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)
Condition: Metastatic Hormone-Sensitive Prostate Cancer
MeSH terms: Prostatic Neoplasms; Hypersensitivity
Intervention: Pembrolizumab; Enzalutamide; Androgen Deprivation Therapy (ADT); Placebo
Intervention description: Pembrolizumab is administered as an IV infusion at 200 mg on Day 1 of each 21-day cycle for up to 35 cycles.; Enzalutamide is administered orally as capsules/tablets at a dosage of 160 mg daily. Enzalutamide is administered continuously until criteria for discontinuation are met.; Stable regimen of ADT (LHRH agonist or antagonist) at a dose and frequency of administration that is consistent with the local product label.; Placebo infusion solution is administered as an IV infusion on Day 1 of each 21-day cycle for up to 35 cycles.
Intervention MeSH terms: Pembrolizumab; Androgens
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 1251.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Programmed Cell Death-1 (PD1, PD-1),; Programmed Death-Ligand 1 (PDL1, PD-L1)

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.
    

Eligibility criteria:

        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