264-9 5. Petrlyak D, et al. Lancet Oncol 2015;16(4):417-25 6. Quinn DI, et al. Lancet Oncol 2013;14(9):893-900 7. Tannock IF, et al. Lancet Oncol 2013;14(8):760-8 8. Fizazi KS, et al. J Clin Oncol 2013;31(14):1740-7 9. Araujo JC, et al. Lancet Oncol 2013;14(13):1307-16 10. Chi KN, et al. Lancet Oncol 2017;18(4):473-485 Docetaxel-Aflibercept 7 Docetaxel-Zibotentan 8 Docetaxel-Dasatinib 9 Docetaxel-Custirsen 10
OVERALL SURVIVAL WITH DOCETAXEL Trial Agent Nº of patients Median OS (mo) TAX 327 1 Mitoxantrone 335 18.9 CALGB 90401 2 Bevacizumab 526 21.5 VENICE 3 Aflibercept 612 21.2 READY 4 Dasatinib 760 21.2 SYNERGY 5 Custirsen 512 22.2 1 Tannock IF, et al. N Engl J Med 2004;351(15):1502-12 2 Kelly WK, et al. J Clin Oncol. 2012;30(13):1534-40 3 Tannock IF, et al. Lancet Oncol 2013;14(8):760-8 4 Araujo JC, et al. Lancet Oncol 2013;14(13):1307-16 5 Chi KN, et al. Lancet Oncol 2017;18(4):473-485
CPRC 2004-2010: DOCETAXEL
TRATAMIENTOS APROBADOS EN CPRCm EU approvals Docetaxel Abiraterone acetate (Post-chemo-301) Cabazitaxel Abiraterone acetate (Chemo-naïve-302) Enzalutamide (Post-chemo) Sipuleucel-T Radium-223 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 Docetaxel US approvals Sipuleucel-T Cabazitaxel Abiraterone acetate (Post-chemo-301) Enzalutamide (Chemo-naive) Radium-223 Abiraterone acetate (Chemo-naïve-302) Enzalutamide (Post-chemo)
CPRC: ACTUALMENTE
PHASE III TRIALS IN METASTATIC CASTRATION-RESISTANT PROSTATE CANCER AGENT/TRIAL STATUS CONTROL ARM OS (MONTHS) HAZARD RATIO P VALUE SIPULEUCEL-T IMPACT ABIRATERONE-P COU-AA-302 ENZALUTAMIDE PREVAIL DOCETAXEL-P TAX-327 ABIRATERONE-P COU-AA-301 ENZALUTAMIDE AFFIRM CABAZITAXEL-P TROPIC RADIUM 223 ALSYMPCA QT naïve Placebo 25.8 0.78 0.03 QT naïve Prednisone 34.7 0.81 0.0033 QT naïve Placebo 32.4 0.70 <0.0001 QT naïve Mitoxantrone-P 18.9 0.76 0.009 Post-docetaxel Prednisone 15.8 0.74 <0.0001 Post-docetaxel Placebo 18.4 0.63 <0.0001 Post-docetaxel Mitoxantrone-P 15.1 0.70 <0.0001 Pre&Post-docetaxel Placebo 14.9 0.70 <0.001 DENOSUMAB* Bone mets Zoledronic 20.7* 0.82 0.008 Kantoff PW, et al. N Engl J Med 2010;363:411-22. Ryan CJ, et al. Lancet Oncol 2015;16(2):152-60. Tannock IF, et al.n Engl J Med 2004;351(15):1502-12. De Bono JS, et al. Lancet 2010;376:1147-54. Fizazi K, et al. Lancet Oncol 2012;13(10):983-92. Scher HI, et al. N Engl J Med 2012;367(13):1187-97. Parker C, et al. N Engl J Med 2013;369:213-23. Fizazi K, et al. Lancet 2011;377(9768):813-22. Beer TM, et al. N Engl J Med 2014;371(5):424-33.
MECANISMO DE ACCIÓN DE SIPULEUCEL-T PAP antigen APC Recombinant PAP antigen combines with resting APC APC takes up the antigen Antigen is processed and presented on the APC surface Fully activated, the APC is now sipuleucel-t Active T-cell INFUSE PATIENT T-cells proliferate and attack cancer cells Sipuleucel-T activates T-cells in the body
Kantoff P, et al. N Engl J Med 2010;363:411-22 25.8 vs 21.7 mo HR 0.78; p =0.03
CABAZITAXEL Similar potencia en la estabilización de los microtúbulos Similar actividad en líneas celulares sensibles Cabazitaxel Mayor potencia en líneas celulares resistentes Escasa afinidad por la p-gp Penetra la barrera hematoencefálica Estabilización microtúbulos Vrignaud P, et al. Clin Cancer Res 2013;19(11):2973-83. Attard G, et al. Pathol Biol 2006;54:72 84. Mita AC, et al. Clin Cancer Res 2009;15:723 730. Galsky M. Nat Rev Drug Discov 2010;9(9):677-8
MP CBZP OS (months) 12.7 15.1 Hazard ratio 0.70 95% CI 0.59-0.83 p-value <0.0001 de Bono JS, et al. Lancet 2010;376:1147-54
TOXICIDAD DE CABAZITAXEL TROPIC 1 N=371 ATU Francia 2 N=184 EAP Italia 3 N=90 CUP Alemania 4 N=111 EAP UK 5 N=41 EAP EU 6,7 N=745 Edad >75 años 18% >70 años 38% >75 años 22% >75 años 18% >75 años 24% >70 años 44% Grado > 3 Neutropenia febril 8% 3% 3.3% 3.6% 4.9% 5.4% Diarrea 6% 3% 1.1% 0.9% 2.4% 2.8% Fatiga 5% - 3.3% - 2.4% 4.2% Astenia 5% 0.5% - - - 2.9% 1 De Bono et al. Lancet 2010; 376:1147-54. 2 Houédé et al. Ann Oncol 2012, 23 (suppl 9): p xi 314 (abstract 955). 3 Bracarda S. J Clin Oncol 30, 2012 (suppl; abstr e15185). 4 EAU 2012- Heidenreich et al., abstr 128. 5 Bahl et al. ASCO GU 2012. 6 DeVelasco G. ASCO 2012 abstract e15149). 7 Heidenreich et al. ESMO 2012 (poster 932P)
ESTUDIO PROSELICA Median OS, months (95% CI) CABA 20 + P 13.4 (12.19-14.88) CABA 25 + P 14.5 (13.47-15.28) Eisenberger M, et al. J Clin Oncol. 2017;35(28):3198-3206
AR IS ALWAYS PRESENT DURING THE DISEASE EVOLUTION EL RECEPTOR ANDROGÉNICO SE HALLA PRESENTE A LO LARGO DE LA EVOLUCIÓN DEL CÁNCER DE PRÓSTATA.
ENSAYOS FASE III CON NUEVOS AGENTES HORMONALES EN CPRCm Órsola A, Bellmunt J. Eur Urol 2015;67(1):30-2
MECANISMO DE ACCIÓN DE ABIRATERONA
MECANISMO DE ACCIÓN DE ENZALUTAMIDA
BENEFICIO EN SG EN 2ª LÍNEA DE ABIRATERONA Y ENZALUTAMIDA Fizazi K, et al. Lancet Oncol 2012;13:983-92 Scher HI, et al. N Engl J Med 2012;367(13):1187-97
BENEFICIO EN SG EN 1ª LÍNEA DE ABIRATERONA Y ENZALUTAMIDA Ryan CJ, et al. Lancet Oncol 2015;16(2):152-160 Beer TM, et al. N Engl J Med 2014;371:424-433
RADIUM-223 Tropismo por el hueso (bone-seeker) por propiedades calcio-miméticas Emisor de partículas radioactivas α - Vida media de 11,4 días Partículas α presentan corto alcance (2 10 células) - Por ello, el daño en los tejidos circundantes es mínimo Solución de dicloruro de radio ( 223 RaCl 2 ) Excreción por vía intestinal Henriksen et al. Can Res 2002;62:3120. Nilsson et al. Presented at: ASCO meeting 2010: Poster 2385. McDevitt et al. Eur J Nucl Med 1998;25:1341. Lewington et al. Presented at: Genitourinary Cancers Symposium 2010: Poster 216.
Median OS (months) Radium 223 Placebo 14.9 11.3 Hazard ratio 0.695 95% CI 0.581 0.832 P < 0.0001 Parker C, et al. N Engl J Med 2013;369:213-23
ESTUDIO FIRSTANA Median OS, months (95% CI) DOC + P 24.3 (22.18-27.60) CABA 20 + P 24.5 (21.75-27.20) CABA 25 + P 25.2 (22.90-26.97) Oudard S, et al. J Clin Oncol 2017;35(28):3189-3197
PROSTATE CANCER LANDSCAPE AND THERAPIES Abiraterone Enzalutamide Docetaxel Cabazitaxel Radium-223 Castration nmcrpc Clinically Localized Disease Rising PSA Noncastrate mcrpc: 1st line mcrpc: 2nd line mcrpc: n line Castration Clinical Metastases: Noncastrate Scher HI, et al. J Clin Oncol 2016;34:1402-1418
INFLUENCIA DE NUEVOS FÁRMACOS EN SUPERVIVENCIA EN CPRC DANA-FARBER TRENTO Francini E, et al.j Clin Oncol 36, 2018 (suppl 6S; abstr 203) Caffo O, et al. J Clin Oncol 36, 2018 (suppl 6S; abstr 323)
PROSTATE CANCER LANDSCAPE Castration nmcrpc Clinically Localized Disease Rising PSA Noncastrate mcrpc: 1st line mcrpc: 2nd line mcrpc: n line Castration Clinical Metastases: Noncastrate Scher HI, et al. J Clin Oncol 2016;34:1402-1418
DOCETAXEL Y ABIRATERONA SON ESTÁNDAR EN 1ª LÍNEA EN CÁNCER DE PRÓSTATA HORMONOSENSIBLE Sweeney CJ, et al. N Engl J Med 2015;373:737-46. James NJ, et al. Lancet 2016;387:1163 77 Fizazi K, et al. N Engl J Med 2017;377:352-60. James ND, et al. N Engl J Med 2017;377:338-51
DISEÑO DEL ESTUDIO STAMPEDE
DOCETAXEL ES ESTÁNDAR EN 1ª LÍNEA EN CÁNCER DE PRÓSTATA HORMONOSENSIBLE CHAARTED STAMPEDE Sweeney CJ, et al. N Engl J Med 2015;373:737-46 James NJ, et al. Lancet 2016;387:1163 77
Vale CL, et al. Lancet Oncol 2016;17(2):243-56 METAANÁLISIS CPHS M1 DOCETAXEL
TOXICIDAD DE DOCETAXEL EN 1ª LÍNEA STAMPEDE James ND, et al. Lancet 2016;387:1163 77
ABIRATERONA ES ESTÁNDAR EN 1ª LÍNEA EN CÁNCER DE PRÓSTATA HORMONOSENSIBLE Fizazi K, et al. N Engl J Med 2017;377:352-60 James ND, et al. N Engl J Med 2017;377:338-51
TOXICIDAD DE ABIRATERONA EN 1ª LÍNEA STAMPEDE James ND, et al. N Engl J Med 2017;377:338-51
PROSTATE CANCER LANDSCAPE AND THERAPIES Abiraterone Enzalutamide Docetaxel Cabazitaxel Radium-223 Castration nmcrpc Clinically Localized Disease Rising PSA Noncastrate mcrpc: 1st line mcrpc: 2nd line mcrpc: n line Castration Clinical Metastases: Noncastrate Abiraterone Docetaxel Scher HI, et al. J Clin Oncol 2016;34:1402-1418
PROSTATE CANCER LANDSCAPE Castration nmcrpc Clinically Localized Disease Rising PSA Noncastrate mcrpc: 1st line mcrpc: 2nd line mcrpc: n line Castration Clinical Metastases: Noncastrate Scher HI, et al. J Clin Oncol 2016;34:1402-1418
ENSAYOS PROSPER Y SPARTAN BENEFICIO EN SUPERVIVENCIA LIBRE DE METÁSTASIS Hussain M, et al. J Clin Oncol 36, 2018 (suppl 6S;abstr 3) Smith MR, et al. N Engl J Med 2018 Feb 8. doi: 10.1056/NEJMoa1715546. [Epub ahead of print]
Xie W, et al. J Clin Oncol 2017;25(37):3097-3104
Lorente D, et al. Lancet Oncol 2015:16(6):e279-92 M0 CRPC: SOME PATIENTS ARE REAL M1
Hussain M, et al. J Clin Oncol 36, 2018 (suppl 6S;abstr 3) PROSPER TOXICIDAD
Hussain M, et al. J Clin Oncol 36, 2018 (suppl 6S;abstr 3) PROSPER TOXICIDAD
SPARTAN TOXICIDAD Smith MR, et al. N Engl J Med 2018 Feb 8. doi: 10.1056/NEJMoa1715546. [Epub ahead of print]
Table S5. Causes of Death. SPARTAN TOXICIDAD Apalutamide (n=803) Placebo (n=398) no. of patients (%) All deaths within 28 days of last dose 10 (1.2) 1 (0.3) Adverse event 7 (0.9) 1 (0.3) Death due to prostate cancer 3 (0.4) 0 Other 0 0 Adverse events leading to death 10 1 Acute myocardial infarction 1 (0.1) 0 Cardio-respiratory arrest 1 (0.1) 1 (0.3) Cerebral hemorrhage 1 (0.1) 0 Myocardial infarction 1 (0.1) 0 Multiple organ dysfunction 1 (0.1) 0 Pneumonia 1 (0.1) 0 Prostate cancer 2 (0.2) 0 Sepsis 2 (0.2) 0 Smith MR, et al. N Engl J Med 2018 Feb 8. doi: 10.1056/NEJMoa1715546. [Epub ahead of print]
PROSTATE CANCER LANDSCAPE AND THERAPIES IN 2018 APALUTAMIDE ENZALUTAMIDE ABIRATERONE ENZALUTAMIDE DOCETAXEL CABAZITAXEL RADIUM-223 CASTRATION nmcrpc Clinically Localized Disease Rising PSA Noncastrate mcrpc: 1st line mcrpc: 2nd line mcrpc: n line CASTRATION Clinical Metastases: Noncastrate ABIRATERONE DOCETAXEL Scher HI, et al. J Clin Oncol 2016;34:1402-1418
SELECCIÓN Y SECUENCIA DE TRATAMIENTOS 1. Qué tratamiento elegimos como primera opción? 2. Cuál es la mejor secuencia de tratamientos? 3. Qué factores clínicos utilizamos para la selección? 4. Disponemos de factores moleculares útiles para identificar subgrupos y predecir mayor beneficio a los tratamientos?
ELECCIÓN DE TRATAMIENTO EN CPHS N POBLACIÓN OS (exp) OS (control) OS HR (IC95%) Docetaxel (CHAARTED) 790 M1 57,6 m 44 m 13,6 m 0.61 (0,47-0,8) Docetaxel (CHAARTED HV) 513 Docetaxel (STAMPEDE) 1776 Docetaxel (STAMPEDE) M1 Abiraterona (STAMPEDE) High volume M1 (>3 bone mets, visc mets) M1 High risk M0 (G8, PSA 40, T3-T4) 49.2 m 32.2 m 17 m 0.60 (0.45-0.81) 81 m 71 m 10 m 0.78 (0,66-0,93) 1087 M1 65 m 43 m 22 m 1917 Abiraterona (LATITUDE) 1199 M1 High risk M0 (G8, PSA 40, T3-T4) High-risk M1 (GS>=8, >=3 bone mets, visceral mets) - - - NR 34,7 m - 0.73 (0.59, 0.89) 0.63 (0.52 to 0.76) 0,62 (0.51 to 0.76)
COMPARACIÓN ABIRATERONA-DOCETAXEL EN STAMPEDE Overall survival [primary outcome measure] Comparación directa de 566 pacientes incluidos entre Nov 2011 y Mar 2013 SOC+DocP SOC+AAP Failure-free P-va survival H All (0.82 to 1.65) 0.40 Progression-free survival Metastatic progression-free Favours SOC+AAP Favours SOC+DocP M0 survival (0.58 to 3.93) 0.40 W M1 (0.77 to 1.66) 0.53 events N Symptomatic skeletal Cause-specific survival S St Overall survival SOC+DocP Hazard ratio SOC To Sydes M, et al. ESMO 2017 LBA31_PR Key: HR<1 favours SOC+AAP
COMPARACIÓN ENTRE LATITUDE Y CHAARTED (ALTO VOLUMEN) Median OS 3-y OS rate HR (IC95%) Control (meses) Interv (meses) Control Interv N (muertes) LATITUDE 0.62 (0.51-0.76) 34.7 NR 49% 66% 1199 (406) CHAARTED High volume 0.63 (0.50-0.79) 34.4 51.2 50% 65% 513 (299)
Platinum Priority Review Prostate Cancer Editorial by XXX on pp. x y of this issue Comparison of Abiraterone Acetate and Docetaxel with Androgen Deprivation Therapy in High-risk and Metastatic Hormone-naïve Prostate Cancer: A Systematic Review and Network Meta-analysis Christopher J.D. Wallis a,y, *, Zachary Klaassen a,b,y, Bimal Bhindi c, Hanan Goldberg a,b, Thenappan Chandrasekar a,b, Ann M. Farrell d, Stephen A. Boorjian c, Girish S. Kulkarni a,b, Robert Jeffrey Karnes c, Raj Satkunasivam a,e a Division of Urology, Department of Surgery, University of Toronto, Toronto, ON, Canada; b Division of Urology, Department of Surgery, Princess Margaret Hospital, University Health Network, Toronto, ON, Canada; c Department of Urology, Mayo Clinic, Rochester, MN, USA; d Mayo Clinic Libraries, Mayo Clinic, Rochester, MN, USA; e Department of Urology and Center for Outcomes Research, Houston Methodist Hospital, Houston, TX, USA Article info Article history: Accepted October 2, 2017 Associate Editor: Giacomo Novara Statistical Editor: Melissa Assel Keywords: Metastatic prostate cancer Locally advanced prostate cancer Hormone-naïve Docetaxel Abiraterone Androgen deprivation therapy Abstract Context: Randomized clinical trials have recently examined the benefit of adding docetaxel or abiraterone to androgen deprivation therapy (ADT) in hormone-naïve advanced prostate cancer (PCa). Objective: To perform a systematic review and network meta-analysis of randomized clinical trials, indirectly evaluating overall survival (OS) for men treated with abiraterone acetate plus prednisone/prednisolone with ADT (Abi-ADT) versus docetaxel with ADT (Doce-ADT) in hormone-naïve high-risk and metastatic PCa. Evidence acquisition: Medline, Embase, Web of Science, Scopus, and Clinicaltrials.gov databases were searched in August 2017. We pooled results using the inverse variance technique and random-effects models. The Bucher technique for indirect treatment comparison was used to compare Abi-ADT with Doce-ADT. A priori subgroup and sensitivity analyses were performed. Evidence synthesis: Overall, 6067 patients from five trials were included: 1181 (19.5%) patients who received Doce-ADT, 1557 (25.7%) patients who received Abi-ADT, and 3329 (54.9%) patients who received ADT-alone. There was a total of 1921 deaths: 391 in the Doce-ADT group, 353 in the Abi-ADT group, and 1177 in the ADT-only group. The pooled hazard ratio (HR) for OS was 0.75 (95%confidence interval [CI]: 0.63 0.91, I 2 = 51%, 3 trials, 2951 patients) for Doce-ADT versus ADT-alone and 0.63 (95%CI: 0.55 0.72, I 2 = 0%, 2 trials, 3116 patients) for Abi-ADT versus ADT-alone. The indirect comparison of Abi-ADT to Doce-ADT demonstrated no statistically significant difference in OS between these approaches (HR: 0.84, 95% CI: 0.67 1.06). Findings were similar in various a priori subset analyses, including patients with metastatic disease. Bayesian analyses demonstrated comparable results (HR: 0.83, 95%CI: 0.63 1.16). Despite the lack of statistical significance, Surface Under the Cumulative Ranking Analysis demonstrated an 89%probability that Abi-ADT was preferred. y These authors are co-first authors. * Corresponding author. Division of Urology, Department of Surgery, University of Toronto, 149 College Street, Room 503G, Toronto, ON M5T 1P5, Canada. Tel. +1 416 77 2960; Fax: +1 416 480 6934. E-mail address: wallis.cjd@gmail.com (Christopher J.D. Wallis). https://doi.org/10.1016/j.eururo.2017.10.002 Wallis CJD, et al. Eur Urol. 2017 Oct 13. pii: S0302-2838(17)30849-7. 0302-2838/ doi: 2017 10.1016/j.eururo.2017.10.002. European Association of Urology. Published by [Epub Elsevier ahead B.V. All rights of print] reserved. Please cite this article in press as: Wallis CJD, et al. Comparison of Abiraterone Acetate and Docetaxel with Androgen Deprivation Therapy in High-risk and Metastatic Hormone-naïve Prostate Cancer: A Systematic Review and Network Meta-analysis. Eur Urol (2017), https://doi.org/10.1016/j.eururo.2017.10.002
COMPARACIÓN ABIRATERONA-DOCETAXEL EN STAMPEDE Tratamiento tras la progresión en 566 pacientes tratados con Abi o Doce Overall survival [primary outcome measure] SOC+DocP SOC+AAP Patients progressing P-val All (0.82 to 1.65) 0.40 Any therapy Doc arm (N=311) 135 (43%) Abi arm (N=248) 131 (53%) M0 (0.58 to 3.93) 0.40 Docetaxel 14% 46% M1 (0.77 to 1.66) 0.53 Enzalutamide 7% 10% Abiraterone 28% 3% SOC+DocP Radium-223 6% 8% SOC+ Cabazitaxel 1% 6% Sydes M, et al. ESMO 2017 LBA31_PR Key: HR<1 favours SOC+AAP
Trat. DOCETAXEL + TDA RCEI Ensayo CHAARTED (High volume) Variable evaluada Mediana SG 51,2 meses Variable: Mediana SG Sc = 1, 75 m 2 Dif erencia de ef icacia 51,2 34,4 m = 16,8 m Dif erencia de cost es f armacológicos RCEI 4.074,29 (1) 2.910,2 / AVG (1) TDA 34,4 meses 16,8 m = 1,4 años CEI: Coste por año de vida ganado (AVG) (1) INCLUYE: DOCETAXEL, FACTORES DE CRECIMIENTO HEMATOPOYETICO Y COSTES DE ADMINISTRACIÓN EN HDDA RCEI Ensayo pivot al LATI TUDE(*) Variable: Mediana SG Trat. Variable evaluada Mediana SG Dif erencia de ef icacia Dif erencia de cost es f armacológicos RCEI ABI RATERONA + PREDNI SONA + TDA PLACEBO + PREDNI SONA +TDA 51,2* meses 51,2 34,7 m = 16,5 m 34,7meses* 16,5 m = 1,375 años 103.785 (1) 75.480 / AVG (1) Gines J. Congreso SEFH, CEI: 2017 Coste por año de vida ganado (AVG), teniendo en cuenta solamente el coste farmacológico (1) PVL Descuento 7,5% (RDL 8/2010)
Mínimamente sintomáticos Sintomáticos ELECCIÓN DE TRATAMIENTO EN CPRC N OS (exp) OS (control) OS HR RECIST Resp PSA Resp Docetaxel - TAX-327 1006 18,9 m 16,5 m 2,4 m 0,76 12% vs 7% 45% vs 32% Cabazitaxel - TROPIC 755 15,1 m 12,7 m 2,4 m 0,70 14.4% vs 4.% 39% vs 18% Abiraterona - COU-301 1195 15,8 m 11,2 m 3,4 m 0,74 14,8% vs 3,3% 29,5% vs 6% Enzalutamida - AFFIRM 1199 18,4 m 13,6 m 4,8 m 0,63 29% vs 4% 54% vs 2% Ra-223 - ALSYMPCA 921 14,9 m 11,3 m 3,6 m 0,70-16% vs 6% Abiraterona - COU-302 1088 34,7 m 30,3 m 4,4 m 0,81 36% vs 16% 62% vs 24% Enzalutamida - PREVAIL 1717 32,4 m 30,2 m 2,2 m 0,71 59% vs 5% 78% vs 3% Docetaxel - TAX-327 1006 18,9 m 16,5 m 2,4 m 0,76 12% vs 7% 45% vs 32%
RESISTENCIA CRUZADA ABIRATERONA-ENZALUTAMIDA De Bono JS, et al. ASCO GU 2017
RESISTENCIA CRUZADA ABI/ENZA DOCETAXEL (1) Mezynski et al. Ann Oncol 2012; Suzman et al. Prostate 2014; Schweizer et al. Eur Urol 2014; Azad et al. ASCO GU 2014; Zhang et al. Clin GU Cancer 2015; Aggarwal et al. Clin GU Cancer 2014 (2) Templeton et al. Ann Oncol 2013 (3) Berthold et al. J Clin Oncol 2008 (4) de Bono et al Eur Urol 2017
RESISTENCIA CRUZADA ABI/ENZA CABAZITAXEL Sella et al. Clin GU Cancer 2016; Al Nakouzi et al. Eur Urol 2014; Pezaro et al. Eur Urol 2014; Caffo et al. Eur Urol 2014; Sonpavde et al. Clin GU Cancer 2015; de Bono et al. Lancet 2010.
RESISTENCIA CRUZADA RADIUM 223 DOCETAXEL ALSYMPCA trial Similar beneficio de supervivencia en pre y post-docetaxel. Más toxicidad hematológica (trombopenia, neutropenia) en post-docetaxel. Docetaxel tras ALSYMPCA 2 Similar duración de docetaxel en post-placebo o Ra-223. G3-4 Hemato tox < 10%. Similar supervivencia con docetaxel en post-placeboy Ra-223. (1) Hoskin P et al. Lancet Oncol 2014 (2) Sartor O. et al Prostate 2016
CÓMO SELECCIONAR TERAPIAS Y PACIENTES? No disponemos de biomarcadores suficientemente validados que permitan la estratificación de los pacientes para mejorar la probabilidad de respuesta. No obstante, una aproximación pragmática es identificar grupos de pacientes a partir de criterios de inclusión, características de los fármacos y factores pronósticos.
CRITERIOS DE INCLUSIÓN EN ENSAYOS FASE III CPRC TAX327: Sintomáticos o asintomáticos COU-AA-302, PREVAIL: Mínimamente sintomáticos COU-AA-302, ALSYMPCA: Excluyen mets viscerales ALSYMPCA: Mets óseas sintomáticas Lorente et al, Lancet Oncol 2015;16:279-92 CPHS Diferente extensión de neoplasia: STAMPEDE: M1 o M0 alto riesgo CHAARTED: M1 (bajo/alto volumen) LATITUDE: M1 alto riesgo
CARÁCTERÍSTICAS DE LOS PACIENTES EN ESTUDIOS FASE III de Bono JS, et al. Lancet 2010;376:1147-54. Fizazi K, et al. Lancet Oncol 2012;13:983-92 Scher HI, et al. N Engl J Med 2012;367:1187-97. Parker C, et al. N Engl J Med 2013;369:213-23
TOXICIDAD DE LOS FÁRMACOS mhspc Similar rate of overall G3 events Early vs delayed toxicity?
FACTORES PRONÓSTICOS EN CÁNCER DE PRÓSTATA Gleason Niveles de PSA Tiempo de duplicación del PSA (PSA-DT) ECOG PS Presencia de dolor Tratamiento con opiáceos Metástasis viscerales Niveles basales de andrógenos Respuesta y duración del tratamiento hormonal previo Respuesta previa a docetaxel Tipo de progresión (factores de progresión) Niveles basales de albúmina, fosfatasas alcalinas, LDH, hemoglobina Ratio neutrófilos/linfocitos
ALGORITMO DE TRATAMIENTO EN 1ª LÍNEA EN CPRC Maroto P, et al. Crit Rev Oncol Hematol. 2016;100:127-36
MECANISMOS DE RESISTENCIA EN CÁNCER DE PRÓSTATA Dependientes del receptor androgénico Resistencia a quimioterapia EMT. Mutaciones de tubulina. P-glicoproteína. TMPRSS- ERG Fenotipos agresivos Tumores neuroendocrinos. Célula pequeña. Indiferenciados. Heterogeneidad tumoral
AR ADDICTION: A HARD HABIT TO BREAK * Elevación del PSA en la mayoría de casos de tumores resistentes a la castración Terapias hormonales que mantienen actividad antitumoral Niveles altos de andrógenos intratumorales a pesar de castración Mecanismos de resistencia que involucran al receptor androgénico Amplificación del RA (génica) Mutaciones del RA, que aumentan la actividad Aumento de actividad del RA en líneas de CaP resistentes Reactivación del RA en tumores resistentes a abiraterona y enzalutamida Translocaciones/fusiones oncogénicas (ETS: TMPRSS2/ERG) relacionadas con el RA * Attard G, et al. Cancer Cell 2009;16:458-462
RESISTENCIA A ABIRATERONA Open-label phase II study of 62 mcrpc patients treated with abiraterone + prednisone. Transilial bone marrow biopsies before treatment, at 8 weeks and at end of study. Efstathiou E, et al. J Clin Oncol 2012;30:637-43
RESISTENCIA A ENZALUTAMIDA 60 patients with bone mcrpc treated with enzalutamide. Transilial bone marrow biopsies before treatment and at 8 wk of treatment Efstathiou E, et al. Eur Urol 2015;67:53-60
ALTERACIONES EN ctdna DEL RECEPTOR ANDROGÉNICO SE RELACIONA CON RESISTENCIA A ABIRATERONA Romanel A, et al. Sci Transl Med 2015;7(312):312re10
Antonarakis ES, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 5001) AR SPLICE VARIANT: AR-V7
AR-V7 CONFIERE RESISTENCIA A ABI-ENZA, PERO NO A CABAZITAXEL Cabazitaxel Antonarakis ES, et al. N Engl J Med 2014;371:1028-38 Onstenk W, et al. Eur Urol 2015;68:939-45
Brief Correspondence TMPRSS2-ERG in Blood and Docetaxel Resistance in Metastatic Castration-resistant Prostate Cancer Òscar Reig a,b,y, Mercedes Marín-Aguilera a,c,y, Gemma Carrera d, Natalia Jiménez a,c, Laia Paré a,c, Susana García-Recio a,c, Lydia Gaba b, Maria Verónica Pereira b, Pedro Fernández e,f, Aleix Prat a,b,f, Begoña Mellado a,b, * a Translational Genomics and Targeted Therapeutics in Solid Tumours Group, Institut d Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; b Medical Oncology Department, Hospital Cl ínic, Barcelona, Spain; c Fundació Clínic per a la Recerca Biomèdica, Barcelona, Spain; d Medical Oncology Department, Hospital Plató, Barcelona, Spain; e Department of Pathology, Hospital Clínic, Barcelona, Spain; f University of Barcelona, Barcelona, Spain Article info Article history: Accepted February 11, 2016 Associate Editor: James Catto Keywords: Biomarker Docetaxel Prostate cancer Resistance TMPRSS2-ERG Reig O, et al. Eur Urol 2016;70(5):709-713 Abstract TMPRSS2-ERG rearrangement is a genetic alteration exclusive to prostate cancer, associated with taxane resistance in preclinical models. Its detection in blood samples of metastatic resistant prostate cancer (mcrpc) patients may indicate the presence of circulating tumour cells with this genetic alteration and may predict taxane resistance. To test this hypothesis, we evaluated TMPRSS2-ERG expression using quantitative reverse transcription polymerase chain reaction in peripheral blood mononuclear cells and tumour tissue from mcprc patients treated with taxanes. We examined peripheral blood mononuclear cells from 24 healthy controls, 50 patients treated with docetaxel, and 22 with cabazitaxel. TMPRSS2-ERG was detected in 0%, 16%, and 22.7%of them, respectively. In docetaxel-treated patients TMPRSS2-ERG detection correlated with lower prostatic-specific antigen (PSA) response rate (12.5%vs 68.3%, p = 0.005), PSAprogression-free survival (PFS; 3.1 mo vs 7.5 mo, p < 0.001), clinical/radiological-pfs (3.1 mo vs 8.2 mo, p < 0.001), and it was independently associated with PSA-PFS (hazard ratio 3.7; p = 0.009) and clinical/radiological- PFS (hazard ratio 6.3; p < 0.001). Moreover, TMPRSS2-ERG also predicted low PSA-PFS to cabazitaxel. At progression, a switch from negative to positive TMPRSS2-ERG was observed in 41%of patients with undetected TMPRSS2-ERG at the baseline sample. Tissue TMPRSS2-ERG expression correlated with lower PSA-PFS (p = 0.02) to docetaxel. Our findings support the potential role of TMPRSS2-ERG detection as a biomarker to tailor treatment strategies. Patient summary: Taxanes are the most active chemotherapy agents in metastatic resistant prostate cancer. However, not all patients respond to this therapy. In the present study we show that the detection of TMPRSS2-ERG in blood from metastatic resistant prostate cancer patients predicts resistance to docetaxel and it may be useful to
FENOTIPOS AGRESIVOS EN CÁNCER DE PRÓSTATA
RESPUESTA A PLATINO EN CÁNCER DE PRÓSTATA AGRESIVO
CRITERIOS CLÍNICOS DE CARCINOMA ANAPLÁSICO DE PRÓSTATA Aparicio AM, et al. Clin Cancer Res 2013;19(13):3621-30
GENES REPARADORES DEL ADN Mateo J, et al. DNA Repair in Prostate Cancer: Biology and Clinical Implications. Eur Urol 2017;71(3):417-425
GENES REPARADORES DEL ADN Pritchard et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med 2016;375:443-453
23% DE CPRC PRESENTAN ALTERACIONES DE GENES REPARADORES DEL ADN Robinson D, et al. Cell 2015;161:1215-1228
GENES REPARADORES DEL ADN: VALOR PREDICTOR?
Pomerantz et al. Cancer 2017;123(18):3532-3539 GENES REPARADORES DEL ADN: VALOR PREDICTOR?
Mateo J, et al. N Engl J Med 2015;373:1697-708
PROSTATE CANCER LANDSCAPE AND THERAPIES IN 2018 AND BEYOND APALUTAMIDE ENZALUTAMIDE ABIRATERONE ENZALUTAMIDE DOCETAXEL CABAZITAXEL RADIUM-223 CASTRATION nmcrpc Clinically Localized Disease Rising PSA Noncastrate mcrpc: 1st line mcrpc: 2nd line mcrpc: n line CASTRATION Clinical Metastases: Noncastrate Scher HI, et al. J Clin Oncol 2016;34:1402-1418 ABIRATERONE DOCETAXEL PERSONALIZED SEQUENCE OF THERAPIES
CONSIDERACIONES FINALES En los últimos años, y continúa, el panorama del cáncer de próstata ha experimentado importantes cambios en el conocimiento, los paradigmas y las secuencias de tratamiento. El mejor conocimiento de las características clínicas y sobre todo moleculares nos debería permitir mejorar la supervivencia y la calidad de vida de los pacientes.
Enrique Gallardo egallardo@tauli.cat @EnriqueGallar12