avances en el tratamiento hormonal del cprc sin metástasis · • in a separate study, psa was a...

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.

5

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.

7

7

8

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

10

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

12

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

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 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)

17

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.

18

• 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

19

20

Nota de prensa estudio ARAMIS

Octubre de 2018

21

Slide 5

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

22

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

25

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

31

Slide 23

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

32

Slide 25

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

Estudio SPARTAN

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

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Subgroup Analysis of MFS

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

37

Overall Survival: First Interim Analysis

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

38

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

40

41

42

43

44

Conclusions

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

45

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

53

MFS

OS

54

55N Engl J Med 2018 (June )

N Engl J Med 2018 (June )56

57

de Almeida, ESMO 2018

66

de Almeida, ESMO 2018

67

• 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

68

Gracias por su atención