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

Merck Sharp & Dohme LLC186 enrolled

Overview

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.

The China extension study will include participants previously enrolled in China in the global study for MK-3475-991 (NCT04191096) plus those enrolled during the China extension enrollment period. A total of approximately 186 Chinese participants will be enrolled.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Interventions

PembrolizumabBIOLOGICAL

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

EnzalutamideDRUG

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

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.

PlaceboOTHER

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

Eligibility

Sex: MALEMin age: 18 Years

Medical Language ↔ Plain English

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 (24)

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

Sun Yat-Sen University Cancer Center ( Site 0825)

Guangzhou, Guangdong, China

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: Up to approximately 17 months

Secondary Outcomes

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

TFST was defined as the time from randomization to initiation of the first subsequent anti-cancer therapy or death; whichever occurred first. The TFST was calculated using the product limit (Kaplan-Meier) method for censored data. Participants without documented event at time of analysis will be censored at the date of last known time to have not received subsequent new anti-cancer therapy.

Time frame: Up to Approximately 17 months

Time to First Symptomatic Skeletal-related Event (TTSSRE)

TTSSRE was the time from randomization to the first symptomatic skeletal-related event defined as: use of external-beam radiation therapy (EBRT) to prevent or relieve skeletal symptoms, occurrence of new symptomatic pathologic bone fracture (vertebral or nonvertebral), occurrence of spinal cord compression, or tumor-related orthopedic surgical intervention, whichever occurs first. The TTSSRE was calculated using the Kaplan-Meier method for censored data. Participants without symptomatic skeletal-related events were censored at the last evaluable assessment.

Time frame: Up to Approximately 17 months

Time to Prostate-specific Antigen (PSA) Progression

Time to PSA progression was the time from randomization to PSA progression. The PSA progression date was defined as the date of 1) ≥25% increase and ≥2 ng/mL above the nadir, confirmed by a second value ≥3 weeks later if there is PSA decline from baseline, or 2) ≥25% increase and ≥2 ng/mL increase from baseline beyond 12 weeks if there is no PSA decline from baseline. Time to PSA was calculated using Kaplan-Meier method for censored data. Participants without PSA progression were censored at the last PSA date.

Time frame: 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

The time to radiographic soft tissue progression was defined as the time from randomization to radiographic soft tissue progression per soft tissue rules of PCWG-modified RECIST 1.1 as assessed by BICR. Progression was defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered progression. Time to radiographic soft tissue progression was calculated using the product-limit (Kaplan-Meier) method for censored data. Participants without radiographic soft tissue progression were censored at the last evaluable assessment.

Time frame: 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

TTPP was defined as the time from randomization to pain progression as determined by Item 3 of the BPI-SF. Pain progression was defined as: 1) For participants asymptomatic at baseline: a \>2-point change from baseline in the average BPI-SF item 3 score at 2 consecutive visits or initiation of opioid use for pain 2) For participants symptomatic at baseline (average BPI-SF Item 3 score \>0 and/or currently taking opioids; a \>2-point change from baseline in the average BPI-SF Item 3 score and the average worst pain score \>4 and no decrease in average opioid use. TTPP was calculated using the Kaplan-Meier method for censored data. Participants who had \> 2 consecutive visits that were not evaluable for pain progression were censored at the last evaluable assessment.

Time frame: Up to Approximately 17 months

Time From Randomization to Disease Progression as Determined by Investigator Assessment After Next-line of Therapy or Death From Any Cause, Whichever Occurs First (PFS2)

PFS2 was defined as the time from randomization to disease progression as determined by investigator assessment of radiological or clinical progression after next-line of therapy or death from any cause, whichever occurs first.

Time frame: Up to Approximately 17 months

Prostate-specific Antigen (PSA) Response Rate

PSA response rate was the percentage of participants who had PSA response defined as a reduction in the PSA level from baseline by \>50%. The reduction in PSA level was confirmed by an additional PSA evaluation performed \>3 weeks from the original response.