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NCT04191096

PHASE3

Efficacy and Safety of Pembrolizumab (MK-3475) Plus Enzalutamide Plus Androgen Deprivation Therapy (ADT) Versus Placebo Plus Enzalutamide Plus ADT in Participants With Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) (MK-3475-991/KEYNOTE-991)

Sponsor: Merck Sharp & Dohme LLC

View on ClinicalTrials.gov

Summary

This study will assess the efficacy and safety of pembrolizumab plus enzalutamide plus Androgen Deprivation Therapy (ADT) versus placebo plus enzalutamide plus ADT in participants with mHSPC. The primary hypothesis is that in participants with mHSPC, the combination of pembrolizumab plus enzalutamide plus ADT is superior to placebo plus enzalutamide plus ADT with respect to 1) radiographic progression-free survival (rPFS) per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as assessed by blinded independent central review (BICR) and 2) overall survival (OS). As of 19-JAN-2023, the study was unblinded and all study participants stopped ongoing treatment with pembrolizumab/placebo and will continue to receive Standard of Care treatment until meeting protocol-specified discontinuation criteria if deriving clinical benefit. Safety analysis will be performed at the end of the study; there will be no further analyses for efficacy and electronic patient-reported outcome (ePRO) endpoints collected from participants beyond the IA1 cutoff date. All study participants will stop ongoing treatment with pembrolizumab/placebo. Exceptions may be requested for study participants who, in the assessment of their study physician, are benefitting from the combination of enzalutamide and pembrolizumab, after consulting with the Sponsor. All other study participants should be discontinued from study and be offered standard of care (SOC) treatment as deemed necessary by the Investigator. If enzalutamide as SOC is not accessible off study to the participant, central sourcing may continue. As of Amendment 04, disease progression will no longer be centrally verified, participants will only be assessed locally. As of Amendment 4, Second Course treatment is not an option for participants. There are currently no participants in the Second Course Phase.

Official title: A Phase 3, Randomized, Double-blind Trial of Pembrolizumab (MK-3475) Plus Enzalutamide Plus ADT Versus Placebo Plus Enzalutamide Plus ADT in Participants With Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) (KEYNOTE-991)

Key Details

Gender

MALE

Age Range

18 Years - Any

Study Type

INTERVENTIONAL

Enrollment

1251

Start Date

2020-02-12

Completion Date

2026-04-08

Last Updated

2026-09-28

Healthy Volunteers

Conditions

Metastatic Hormone-Sensitive Prostate Cancer

Interventions

BIOLOGICAL

Pembrolizumab

Pembrolizumab is administered as an IV infusion at 200 mg on Day 1 of each 21-day cycle for up to 35 cycles.

DRUG

Enzalutamide

Enzalutamide is administered orally as capsules/tablets at a dosage of 160 mg daily. Enzalutamide is administered continuously until criteria for discontinuation are met.

DRUG

Androgen Deprivation Therapy (ADT)

Stable regimen of ADT (LHRH agonist or antagonist) at a dose and frequency of administration that is consistent with the local product label.

OTHER

Placebo

Placebo infusion solution is administered as an IV infusion on Day 1 of each 21-day cycle for up to 35 cycles.

Inclusion Criteria: * Male participants with histologically- or cytologically-confirmed adenocarcinoma of the prostate without small cell histology * Has metastatic disease assessed by investigator and verified by BICR by either ≥2 bone lesions on bone scan and/or visceral disease by computed tomography/magnetic resonance imaging (CT/MRI) * Willing to maintain continuous Androgen Deprivation Therapy (ADT) with a luteinizing-hormone releasing hormone (LHRH) agonists or antagonists during study treatment or have a history of bilateral orchiectomy * Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 10 days of randomization * Participants receiving bone resorptive therapy (including, but not limited to, bisphosphonate or denosumab) must have been on stable doses prior to randomization * Has adequate organ function * Has provided newly obtained core or excisional biopsy (obtained within 12 months of screening) from soft tissue not previously irradiated (samples from tumors progressing in a prior site of radiation are allowed). Participants with bone only or bone predominant disease may provide a bone biopsy sample * Male participants must agree to the following during the intervention period and for at least 120 days after the last dose of study intervention: Refrain from donating sperm PLUS either be abstinent from heterosexual intercourse and agree to remain abstinent OR agree to use contraception, unless confirmed to be azoospermic * Male participants must agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person of any sex Exclusion Criteria: * Has a known additional malignancy that is progressing or has required active treatment in the last 3 years * Has an active autoimmune disease that has required systemic treatment in past 2 years * Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy * Has undergone major surgery including local prostate intervention (excluding prostate biopsy) within 28 days prior to randomization and not recovered adequately from the toxicities and/or complications * Has a gastrointestinal disorder affecting absorption or is unable to swallow tablets/capsules * Has an active infection (including tuberculosis) requiring systemic therapy * Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis * Has known active human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) infection * Has known or suspected central nervous system (CNS) metastases and/or carcinomatous meningitis * Has a history of seizure or any condition that may predispose to seizure * Has a history of loss of consciousness within 12 months of screening * Has had myocardial infarction or uncontrolled angina within 6 months prior to randomization, or has New York Heart Association class III or IV congestive heart failure or a history of New York Heart Association class III or IV congestive heart failure * Has hypotension (systolic blood pressure \<86 millimeters of mercury \[mmHg\]) or uncontrolled hypertension (systolic blood pressure \>170 mmHg or diastolic blood pressure \>105 mmHg) at the screening visit * Has a history of clinically significant ventricular arrhythmias * Has hypersensitivity to pembrolizumab and/or enzalutamide and/or any of their excipients * Has received prior ADT as neoadjuvant/adjuvant therapy for non-metastatic prostate cancer for \>39 months in duration or within 9 months prior to randomization or with evidence of disease progression while receiving ADT * Has had prior treatment with a next generation hormonal agent (eg, abiraterone, enzalutamide, apalutamide, darolutamide) * Has received prior therapy with an anti-programmed cell death-1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti-programmed cell death-ligand 2 (anti PD-L2) agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor * Has received a live vaccine within 30 days prior to randomization * Has a "superscan" bone scan * Has had an allogenic tissue/solid organ transplant * Is expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment * Has received any prior pharmacotherapy, radiation therapy or surgery for metastatic prostate cancer with the following exceptions: 1. Up to 3 months of ADT or orchiectomy with or without concurrent first-generation antiandrogens, if patient was not treated with docetaxel 2. May have 1 course of palliative radiation or surgical therapy to treat symptoms resulting from metastatic disease if it was administered at least 4 weeks prior to randomization 3. For participants with low volume metastatic disease, may have 1 course of definitive radiotherapy if it was administered at least 4 weeks prior to randomization 4. Up to 6 cycles of docetaxel therapy with final treatment administration completed within 2 months of randomization and no evidence of disease progression. In these participants up to 6 months of ADT permitted

Locations (234)

Alaska Clinical Research Center ( Site 0274)

Anchorage, Alaska, United States

Providence Alaska Medical Center ( Site 0276)

Anchorage, Alaska, United States

City of Hope Medical Center ( Site 0217)

Duarte, California, United States

UCLA Hematology/Oncology - Santa Monica ( Site 0241)

Los Angeles, California, United States

University of Colorado, Anschutz Cancer Pavilion ( Site 0236)

Aurora, Colorado, United States

Hartford HealthCare Medical Group ( Site 0212)

Manchester, Connecticut, United States

Smilow Cancer Center at Yale-New Haven ( Site 0250)

New Haven, Connecticut, United States

Sibley Memorial Hospital ( Site 0275)

Washington D.C., District of Columbia, United States

Winship Cancer Institute of Emory University ( Site 0209)

Atlanta, Georgia, United States

The University of Chicago ( Site 0264)

Chicago, Illinois, United States

Springfield Clinic [Springfield, IL] ( Site 0240)

Springfield, Illinois, United States

Cotton-O'Neil Cancer Center ( Site 0228)

Topeka, Kansas, United States

The Sidney Kimmel Comprehensive Cancer Center ( Site 0204)

Baltimore, Maryland, United States

St. Vincent Frontier Cancer Center-Research ( Site 0213)

Billings, Montana, United States

Comprehensive Cancer Centers of Nevada ( Site 0269)

Las Vegas, Nevada, United States

Laura and Isaac Perlmutter Cancer Center at NYU Langone Health ( Site 0270)

New York, New York, United States

Weill Cornell Medical College ( Site 0263)

New York, New York, United States

Associated Medical Professionals of NY ( Site 0251)

Syracuse, New York, United States

Duke University ( Site 0206)

Durham, North Carolina, United States

TriState Urologic Services PSC Inc. dba The Urology Group ( Site 0253)

Cincinnati, Ohio, United States

MidLantic Urology ( Site 0273)

Bala-Cynwyd, Pennsylvania, United States

Ralph H. Johnson VA Center ( Site 0256)

Charleston, South Carolina, United States

Carolina Urologic Research Center ( Site 0259)

Myrtle Beach, South Carolina, United States

Urology Associates [Nashville, TN] ( Site 0233)

Nashville, Tennessee, United States

Inova Health System ( Site 0205)

Fairfax, Virginia, United States

Urology of Virginia ( Site 0224)

Virginia Beach, Virginia, United States

Fred Hutchinson Cancer Center ( Site 0258)

Seattle, Washington, United States

Chris OBrien Lifehouse ( Site 0300)

Camperdown, New South Wales, Australia

Port Macquarie Base Hospital ( Site 0301)

Port Macquarie, New South Wales, Australia

Riverina Cancer Care Center ( Site 0302)

Wagga Wagga, New South Wales, Australia

Gallipoli Medical Research Ltd ( Site 0309)

Greenslopes, Queensland, Australia

John Flynn Hospital & Medical Centre ( Site 0308)

Tugun, Queensland, Australia

Box Hill Hospital ( Site 0304)

Box Hill, Victoria, Australia

Monash Health ( Site 0305)

Clayton, Victoria, Australia

Peter MacCallum Cancer Centre-Parkville Cancer Clinical Trials Unit (PCCTU) ( Site 0306)

Melbourne, Victoria, Australia

Fiona Stanley Hospital ( Site 0311)

Perth, Western Australia, Australia

Ordensklinikum Linz GmbH Elisabethinen ( Site 0901)

Linz, Upper Austria, Austria

Landeskrankenhaus Salzburg - Universitatklinikum der PMU ( Site 0900)

Salzburg, Austria

Krankenhaus der Barmherzigen Brüder Wien ( Site 0904)

Vienna, Austria

Medizinische Universität Wien ( Site 0903)

Vienna, Austria

Oncocentro Ceara ( Site 2309)

Fortaleza, Ceará, Brazil

Instituto de Cancer e Transplante de Curitiba ICTR ( Site 2306)

Curitiba, Paraná, Brazil

Hospital Sao Vicente de Paulo ( Site 2303)

Passo Fundo, Rio Grande do Sul, Brazil

Hospital de Clinicas de Porto Alegre ( Site 2304)

Porto Alegre, Rio Grande do Sul, Brazil

Clinica de Oncologia Reichow ( Site 2308)

Blumenau, Santa Catarina, Brazil

Fundacao Dr Amaral Carvalho ( Site 2302)

Jaú, São Paulo, Brazil

Instituto do Cancer do Estado de Sao Paulo - ICESP ( Site 2305)

São Paulo, Brazil

The Ottawa Hospital ( Site 0100)

Ottawa, Ontario, Canada

Niagara Health System - St. Catharines ( Site 0107)

St. Catharines, Ontario, Canada

CISSS de la Monteregie-Centre ( Site 0105)

Greenfield Park, Quebec, Canada

Centre Hospitalier de l Universite de Montreal - CHUM ( Site 0109)

Montreal, Quebec, Canada

CIUSSS Ouest de l Ile - St-Mary s Hospital ( Site 0106)

Montreal, Quebec, Canada

Centre intégré de cancérologie du CHU de Québec Université Laval, Hôpital de l'Enfant-Jésus ( Site 0101)

Québec, Quebec, Canada

Centro Investigación del Cáncer James Lind ( Site 2401)

Temuco, Araucania, Chile

IC La Serena Research ( Site 2406)

La Serena, Coquimbo Region, Chile

Clinica Universidad Catolica del Maule ( Site 2407)

Talca, Maule Region, Chile

Clinica Alemana ( Site 2408)

Santiago, Region M. de Santiago, Chile

Pontificia Universidad Catolica de Chile ( Site 2402)

Santiago, Region M. de Santiago, Chile

Bradfordhill ( Site 2403)

Santiago, Region M. de Santiago, Chile

Oncocentro ( Site 2400)

Viña del Mar, Valparaiso, Chile

Peking University First Hospital ( Site 0800)

Beijing, Beijing Municipality, China

Beijing Cancer Hospital ( Site 0802)

Beijing, Beijing Municipality, China

Chongqing Cancer Hospital ( Site 0815)

Chongqing, Chongqing Municipality, China

The First Affiliated Hospital of Xiamen University ( Site 0816)

Xiamen, Fujian, China

The First Affiliated Hospital of Guangzhou Medical University-Urology ( Site 0837)

Guangdong, Guangdong, China

Sun Yat-Sen University Cancer Center ( Site 0825)

Guangzhou, Guangdong, China

Sun Yat Sen Memorial Hospital ( Site 0819)

Guangzhou, Guangdong, China

Southern Medical University Nanfang Hospital ( Site 0838)

Guangzhou, Guangdong, China

Harbin Medical University Cancer Hospital ( Site 0822)

Harbin, Heilongjiang, China

Henan Cancer Hospital ( Site 0818)

Zhengzhou, Henan, China

Union Hospital Tongji Medical College Huazhong University of Science and Technology ( Site 0829)

Wuhan, Hubei, China

Hubei Cancer Hospital ( Site 0833)

Wuhan, Hubei, China

Hunan Cancer Hospital ( Site 0817)

Changsha, Hunan, China

Nanjing Drum Tower Hospital ( Site 0811)

Nanjing, Jiangsu, China

The First Affiliated Hospital of Nanchang University ( Site 0821)

Nanchang, Jiangxi, China

The Second Affiliated Hosp of Xi'an Jiaotong Univ College of Medicine ( Site 0831)

Xi'an, Shaanxi, China

Renji Hospital Shanghai Jiaotong University School of Medicine ( Site 0807)

Shanghai, Shanghai Municipality, China

The first affiliated Hospital of Xi an Jiaotong University ( Site 0812)

Xi’an, Shanxi, China

Tianjin Medical University Cancer Institute & Hospital ( Site 0804)

Tianjin, Tianjin Municipality, China

2nd Affil Hosp of Zhejiang University College of Medicine ( Site 0808)

Hangzhou, Zhejiang, China

The 1st Affil Hosp of College of Medicine, Zhejiang Univ ( Site 0830)

Hangzhou, Zhejiang, China

Zhejiang Provincial People's Hospital ( Site 0809)

Hangzhou, Zhejiang, China

Ningbo First Hospital-Urology ( Site 0835)

Ningbo, Zhejiang, China

The First Affiliated Hospital of Wenzhou Medical University ( Site 0834)

Wenzhou, Zhejiang, China

Clinica de la Costa S.A.S. ( Site 2504)

Barranquilla, Atlántico, Colombia

Administradora Country SA - Clinica del Country ( Site 2507)

Bogotá, Bogota D.C., Colombia

Instituto Nacional de Cancerologia E.S.E ( Site 2506)

Bogotá, Bogota D.C., Colombia

Sociedad de Oncología Y Hematología del Cesar S.A.S. ( Site 2509)

Valledupar, Cesar Department, Colombia

Hemato Oncologos ( Site 2503)

Cali, Valle del Cauca Department, Colombia

Rigshospitalet ( Site 1005)

Copenhagen, Capital Region, Denmark

Herlev og Gentofte Hospital. ( Site 1004)

Herlev, Capital Region, Denmark

Aalborg Universitetshospital ( Site 1000)

Aalborg, North Denmark, Denmark

Odense Universitetshospital ( Site 1003)

Odense, Region Syddanmark, Denmark

Vejle Sygehus ( Site 1002)

Vejle, Region Syddanmark, Denmark

Keski-Suomen keskussairaala ( Site 1017)

Jyväskylä, Central Finland, Finland

Tampereen yliopistollinen sairaala ( Site 1022)

Tampere, Pirkanmaa, Finland

HYKS ( Site 1020)

Helsinki, Southwest Finland, Finland

TYKS T-sairaala Syopatautien pkl ( Site 1019)

Turku, Southwest Finland, Finland

Institut de cancérologie Strasbourg Europe (ICANS) ( Site 1114)

Strasbourg, Alsace, France

Centre Georges Francois Leclerc ( Site 1112)

Dijon, Cote-d Or, France

And 134 more locations on ClinicalTrials.gov

Clinical Research Directory

Efficacy and Safety of Pembrolizumab (MK-3475) Plus Enzalutamide Plus Androgen Deprivation Therapy (ADT) Versus Placebo Plus Enzalutamide Plus ADT in Participants With Metastatic Hormone-Sensitive Prostate Cancer (mHSPC) (MK-3475-991/KEYNOTE-991)

Summary

Key Details

Conditions

Interventions

Eligibility Criteria

Locations (234)