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)

Completed · Phase 3 · Has a placebo group

Conditions studied: Metastatic Hormone-Sensitive Prostate Cancer

In brief

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.

Key facts

Study ID: NCT04191096
Run by: Merck Sharp & Dohme LLC
People needed: 1251
Starts: 2020-02-12
Expected to finish: 2026-04-08
Last updated by the study team: 2026-04-29

Who can join

Age: 18 and older. Sex: male. Healthy volunteers: not accepted.

You may qualify if…

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

You may not qualify if…

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:
Up to 3 months of ADT or orchiectomy with or without concurrent first-generation antiandrogens, if patient was not treated with docetaxel
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

Where it is running

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
Alaska Clinical Research Center ( Site 0274) — Anchorage, Alaska, United States

Full record on ClinicalTrials.gov

Trial information comes from ClinicalTrials.gov and is refreshed daily. TrialsForMe does not provide medical care and does not run the studies it lists.