Post on 30-Mar-2020
Avances en el tratamiento hormonal del CPRC sin metástasis
Javier CassinelloHospital Universitario de Guadalajara
• 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
Agenda
1
• 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
Agenda
2
• 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 2 (PCWG2)
The Prostate Cancer Clinical Trials Working Group 3 (PCWG3)
A rising PSA with no detectable disease in the primary site, in bone byradionuclide bone scan or CT or in visceral organs
Nonmetastatic (nmCRPC)
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.
3
Definición de CPRC M0
PROSTATE CANCER LANDSCAPE AND THERAPIES IN 2018
Scher HI, et al. J Clin Oncol 2016;34:1402-18
ClinicalMetastases: Noncastrate
ClinicallyLocalizedDisease
RisingPSA
Noncastrate
nmCRPC
mCRPC:1st line
mCRPC:2nd line
mCRPC:“n” line
AbirateroneDocetaxel
AbirateroneEnzalutamide
DocetaxelCabazitaxelRadium-223
Castration
NO STANDARD THERAPY
M0
5
30%
10-20%
TDA
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.
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Número de CPRC M0
M0
100.000 pacientes en USAIncidencia anual de 50-60.000
Sin tratamiento, el 30-50% de estos pacientesCPRC M0 desarrollarán metástasis en lossiguientes 2 años
CPRC M0:
St. Gallen 2015. M0 is an “artificial disease stage designation”.
The definition of M0 is dependent upon the imagen technologychosen”. There is a high likelihood that systemic micro-metastases aremissed by commonly used imaging tools (CT and bone scintigraphy).
– St. Gallen 2015 (77%): In daily clinical practise a negative CTand a negative Bone Scan are suficient for diagnosis of M0disease.
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Definición “artificial” de CPRC M0
Información Ventajas Limitaciones
GGO Actividad osteoblástica
Cuerpo completo
- Baja Esp- Lesiones líticas
TAC Densidad ósea - Cuerpo completo
- Alta Esp
Lesiones medulares
RM Alteraciones de señal
- Lesiones medulares
- Alta Se
Lesiones corticales
PET
colina
Proliferación celular (carga tumoral)
- Cuerpo completo
- Alta Se
Disponibilidad
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.
Papel de distintas técnicas de imagen en la valoración inicial MO.
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7
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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.
9
Disminución del número de CPRC M0 real con las nuevas técnicas
“M0”PET-colina
PSMA
“M0”
• 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
Agenda
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Prospective data on the natural history of M0 CRPC: phase III trials
11
Risk Factors for Bone Metastases:
comparison of the placebo arms
Supervivencia Libre de Metástasis (SLM): 25-30 m
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Risk Factors for Bone Metastases:
comparison of the placebo arms
30-40 % de estos pacientes desarrollan metástasis a 2 años
13
Risk Factors for Bone Metastases:
comparison of the placebo arms
Importancia del PSADT 14
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
1.432 CPRC
PSA ≥ 8 ng/mLPSA-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)
ALEATORIZACIÓN
1:1
Denosumab 120 mg sccada 4 semanas
N=716
Placebo 120 mg sccada 4 semanas
N=716
Objetivo principal:
• Supervivencia libre de metástasis ósea o muerte
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Shorter PSA Doubling Time is a Predictor of Increasing Risk for Bone Metastasis and Death
PSA Doubling Time in Months
Rela
tive R
isk f
or
Bo
ne M
eta
sta
sis
or
Death
Median
PSA DT at
study
entry
1.4
1.6
1.8
2.0
2.2
2.4
2.6
2.8
3.0
20 18 16 14 12 10 8 6 4 2
PSA DT
eligibility
criteria
Placebo arm, N = 716
• 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 survival1
Smith et al 16
Shorter PSA Doubling Time is a Predictor of Increasing Risk for Bone Metastasis and Death
PSA Doubling Time in Months
Rela
tive R
isk f
or
Bo
ne M
eta
sta
sis
or
Death
Median
PSA DT at
study
entry
1.4
1.6
1.8
2.0
2.2
2.4
2.6
2.8
3.0
20 18 16 14 12 10 8 6 4 2
PSA DT
eligibility
criteria
Placebo arm, N = 716
• 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 survival1
Smith et al (2005)
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CPRCM0: 2 types of patients
High risk for rapid progression (and may benefit
from earlier initiation of ADT)
• PSA ≥ 8 ng/ml and
PSADT ≤ 10 months
Observation may be employed if
• Lower PSA levels and
PSADT > 10 months
Smith MR et al. J Clin Oncol. 2013;31(30):3800–6.
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• 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 de alto riesgo
Agenda
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Nota de prensa estudio ARAMIS
Octubre de 2018
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Slide 5
Presented By Eric Small at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
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N= 1.207
Slide 7
Presented By Eric Small at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
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Slide 8
Presented By Eric Small at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
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Slide 9
Presented By Eric Small at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
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Slide 13
Presented By Eric Small at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
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Slide 17
Presented By Eric Small at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
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Slide 15
Presented By Eric Small at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
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Slide 16
Presented By Eric Small at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
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Slide 21
Presented By Eric Small at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
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Conclusions
Presented By Eric Small at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
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Slide 23
Presented By Eric Small at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
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Slide 25
Presented By Eric Small at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
Estudio SPARTAN
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PROSPER Study Design
Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
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Baseline Patient Characteristics (N = 1401)
Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
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Primary Endpoint: MFS
Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
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Subgroup Analysis of MFS
Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
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Overall Survival: First Interim Analysis
Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
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Time to PSA Progression
Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
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Time to First Use of New Antineoplastic Therapy
Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
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Conclusions
Presented By Maha Hussain at 2018 Genitourinary Cancers Symposium: Translating Evidence to Multidisciplinary Care
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Estudio PROSPER
46
• 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.
Conclusiones aceptadas sobre SPARTAN y PROSPER
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Apalutamida yEnzalutamidaen M0
Apalutamida yEnzalutamidaen M0
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Opinión positiva EMA nueva indicación enzalutamida en CPRCnm de alto riesgo
url: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002639/smops/Positive/human_smop_001356.jsp&mid=WC0b01ac058001d127. Ultimo acceso 25 sept 2018
Septiembre 2018
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Aprobación ENZALUTAMIDA EN CPRCnm por la EMA
24Octubre
Mateo J, et al. Managing Nonmetastatic Castration-resistant Prostate Cancer. Eur Urol (2018)
La aprobación de apalutamida y enzalutamida por la FDA en CPRC nm es la 1ª aprobación basada en beneficio de MFS en CaP y sienta un precedente para un cambio de paradigma en los ensayos clínicos de CaP
Opinión positiva EMA apalutamida en CPRCnm de alto riesgo
Noviembre 2018
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• ¿SLM como subrogado de SG en M0?
• Nuevos datos en ASCO Y ESMO 2018
Controversias y nuevos datos
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• ¿SLM como subrogado de SG en M0?
Controversia
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MFS
OS
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55N Engl J Med 2018 (June )
N Engl J Med 2018 (June )56
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de Almeida, ESMO 2018
66
de Almeida, ESMO 2018
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• 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 (aceptado por la FDA y EMA 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
CONCLUSIONES
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Gracias por su atención