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)-China Extension

NCT04934722 | Completed Phase 3 Results DMC FDA Drug

• 4 other identifiers: 3475-991 China ExtensionMK-3475-991 China ExtensionKEYNOTE-991jRCT2080225171
• Study Type: interventional
• Target: 186
• Locations: 1 country
• Sites: 24

Brief Summary

This study will assess the efficacy and safety of pembrolizumab plus enzalutamide plus ADT versus placebo plus enzalutamide plus ADT in Chinese 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 Amendment 4, the study is being stopped for futility. All the prespecified interim analysis after interim analysis (IA1) and final analysis of the study described the statistical analysis plan (SAP) will not be performed. 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.

Conditions

Metastatic Hormone-Sensitive Prostate Cancer

Keywords

Programmed Cell Death-1 (PD1, PD-1),; Programmed Death-Ligand 1 (PDL1, PD-L1)

Outcome Measures

Primary Outcomes (2)

• 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 (BICR)

  rPFS was defined as the time from randomization to occurrence of: radiological tumor progression using RECIST 1.1 as assessed by BICR; progression of bone lesions using PCWG criteria; or death due to any cause. Progression as per modified RECIST 1.1 was ≥20% increase in sum of diameters of target lesions and progression of existing non-target lesions. Progression of bone lesions by PCWG criteria was the appearance of ≥2 new bone lesions on bone scan, that have been confirmed to not represent tumor flare, and was persistent for ≥6 weeks. The rPFS was calculated using the product-limit (Kaplan-Meier) method for censored data. Participants without a rPFS event were censored at the date of last disease assessment.

  Up to approximately 17 months

• Overall Survival (OS)

  OS was defined as the time from randomization to death due to any cause. The OS was calculated using the product-limit (Kaplan-Meier) method for censored data. Participants without documented death at the time of the analysis were censored at the date of the last follow-up.

  Up to approximately 17 months

Secondary Outcomes (12)

• Time to Initiation of the First Subsequent Anti-cancer Therapy or Death (TFST)

  Up to Approximately 17 months

• Time to First Symptomatic Skeletal-related Event (TTSSRE)

  Up to Approximately 17 months

• Time to Prostate-specific Antigen (PSA) Progression

  Up to Approximately 17 months

• Time to Radiographic Soft Tissue Progression Per Soft Tissue Rules of PCWG-Modified RECIST 1.1 as Assessed by BICR

  Up to Approximately 17 months

• Time to Pain Progression (TTPP) as Assessed by Brief Pain Inventory-Short Form (BPI-SF) Item #3 ("Worst Pain in 24 Hours") and Opiate Use

  Up to Approximately 17 months

Study Arms (2)

Pembrolizumab + Enzalutamide + ADT

EXPERIMENTAL

Starting on Day 1 of each 21-day cycle, participants receive 200 mg pembrolizumab intravenously (IV) every 3 weeks (Q3W) for up to 35 cycles (approximately 2 years), plus 160 mg enzalutamide taken orally once daily, while maintaining continuous ADT with a luteinizing-hormone releasing hormone (LHRH) agonist or antagonist during study treatment. Participants will continue to receive enzalutamide and ADT until criteria for discontinuation are met.

Biological: Pembrolizumab; Drug: Enzalutamide; Drug: Androgen Deprivation Therapy (ADT)

Placebo + Enzalutamide + ADT

PLACEBO COMPARATOR

Starting on Day 1 of each 21-day cycle, participants receive placebo IV Q3W for up to 35 cycles (approximately 2 years), plus 160 mg enzalutamide taken orally once daily, while maintaining continuous ADT with a LHRH agonist or antagonist during study treatment. Participants will continue to receive enzalutamide and ADT until criteria for discontinuation are met.

Drug: Enzalutamide; Drug: Androgen Deprivation Therapy (ADT); Other: Placebo

Interventions

Pembrolizumab BIOLOGICAL

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

Also known as: KEYTRUDA®, MK-3475

Pembrolizumab + Enzalutamide + ADT

Enzalutamide DRUG

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

Also known as: XTANDI®

Pembrolizumab + Enzalutamide + ADT; Placebo + Enzalutamide + ADT

Androgen Deprivation Therapy (ADT) DRUG

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

Pembrolizumab + Enzalutamide + ADT; Placebo + Enzalutamide + ADT

Placebo OTHER

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

Placebo + Enzalutamide + ADT

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

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

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Study Sites (24)

Peking University First Hospital ( Site 0800)

Beijing, Beijing Municipality, 100034, China

Location

Beijing Cancer Hospital ( Site 0802)

Beijing, Beijing Municipality, 100142, China

Location

Chongqing Cancer Hospital ( Site 0815)

Chongqing, Chongqing Municipality, 400030, China

Location

The First Affiliated Hospital of Xiamen University (Site 0816)

Xiamen, Fujian, 361000, China

Location

Sun Yat-Sen University Cancer Center ( Site 0825)

Guangzhou, Guangdong, 510060, China

Location

The First Affiliated Hospital of Guangzhou Medical University-Urology ( Site 0638)

Guangzhou, Guangdong, 510120, China

Location

Sun Yat Sen Memorial Hospital (Site # 0819)

Guangzhou, Guangdong, 510220, China

Location

Southern Medical University Nanfang Hospital ( Site 0838)

Guangzhou, Guangdong, 510515, China

Location

Harbin Medical University Cancer Hospital ( Site 0822)

Harbin, Heilongjiang, 150081, China

Location

Henan Cancer Hospital ( Site 0818)

Zhengzhou, Henan, 450008, China

Location

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

Wuhan, Hubei, 430000, China

Location

Hubei Cancer Hospital ( Site 0833)

Wuhan, Hubei, 430079, China

Location

Hunan Cancer Hospital ( Site 0817)

Changsha, Hunan, 410013, China

Location

Nanjing Drum Tower Hospital ( Site 0811)

Nanjing, Jiangsu, 210008, China

Location

The First Affiliated Hospital of Nanchang University ( Site 0821)

Nanchang, Jiangxi, 330006, China

Location

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

Xi'an, Shaanxi, 710004, China

Location

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

Shanghai, Shanghai Municipality, 200127, China

Location

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

Xi’an, Shanxi, 710061, China

Location

Tianjin Medical University Cancer Institute & Hospital ( Site 0804 )

Tianjin, Tianjin Municipality, 300000, China

Location

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

Hangzhou, Zhejiang, 310009, China

Location

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

Hangzhou, Zhejiang, 310009, China

Location

Zhejiang Provincial People's Hospital ( Site 0809)

Hangzhou, Zhejiang, 310014, China

Location

Ningbo First Hospital-Urology (0835)

Ningbo, Zhejiang, 315010, China

Location

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

Wenzhou, Zhejiang, 325000, China

Location

Related Links

• Merck Clinical Trials Information

MeSH Terms

Conditions

Parkinson Disease 4, Autosomal Dominant Lewy Body

Interventions

pembrolizumab; enzalutamide; Androgen Antagonists

Intervention Hierarchy (Ancestors)

Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Pharmacologic Actions; Chemical Actions and Uses

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme LLC

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 17, 2021
• First Posted: June 22, 2021
• Study Start: May 25, 2021
• Primary Completion: October 31, 2022
• Study Completion: September 10, 2025
• Last Updated: October 1, 2025
• Results First Posted: November 7, 2023

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share

Locations

CN (24)