n y revisión de los avances en cáncer de próstata ... · agent/trial status control arm os (months) hazard ratio p value sipuleucel -t impact qt naïve placebo 25.8 0.78 0.03 abiraterone-p

Actualizacion y revision de los avances en cancer de

prostata resistente a la castracion

Enrique Gallardo [email protected] - @EnriqueGallar12

mailto:[email protected]

• Consultant or Advisory Role: Sanofi, Janssen, Astellas,

Pfizer, Bayer, Roche, Ipsen.

• Speaking: Astellas, Janssen, Sanofi, Bayer.

• Grant support: Astellas, Janssen, Sanofi, Bayer.

• Participation in clinical trials: Sanofi, Astellas, Pfizer, Bayer,

Ipsen, Bavarian-Nordic, Roche, Clovis.

CONFLICTS OF INTEREST

ÍNDICE

• Introducción

• Ensayos recientes en cáncer de próstata resistente a castración M0

–PROSPER

– SPARTAN

• Discusión

• Conclusiones

PROSTATE CANCER LANDSCAPE AND THERAPIES IN 2017

Scher HI, et al. J Clin Oncol 2016;34:1402-1418

Clinical Metastases: Noncastrate

Clinically Localized Disease

Rising PSA

Noncastrate

nmCRPC

mCRPC: 1st line

mCRPC: 2nd line

mCRPC: “n” line

Abiraterone Docetaxel

Abiraterone Enzalutamide

Docetaxel Cabazitaxel Radium-223

Castration

Castration

Biochemical progression

• Three consecutive rises in PSA 1 wk apart, resulting in two 50% increases over the nadir, and PSA >2 ng/ml.

Radiological progression

• The appearance of new lesions: either two or more new bone lesions on bone scan or a soft tissue lesion using RECIST.

DEFINITION OF CASTRATION-RESISTANT PROSTATE CANCER

Cornford P, et al. Eur Urol 2017;71(4):630-642

Castration serum

testosterone < 50 ng/dL or

1.7 nmol/L

Or +

AGENT/TRIAL STATUS CONTROL ARM OS (MONTHS) HAZARD RATIO P VALUE

SIPULEUCEL-T IMPACT

QT naïve Placebo 25.8 0.78 0.03

ABIRATERONE-P COU-AA-302

QT naïve Prednisone 34.7 0.81 0.0033

ENZALUTAMIDE PREVAIL

QT naïve Placebo 32.4 0.70 <0.0001

DOCETAXEL-P TAX-327

QT naïve Mitoxantrone-P 18.9 0.76 0.009

ABIRATERONE-P COU-AA-301

Post-docetaxel Prednisone 15.8 0.74 <0.0001

ENZALUTAMIDE AFFIRM

Post-docetaxel Placebo 18.4 0.63 <0.0001

CABAZITAXEL-P TROPIC

Post-docetaxel Mitoxantrone-P 15.1 0.70 <0.0001

RADIUM 223 ALSYMPCA

Pre&Post-docetaxel Placebo 14.9 0.70 <0.001

DENOSUMAB* Bone mets Zoledronic 20.7* 0.82 0.008

PHASE III TRIALS IN METASTATIC CASTRATION-RESISTANT PROSTATE CANCER

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.

PRESENT THERAPIES IN CASTRATION-RESISTANT PROSTATE CANCER

Lorente D, et al. Lancet Oncol 2015:16(6):e279-92

PROSTATE CANCER LANDSCAPE AND THERAPIES IN 2017

Scher HI, et al. J Clin Oncol 2016;34:1402-18

Clinical Metastases: Noncastrate

Clinically Localized Disease

Rising PSA

Noncastrate

nmCRPC

mCRPC: 1st line

mCRPC: 2nd line

mCRPC: “n” line

Abiraterone Docetaxel

Abiraterone Enzalutamide

Docetaxel Cabazitaxel Radium-223

Castration

Castration

NO STANDARD THERAPY

ANNUAL PROGRESSION AND MORTALITY RATES FOR THE BASE-CASE MODEL IN 2009 AND 2020 PROJECTIONS

Scher HI, et al. PLOS One 2015;10:e0139440


BASE CASE MODEL 2009


OUTCOMES WITH INTRODUCTION OF NEW THERAPY

mCRPC incidence mCRPC prevalence mCRPC mortality

Smith MR, et al. J Clin Oncol 2013;31(30):3800-3806

Smith MR, et al. J Clin Oncol 2013;31(30):3800-3806

ODAC – FDA voted “No” to recommend denosumab indication to prevent bone mets development in high-risk M0

CRPC.

ODAC Chairman, Dr. Wilson: “There’s an assumption that delaying bone metastases is beneficial. We are looking at a

radiographicbenefit here; this is a completely artificial endpoint”.

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:

THE RIGHT PATIENT FOR CLINICAL TRIAL

ClinicalTrials.gov: NCT02003924

PROSPER TRIAL

Enzalutamide

160 mg QD

Placebo QD

R 2:1

N=1401

Non-metastatic (M0) CRPC

Testosterone ≤50 ng/dL

Progressive disease with ongoing ADT

Asymptomatic

PSADT ≤10 months

• PROSPER is a multinational, Phase 3, randomised, double-blind, placebo-controlled trial

• Primary endpoint: Metastasis-free survival

MFS BENEFIT

Secondary endpoints:

• OS

• Time to pain progression

• Time to opiate use for prostate cancer pain

• Time to first use of cytotoxic chemotherapy

• Time to first use of new antineoplastic therapy

• Time to PSA progression

• PSA response rates

• QoL

• Safety

MECANISMO DE ACCIÓN DE ENZALUTAMIDA

ENZALUTAMIDE HAS PROVED SURVIVAL BENEFIT IN 1ST & 2ND LINES IN

MCRPC

Scher HI, et al. N Engl J Med 2012;367(13):1187-97 Beer TM, et al. N Engl J Med 2014;371:424-33

PROSPER – BASELINE CHARACTERISTICS

Hussain M, et al. J Clin Oncol 36, 2018 (suppl 6S;abstr 3)

PROSPER


PROSPER



PROSPER


PROSPER


PROSPER


PROSPER

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


PROSPER


PROSPER

ClinicalTrials.gov: NCT01946204

SPARTAN TRIAL

Apalutamide

240 mg QD

Placebo QD

R 2:1

N=1207

Non-metastatic (M0) CRPC

Testosterone ≤50 ng/dL

Progressive disease with ongoing ADT

Asymptomatic

PSADT ≤10 months

• SPARTAN is a multinational, Phase 3, randomised, double-blind, placebo-controlled trial

• Primary endpoint: Metastasis-free survival

MFS BENEFIT

Secondary endpoints

• Time to metastases

• Progression-free survival (PFS)

• Time to symptomatic progression

• Overall survival

• Time to first use of cytotoxic chemotherapy

Exploratory endpoints

• PFS2

• Time to PSA progression

• PSA decline

• Patient-reported outcomes (FACT-P, EQ-5D-3L)

Smith MR, et al. Eur Urol 2016;70:963-970

Platinum Priority – Prostate CancerEditorial by Daniel M. Geynisman, Elizabeth R. Plimack and Matthew Zibelman on pp. 971–973 of this issue

Phase 2 Study of the Safety and Antitumor Activity of

Apalutamide (ARN-509), a Potent Androgen Receptor Antagonist,

in the High-risk Nonmetastatic Castration-resistant Prostate

Cancer Cohort

Matthew R. Smitha,*, Emmanuel S. Antonarakisb, Charles J. Ryanc, William R. Berryd,

Neal D. Shoree, Glenn Liu f, Joshi J. Alumkal g, Celestia S. Higanoh, Edna Chow[17_TD$DIFF]Maneval i[5_TD$DIFF],

Rajesh Bandekar j, Carla J. deBoer k, Margaret K. Yu l, Dana E. Rathkopf m

aMassachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA; bSidney Kimmel Comprehensive Cancer Center at Johns

Hopkins University, Baltimore, MD, USA; cUCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; dCancer Centers of North

Carolina, Raleigh, NC, USA; eCarolina Urologic Research Center, MyrtleBeach, SC, USA; f University of Wisconsin CarboneCancer Center, Madison, WI, USA;gOregonHealth& ScienceUniversity,Knight Cancer Institute,Portland,OR,USA; hUniversity of Washington,FredHutchinsonCancer ResearchCenter,Seattle,WA,

USA; i Aragon Pharmaceuticals, San Diego, CA, USA; j Janssen Research & Development, [18_TD$DIFF]Spring House, PA, USA; kJanssen Biologics, B.V., Leiden, TheNetherlands;l Janssen Research [19_TD$DIFF]& Development, LosAngeles, CA, USA; mMemorial Sloan KetteringCancer Center and Weill Cornell Medical College, New York, NY, USA

EUROPEAN UROLOGY 70 ( 2016) 963–970

avai lable at www.sciencedi rect .co m

journal homepage: www.europeanurology.com

Article info

Article history:

Accepted April 21, 2016

Associate Editor:

James Catto

Keywords:

Antitumor activity

Apalutamide

Castration-resistant prostate

cancer

Safety

Abstract

Background: Apalutamideisapotent androgenreceptor (AR) antagonist that targetstheARligand-binding

domain and preventsARnuclear translocation,DNAbinding, and transcription of ARgenetargets.

Objective: To evaluate the activity and safety of apalutamide in patients with high-risk nonmetastatic

castration-resistant prostate cancer (nmCRPC).

Design,setting, and participants: Weconducted amulticenter phase2 study of nmCRPCpatientswith a

high risk for progression (prostate-specific antigen [PSA] 8 ng/ml or PSA doubling time [PSA DT] 10

mo).

Intervention: Patients received 240mg/d apalutamide while continuing on androgen-deprivation ther-

apy.

Outcome measurements and statistical analysis: Primary end point was 12-wk PSA response (Prostate

Cancer WorkingGroup 2 criteria). Secondary end pointsincluded safety, timetoPSAprogression (TTPP),

and metastasis-free survival (MFS).

Resultsand limitations: Atotal of 51 patientswereenrolled; [20_TD$DIFF]four patients with metastatic diseasewere

excluded from theefficacy analysis.Patient characteristicsincluded median age,71 yr; Eastern Coopera-

tiveOncology Group performance status 0 (76%); Gleason score 7 (57%); median PSA10.7 ng/ml; and

PSADT 10 mo(45%).At median follow-up of 28.0 mo,18patients (35%) remained in thestudy. Overall,

89%of patients had 50%PSAdecline at 12 wk.Median TTPPwas24.0 mo (95%confidence interval [CI],

16.3mo–not reached[NR]); medianMFSwasNR(95%CI,33.4mo–NR).Most of thepatientsdiscontinued

study treatment (n=33) due to diseaseprogression (n=11 [22%]) or adverse events (AEs) (n=9 [18%]).

Themost common AEwas fatigue (any grade, n=31 [61%]) although grade 3 fatigue wasuncommon

(n=2 [4%]). These represent the first apalutamide nmCRPCpatient clinical data.

Conclusions: In high-risk nmCRPCpatients,apalutamidewassafewith robust activity based on durable

PSA responses and disease control.

Patient summary: Antitumor activity and the safety of apalutamide in patients with nonmetastatic

castration-resistant prostate cancer support continued development in this setting.

Trial registration: ClinicalTrials.gov identifier NCT01171898

# 2016 European Association of Urology. Published by Elsevier B.V. This isan open accessarticle under

the CCBY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

* Corresponding author. Massachusetts General Hospital Cancer Center, Yawkey 7030, 55 Fruit

Street, Boston, MA 02114, USA. Tel. +1 617 724 5257; Fax: +1 617 726 4899.

E-mail address: [email protected] (M.R. Smith).

http://dx.doi.org/10.1016/j.eururo.2016.04.023

0302-2838/# 2016 European Association of Urology. Published by Elsevier B.V. This is an open access article under the CC

BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Downloaded for Anonymous User (n/a) at Parc Tauli Fundation from ClinicalKey.com by Elsevier on April 09, 2018.For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.

SPARTAN – BASELINE CHARACTERISTICS

Smith MR, et al. N Engl J Med 2018 Feb 8. doi: 10.1056/NEJMoa1715546. [Epub ahead of print]

SPARTAN – PRIMARY ENDPOINT: METASTASES-FREE SURVIVAL


40.5 mo

16.2 mo

SPARTAN – MFS SUBGROUP ANALYSIS


SPARTAN – SECONDARY AND EXPLORATORY ENDPOINTS



SPARTAN – MAIN SECONDARY ENDPOINTS

SPARTAN – PATIENT REPORTED OUTCOMES

Small EJ, et al. J Clin Oncol 36, 2018 (suppl 6S;abstr )


SPARTAN – ADVERSE EVENTS

SPARTAN – CAUSES OF DEATH


16

Table S5. Causes of Death.

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

SPARTAN – SUBSEQUENT THERAPIES


• Enzalutamide and apalutamide have

demonstrated a significant benefit in

Metastases-free survival, primary endpoint in

PROSPER and SPARTAN vs. placebo, with HR

0.29 and 0.28, and median MFS of 36.6 and

40.5 months, respectively.

• Also, benefit was present in secondary

objectives.

• However, some caveats may be considered.

PROSPER & SPARTAN

1. Do asymptomatic and M0 patients need to be

treated?

2. Is MFS an adequate endpoint?

3. Do clinical benefit balance side effects? Do

prolonged exposure to drugs provoke safety

concerns?

4. Do benefit justify costs?

PROSPER & SPARTAN

PSA DOUBLING TIME: PREDICTOR OF RISK OF METASTASES

Smith MR, et al. J Clin Oncol 2005;23(13):2918-25 Smith MR, et al. J Clin Oncol 2013;31(30):3800-6 Howard LE, et al. BJU Int 2017;120:E80-E86

Howard LE, et al. BJU Int 2017;120:E80-E86

PSA DOUBLING TIME: PREDICTOR OF SURVIVAL

M0 CRPC: SOME PATIENTS ARE REAL M1

Lorente D, et al. Lancet Oncol 2015:16(6):e279-92

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

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

rPFS MAY PREDICT OS

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

rPFS MAY PREDICT OS


SPARTAN – CLINICAL BENEFIT

SPARTAN – PATIENT REPORTED OUTCOMES


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


SPARTAN – ADVERSE EVENTS

SPARTAN – CAUSES OF DEATH


16

Table S5. Causes of Death.

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

PROSPER


• ¿Son enzalutamida y apalutamida nuevos SOC

en pacientes CRPC M0?

• Sí! Ensayos positivos con objetivo muy

probablemente adecuado (MFS), con

implicación estadística y clínicamente

significativa.

• Pero: Tener en cuenta exposición y toxicidades

a largo plazo, así como el coste de un

tratamiento muy prolongado.

CONCLUSIONES

Enrique Gallardo

[email protected]

@EnriqueGallar12

mailto:[email protected]

PREGUNTAS

1. Tiempo hasta progresión del PSA

2. Tiempo hasta la progresión sintomática

3. Supervivencia libre de progresión

4. Supervivencia libre de metástasis

5. Supervivencia global

¿Qué objetivo consideras adecuado para la evaluación

del beneficio de un fármaco en cáncer de próstata?

1. Sí, porque son pacientes metastásicos.

2. Sí, porque retrasa la aparición de metástasis

y, por tanto, las complicaciones.

3. No, por el riesgo de efectos secundarios.

4. No, por el elevado coste y la falta de estudios

farmacoeconómicos.

5. No, porque no hay beneficio demostrado de

supervivencia global.

¿Indicarías enzalutamida o apalutamida en pacientes

con cáncer de próstata resistente a la castración M0

(con criterios de riesgo??

Documents

n y revisión de los avances en cáncer de próstata ... · agent/trial status control arm os (months) hazard ratio p value sipuleucel -t impact qt naïve placebo 25.8 0.78 0.03 abiraterone-p