CPRC: CPRC M0, opciones terapéuticas. J Cassinello. Oncología Médica. Hospital Universitario de Guadalajara

CPRC: CPRC M0, opciones terapéuticas J Cassinello. Oncología Médica. Hospital Universitario de Guadalajara

Agenda Definición y diagnóstico de CPRC M0 PSA rising Historia natural y factores de riesgo de los pacientes con CPRC M0 Estudios fases III en la población CPRC M0 1

Dynamic progression of prostate cancer PSA Only (non-met CRPC) PSA Only Localized Disease mcrpc asymptomatic mcrpc mildly symptomatic mcrpc symptomatic mcrpc postdocetaxel mchspc Extensive Met ADT ADT + Docetaxel/ ABI in highvolume disease only? Abiraterone Abiraterone Enzalutamide Enzalutamide Docetaxel Radium 223 Sipuleucel-T supportive care (eg denosumab/bisphosphonates) Cabazitaxel 2

Dynamic progression of prostate cancer PSA Only (non-met CRPC) Tratamiento ADT????? PSA Only Localized Disease mcrpc asymptomatic mcrpc mildly symptomatic mcrpc symptomatic mcrpc postdocetaxel mchspc Extensive Met ADT ADT + Docetaxel/ ABI in highvolume disease only? Abiraterone Abiraterone Enzalutamide Enzalutamide Docetaxel Radium 223 Sipuleucel-T supportive care (eg denosumab/bisphosphonates) Cabazitaxel 3

Definición de CPRC M0 The Prostate Cancer Clinical Trials Working Group 2 (PCWG2) Rising PSA [> 2ng/ml, higher 25% than nadir and confirmed by second PSA at 3 weeks] Levels of testosterone < 50 ng/dl or <1.7 nmol/l No radiographic evidence of metastatic disease The Prostate Cancer Clinical Trials Working Group 3 (PCWG3) Nonmetastatic (nmcrpc) A rising PSA with no detectable disease in the primary site, in bone by radionuclide bone scan or CT or in visceral organs 4 Scher HI. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008; 26:1148-59 Sher HI. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol 34:1402-1418.

Definición de CPRC M0. CPRC M0: St. Gallen 2015. M0 is an artificial disease stage designation. The definition of M0 is dependent upon the imagen technology chosen. There is a high likelihood that systemic micro-metastases are missed by commonly used imaging tools (CT and bone scintigraphy). St. Gallen 2015 (77%): In daily clinical practise a negative CT and a negative Bone Scan are suficient for diagnosis of M0 disease. 5

Only technology limits our detection of the extremely small or the extremely remote. Eric Small, 2017 6

Papel de distintas técnicas de imagen en la valoración inicial MO. Información Ventajas Limitaciones GO Actividad osteoblástica Cuerpo completo TC Densidad ósea - Cuerpo completo - Alta Esp RM PET colina Alteraciones de señal Proliferación celular (carga tumoral) 1. Wade AA, et al. AJR 2006, 186:1783-86. 2. Talbot JN, et al. Q J Nucl Med Mol Imaging. 2011;55: 374-410. 3. Costelloe CM, et al. J Cancer 2010; 1: 80-92. 4. WondergemM, et al. Nucl Med Commun. 2013;34:935-45. Review. - Lesiones medulares - Alta Se - Cuerpo completo - Alta Se - Baja Esp - Lesiones líticas Lesiones medulares Lesiones corticales Disponibilidad 7

Extensión Patrón discordante 8 8

Diagnóstico de M0. PET con análogos de colina - Especialmente si los niveles de PSA son > 2 ng/ml o los tiempos de duplicación son bajos (<6 meses) o el Gleason inicial es > 7 1. PSMA? Lo que debiera hacerse según la evidencia. Elevada sensibilidad con niveles de PSA de 0,5 ng/ml [ASCO 2018] Bauman G, et al. 18F-fluorocholine for prostate cancer imaging: a systematic review of the literature. Prostate cancer and prostatic diseases. 2011:1-11. 9

Agenda Definición y diagnóstico de CPRC M0 PSA rising Historia natural y factores de riesgo de los pacientes con CPRC M0 Estudios fases III en la población CPRC M0 10

Prospective data on the natural history of M0 CRPC: phase III trials 11 Smith. et al. J Clin Oncol. 2005;23:2918-25 (Zoledrónico) Nelson et al Cancer 113:2478, 2008 (Atrasentan) Smith et al; Lancet 2012; 379:39 (Denosumab)

Risk Factors for Bone Metastases: comparison of the placebo arms Differences based on PSADT 12

1.432 CPRC PSA 8 ng/ml PSA-DT 10 meses Factores de estratificación: PSA 8 ng/ml y PSA-DT 10 meses (sí o no) QT previa o actual para CaP (sí o no) A L E A T O R I Z A C I Ó N 1:1 Denosumab 120 mg sc cada 4 semanas N=716 Placebo 120 mg sc cada 4 semanas N=716 Objetivo principal: Supervivencia libre de metástasis ósea o muerte Smith MR et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 2013; 379: 39-46 13

Relative Risk for Bone Metastasis or Death Shorter PSA Doubling Time is a Predictor of Increasing Risk for Bone Metastasis and Death 3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6 PSA DT eligibility criteria Median PSA DT at study entry 1.4 Placebo arm, N = 716 20 18 16 14 12 10 8 6 4 2 PSA Doubling Time in Months Placebo arm of the Denosumab study demonstrates shortening PSA doubling time as a predictor of increasing risk for bone metastases development In a separate study, PSA was a key risk factor for bone metastasis and a PSADT 6 months was significantly associated with shorter bone metastasis-free survival 1 Smith et al 15

Relative Risk for Bone Metastasis or Death Shorter PSA Doubling Time is a Predictor of Increasing Risk for Bone Metastasis and Death 3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6 PSA DT eligibility criteria Median PSA DT at study entry 1.4 Placebo arm, N = 716 20 18 16 14 12 10 8 6 4 2 PSA Doubling Time in Months Placebo arm of the Denosumab study demonstrates shortening PSA doubling time as a predictor of increasing risk for bone metastases development In a separate study, PSA was a key risk factor for bone metastasis and a PSADT 6 months was significantly associated with shorter bone metastasis-free survival 1 Smith et al (2005) 16

MSKCC PSADT calculate http://nomograms.mskcc.org/prostate/psadoublingtime.aspx 17

Agenda Definición y diagnóstico de CPRC M0 PSA rising Historia natural y factores de riesgo de los pacientes con CPRC M0 Estudios fases fases III en la población CPRC M0 18

M0 CASTRATION-RESISTANT PROSTATE CANCER: PHASE III CLINICAL TRIAL Trial Enrollment Treatment Primary endpoint PROSPER (NCT02003924) 1401 Enzalutamide 160 mg once daily vs placebo Metastasis-free survival SPARTAN (NCT01946204) 1207 Apalutamide 240 mg once daily vs placebo Metastasis-free survival ARAMIS (NCT02200614) 1509 Darolutamide 600 mg twice daily vs placebo Metastasis-free survival Positive results from the SPARTAN and PROSPER trials. ARAMIS ongoing with recruitment stopped. 22

SPARTAN, a Phase 3 Double-Blind, Randomized Study of Apalutamide vs Placebo in Patients With Nonmetastatic Castration-Resistant Prostate Cancer Presented By Eric Small at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care 23

Presented By Eric Small at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care 24

Presented By Eric Small at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

Conclusions 31 Presented By Eric Small at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

PROSPER: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Enzalutamide in Men With Nonmetastatic Castration-Resistant Prostate Cancer Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care 33

PROSPER Study Design Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care 34

Baseline Patient Characteristics (N = 1401) Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care 35

Primary Endpoint: MFS Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care 36

Subgroup Analysis of MFS Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

Time to PSA Progression Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care 37

Time to First Use of New Antineoplastic Therapy Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

Overall Survival: First Interim Analysis Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care 38

Adverse Events of Special Interest* 39 Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care

Conclusions Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care 40

Is MFS a surrogate for OS? Presented By Philip Kantoff at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care 41

Xie W, et al. J Clin Oncol 2017;25(37):3097-3104 42

rpfs MAY PREDICT OS in COU-AA-302 Morris MJ, et al. J Clin Oncol 2015;33 (12):1356-1363 43

rpfs MAY PREDICT OS in PREVAIL Rathkopf DE, et al. JAMA Oncoll 2018 Mar 8. doi: 10.1001/jamaoncol.2017.5808. [Epub ahead of print] 44

MFS OS 45

Efectos adversos Slide 27 Presented By Philip Kantoff at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care 47

Progression Event by Type 3% Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care 50

Conclusions Presented By Philip Kantoff at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care 66

Conclusiones aceptadas sobre SPARTAN y PROSPER 1. Ambos estudios positivos, demostrando que la inhibición precoz (M0) de la señalización androgénica es eficaz 2. SG todavía no madura. Numerosos análisis apoyan la asociación entre SLM y SG. 3. Los efectos secundarios deben monitorizarse y explicarse de manera adecuada. Esto implica elegir muy bien el tipo de paciente a tratarse con estos agentes.

Estudio PROSPER

SPARTAN y PROSPER Alguna novedad en ASCO 2018?

Smith M, ASCO 2018

Pacientes con reducción 50% de niveles PSA tuvieron significativamente menor riesgo de deterioro de la calidad de vida según puntuación FACT-P El 98% de los pacientes con respuesta PSA recibieron enzalutamida Un aumento clínicamente significativo en la puntuación total FACT-P se asoció con un 7% de reducción del riesgo de metástasis Attard G et al. Association between health-related quality of life and clinical outcomes in non-metastatic castration-resistant prostate cáncer: results from the PROSPER study [poster]. ASCO, Chicago, USA. Poster 237. 2018

Enzalutamida retrasó significativame nte el deterioro en la intensidad del dolor En el grupo de enzalutamida se observó un menor riesgo de deterioro de la calidad de vida Attard G et al. HRQoL deterioration and pain progression in men with non metastatic castration-resistant prostate cáncer: results from the PROSPER study [poster]. ASCO, Chicago, USA. Poster 237. 2018

PROSPER: longitudinal analysis of FACT-P total scores in patients with nm-crpc Median FACT-P value over time In PROSPER, good HRQoL was maintained during the treatment period in both groups Deterioration in HRQoL would be expected as patients progress and age FACT-P: mean change over time (PMM analysis) PMM assumes data missing not at random As expected, patients in both treatment arms experienced meaningful decline in FACT-P total score (>10 points) over time; the rate of decline was significantly slower in patients treated with enzalutamide PMM=pattern mixed model Tombal B, et al. 2018 EAU Meeting, Copnehagen 60

CONCLUSIONES Enzalutamida y apalutamida son nuevos agentes indicados en pacientes CRPC M0 de alto riesgo ( nuevo tratamiento estándar ) El objetivo de Supervivencia libre de Metástasis ( SLM) parece adecuado, al mostrar una cada vez mayor evidencia de una estrecha asociación con la SG en este contexto. Buena tolerancia a ambos tratamientos, aunque deben tenerse en cuenta la exposición a largo plazo y las toxicidades específicas de cada agente

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