CPRC: CPRC M0, opciones terapéuticas...Papel de distintas técnicas de imagen en la valoración...

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

ADT

supportive care (eg denosumab/bisphosphonates)

mCRPC

post-

docetaxel

mCRPC

symptomatic

mCRPC

mildly

symptomatic

mCRPC

asymptomatic

Localized

Disease

Sipuleucel-T

Enzalutamide

Abiraterone Abiraterone

Docetaxel Cabazitaxel

Radium 223

Enzalutamide

ADT +

Docetaxel/

ABI in high-

volume

disease

only?

mCHSPC

Extensive

Met

PSA Only

PSA Only

(non-met

CRPC)

2

Dynamic progression of prostate cancer

ADT

supportive care (eg denosumab/bisphosphonates)

mCRPC

post-

docetaxel

mCRPC

symptomatic

mCRPC

mildly

symptomatic

mCRPC

asymptomatic

Localized

Disease

Sipuleucel-T

Enzalutamide

Abiraterone Abiraterone

Docetaxel Cabazitaxel

Radium 223

Enzalutamide

ADT +

Docetaxel/

ABI in high-

volume

disease

only?

mCHSPC

Extensive

Met

PSA Only

PSA Only

(non-met

CRPC)

3

Tratamiento ADT ?????

Definición de CPRC M0

• 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 by radionuclide 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.

4

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

Información Ventajas Limitaciones

GO

Actividad

osteoblástica

Cuerpo

completo

- Baja Esp

- Lesiones

líticas

TC

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.

7

8

Extensión Patrón discordante

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 > 71.

• ¿PSMA?

– Elevada sensibilidad con niveles de PSA de 0,5 ng/ml [ASCO 2018]

•

Lo que debiera hacerse según la evidencia.

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



• Estudios fases III en la población CPRC M0

10

Prospective data on the natural history of

M0 CRPC: phase III trials

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)

11

Risk Factors for Bone Metastases:

comparison of the placebo arms

12 Differences based on PSADT

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/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

13

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 15

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)

16

MSKCC PSADT calculate

http://nomograms.mskcc.org/Prostate/PsaDoublingTime.aspx

17

Agenda



• Estudios fases fases III en la población CPRC M0

18

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


ARAMIS (NCT02200614) 1509 Darolutamide 600 mg twice daily vs


Positive results from the SPARTAN and PROSPER trials. ARAMIS ongoing with recruitment stopped.

M0 CASTRATION-RESISTANT PROSTATE CANCER:

PHASE III CLINICAL TRIAL

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

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24


25


26


27


28


30

Conclusions


31


32

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


34

Baseline Patient Characteristics (N = 1401)


35

Primary Endpoint: MFS


36

Subgroup Analysis of MFS


Time to PSA Progression


37

Time to First Use of New Antineoplastic Therapy


Overall Survival: First Interim Analysis


38

Adverse Events of Special Interest*


39

Conclusions


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

Morris MJ, et al. J Clin Oncol 2015;33 (12):1356-1363

rPFS MAY PREDICT OS in COU-AA-302

43

Rathkopf DE, et al. JAMA Oncoll 2018 Mar 8. doi: 10.1001/jamaoncol.2017.5808. [Epub ahead of print]

rPFS MAY PREDICT OS in PREVAIL

44

MFS

OS

45


Efectos adversos

47


Efectos adversos

48


Efectos adversos

49

Progression Event by Type


50

3%

Conclusions


66

• 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

Estudio PROSPER

SPARTAN y PROSPER

¿Alguna novedad en ASCO 2018?

Smith M, ASCO 2018

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

Pacientes con reducción ≥50% de niveles PSA tuvieron significativamente menor riesgo de deterioro de la calidad de vida según puntuación FACT-P

Un aumento clínicamente significativo en la puntuación total FACT-P se asoció con un 7% de reducción del riesgo de metástasis

El 98% de los pacientes con respuesta PSA recibieron enzalutamida

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

Enzalutamida retrasó significativamente el deterioro en la intensidad del dolor

En el grupo de enzalutamida se observó un menor riesgo de deterioro de la calidad de vida

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

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

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

Gracias por su atención

CPRC: CPRC M0, opciones terapéuticas...Papel de distintas técnicas de imagen en la valoración...

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