Study of Pembrolizumab (MK-3475) Plus Enzalutamide Versus Placebo Plus Enzalutamide in Participants With Metastatic Castration-resistant Prostate Cancer (mCRPC) (MK-3475-641/KEYNOTE-641)

Completed · Phase 3 · Has a placebo group

Conditions studied: Prostatic Neoplasms

In brief

The purpose of this study is to assess the efficacy and safety of the combination of pembrolizumab (MK-3475) and enzalutamide in the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) who have not received chemotherapy for mCRPC, are abiraterone-naïve, or are intolerant to or progressed on abiraterone acetate. There are two primary study hypotheses. Hypothesis 1: The combination of pembrolizumab plus enzalutamide is superior to placebo plus enzalutamide with respect to Overall Survival (OS). Hypothesis 2: The combination of pembrolizumab plus enzalutamide is superior to placebo plus enzalutamide with respect to Radiographic Progression-free Survival (rPFS) per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded independent central review.

Key facts

Study ID

NCT03834493

Run by

Merck Sharp & Dohme LLC

People needed

1244

Starts

2019-07-28

Expected to finish

2026-06-08

Last updated by the study team

2026-07-09

Who can join

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

You may qualify if…

• Has histologically- or cytologically-confirmed adenocarcinoma of the prostate without small cell histology
• Has prostate cancer progression while on androgen deprivation therapy (or post bilateral orchiectomy) within 6 months prior to randomization
• Has current evidence of metastatic disease documented by either bone lesions on bone scan and/or soft tissue disease by computed tomography/magnetic resonance imaging (CT/MRI)
• Has met one of the following criteria with regard to abiraterone acetate exposure: (1) is abiraterone-naïve; (2) received prior abiraterone acetate for the treatment of mHSPC or mCRPC, for a minimum of 4 weeks and not progressed while on treatment; or (3) received prior abiraterone acetate for the treatment of mHSPC or mCRPC and progressed on treatment after a minimum of 8 weeks treatment (minimum 14 weeks for those with bone progression)
• Has ongoing androgen deprivation with serum testosterone <50 ng/dL (<2.0 nM)
• Participants receiving bone resorptive therapy (including, but not limited to, bisphosphonate or denosumab) must have been on stable doses prior to randomization
• Participants must agree to the following during the study treatment period and for at least 90 days after the last dose of enzalutamide: Refrain from donating sperm, plus EITHER be abstinent OR must agree to use male condom
• 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
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 assessed within 7 days of randomization

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 (noninfectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease
• Has known active human immunodeficiency virus (HIV), concurrent active hepatitis B virus (HBV) or known active hepatitis C virus (HCV) infection
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis
• Has hypersensitivity to pembrolizumab and/or enzalutamide and/or any of their excipients
• 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 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 bradycardia (heart rate of <50 beats per minute) on the screening electrocardiogram (ECG)
• Has history of prostate cancer progression on ketoconazole
• Has had prior treatment with enzalutamide, apalutamide, darolutamide or cytochrome P450 (CYP) 17 inhibitor other than abiraterone acetate
• 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-PD-L2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor
• Has received prior treatment with radium or other therapeutic radiopharmaceuticals for prostate cancer
• Has received prior treatment with docetaxel or another chemotherapy agent for mCRPC
• Has had a prior anti-cancer monoclonal antibody (mAb) prior to randomization
• Has used herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA levels (eg, saw palmetto) prior to randomization
• Has received a live or live attenuated vaccine within 30 days prior to randomization
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment
• Has a "superscan" bone scan
• Is expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 90 days after the last dose of enzalutamide

Where it is running

• Providence Medical Foundation-Oncology ( Site 0069) — Fullerton, California, United States
• UCLA Hematology/Oncology - Santa Monica ( Site 0081) — Los Angeles, California, United States
• University of Colorado Cancer Center ( Site 0022) — Aurora, Colorado, United States
• Smilow Cancer Hospital at Yale New Haven ( Site 0038) — New Haven, Connecticut, United States
• Moffitt Cancer Center ( Site 0080) — Tampa, Florida, United States
• Georgia Cancer Center at Augusta University ( Site 0026) — Augusta, Georgia, United States
• Mount Sinai Hospital ( Site 0042) — Chicago, Illinois, United States
• Methodist Hospitals. ( Site 0008) — Merrillville, Indiana, United States
• Tulane Cancer Center ( Site 0066) — New Orleans, Louisiana, United States
• University of Massachusetts Worcester ( Site 0053) — Worcester, Massachusetts, United States
• Cancer & Hematology Centers of Western Michigan ( Site 0013) — Grand Rapids, Michigan, United States
• Munson Medical Center ( Site 0030) — Traverse City, Michigan, United States
• St. Vincent Frontier Cancer Center ( Site 0016) — Billings, Montana, United States
• Oncology Hematology West, PC dba Nebraska Cancer Specialists ( Site 0034) — Omaha, Nebraska, United States
• Comprehensive Cancer Centers of Nevada ( Site 0092) — Las Vegas, Nevada, United States
• John Theurer Cancer Center at Hackensack University Medical Center ( Site 0004) — Hackensack, New Jersey, United States
• Associated Medical Professionals of NY ( Site 0060) — Syracuse, New York, United States
• W. G. Bill Hefner VA Medical Center ( Site 0029) — Salisbury, North Carolina, United States
• Gabrail Cancer Center-Research ( Site 0096) — Canton, Ohio, United States
• Tri-State Urologic Services PSC, Inc. ( Site 0094) — Cincinnati, Ohio, United States
• University Hospitals Cleveland Medical Center ( Site 0036) — Cleveland, Ohio, United States
• Oregon Health Science University ( Site 0031) — Portland, Oregon, United States
• Carolina Urologic Research Center ( Site 0070) — Myrtle Beach, South Carolina, United States
• Inova Schar Cancer Institute ( Site 0006) — Fairfax, Virginia, United States
• University of South Alabama, Mitchell Cancer Institute ( Site 0065) — Mobile, Alabama, United States

Full record on ClinicalTrials.gov

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