Study of Pembrolizumab (MK-3475) Plus Olaparib Versus Abiraterone Acetate or Enzalutamide in Metastatic Castration-resistant Prostate Cancer (mCRPC) (MK-7339-010/KEYLYNK-010)
Condition: Prostatic Neoplasms
MeSH terms: Prostatic Neoplasms
Intervention: Pembrolizumab; Olaparib; Abiraterone acetate; Prednisone; Enzalutamide; Prednisolone
Intervention description: IV infusion; Oral tablets; Oral tablets; Oral tablets; Oral tablets or oral capsules; Oral tablets
Intervention MeSH terms: Prednisone; Prednisolone; Pembrolizumab; Olaparib; Abiraterone Acetate
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 793.0
Sex: Male
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Programmed Cell Death-1 (PD1, PD-1); Programmed Cell Death 1 Ligand 1 (PDL1, PD-L1); Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)

Summary:

      The purpose of this study is to assess the efficacy and safety of the combination of the
      polyadenosine 5'-diphosphoribose poly (ADP-ribose) polymerase (PARP) inhibitor olaparib and
      pembrolizumab in the treatment of participants with mCRPC who have failed to respond to
      either abiraterone acetate or enzalutamide (but not both) and to chemotherapy.

      The primary study hypotheses are that the combination of pembrolizumab plus olaparib is
      superior to abiraterone acetate or enzalutamide with respect to:

        1. Overall Survival (OS) and

        2. Radiographic progression-free survival (rPFS) per Prostate Cancer Working Group
           (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 as assessed by
           blinded independent central review (BICR)

      As of Amendment 06, the Data Monitoring Committee (DMC) is no longer applicable. Participants
      still on treatment may have the option to continue receiving study intervention or SOC if
      they are deriving clinical benefit, until criteria for discontinuation are met. Participants
      who are still on study treatment and deriving clinical benefit will no longer have tumor
      response assessments by BICR. However, local tumor imaging assessments should continue per
      SOC schedule. In addition, ePRO assessments will no longer be performed and biomarker samples
      will no longer be collected.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Has histologically- or cytologically-confirmed adenocarcinoma of the prostate without
             small cell histology

          -  Has prostate cancer progression while receiving androgen deprivation therapy (or post
             bilateral orchiectomy) within 6 months before screening

          -  Has current evidence of metastatic disease documented by bone lesions on bone scan
             and/or soft tissue disease shown by computed tomography/magnetic resonance imaging
             (CT/MRI)

          -  Has received prior treatment with abiraterone acetate OR enzalutamide, but not both

               -  Have disease that progressed during or after treatment with abiraterone acetate
                  for either metastatic hormone-sensitive prostate cancer (mHSPC) or mCRP or
                  enzalutamide for mCRPC for at least 8 weeks (at least 14 weeks for participants
                  with bone progression)

               -  Participants that received abiraterone acetate for mHSPC may not have received
                  abiraterone acetate or enzalutamide for mCRPC

          -  Have received docetaxel chemotherapy regimen for mCRPC and have had progressive
             disease during or after treatment with docetaxel

          -  Has ongoing androgen deprivation with serum testosterone <50 ng/dL (<2.0 nM)

          -  If receiving bone resorptive therapy, including but not limited to bisphosphonates or
             denosumab, must have been receiving stable doses before randomization

          -  Must agree to refrain from donating sperm during the intervention period and for at
             least the time needed to eliminate each study intervention after the last dose of
             study intervention PLUS be abstinent from heterosexual intercourse OR must agree to
             use contraception unless confirmed to be azoospermic

          -  Contraception use by men should be consistent with local regulations regarding the
             methods of contraception for those participating in clinical studies. If the
             contraception requirements in the local label for any of the study interventions is
             more stringent than the requirement above, the local label requirements are to be
             followed.

          -  Has provided tumor tissue from a fresh core or excisional biopsy (obtained within 12
             months of screening) from soft tissue not previously irradiated. Samples from tumors
             progressing at 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

        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 the past 2
             years

          -  Has a history of (noninfectious) pneumonitis requiring steroids, or has current
             pneumonitis

          -  Has known active human immunodeficiency virus (HIV), hepatitis B virus (e.g.,
             hepatitis B surface antigen reactive) or hepatitis C virus (HCV) infection (e.g., HCV
             RNA [qualitative] is detected)

          -  Has known active 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 myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or has features
             suggestive of MDS/AML

          -  Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy

          -  Has (≥Grade 3) hypersensitivity to pembrolizumab and/or any of its excipients

          -  Has known hypersensitivity to the components or excipients in olaparib, abiraterone
             acetate, prednisone or prednisolone, or enzalutamide

          -  Has symptomatic congestive heart failure (New York Heart Association Class III or IV
             heart disease)

          -  Has received an anticancer monoclonal antibody (mAb) before randomization

          -  Has received prior treatment with olaparib or any other PARP inhibitor

          -  Has received prior treatment with apalutamide or darolutamide

          -  Has received prior treatment with enzalutamide or apalutamide for metastatic
             hormone-sensitive prostate cancer

          -  Has used herbal products that may have hormonal anti-prostate cancer activity and/or
             are known to decrease PSA (e.g., saw palmetto) before the date of randomization

          -  Has received prior treatment with radium or other therapeutic radiopharmaceuticals for
             prostate cancer

          -  Has received prior treatment with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent, or
             with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g.,
             CTLA-4, OX-40, or CD137)

          -  Is currently receiving either strong or moderate inhibitors of cytochrome P450 [CYP]
             (CYP3A4) that cannot be discontinued for the duration of the study

          -  Has received a previous allogenic bone marrow transplant or double umbilical cord
             transplantation (dUCBT) or a solid organ transplant

          -  Has received a live vaccine within 30 days prior to the date of randomization

          -  Is currently participating in or has participated in a study of an investigational
             agent, or has used an investigational device, within 4 weeks before the date of
             randomization

          -  Has a bone "superscan"

          -  Is expecting to father children within the projected duration of the study, starting
             with the screening visit through 90 days after the last dose of study intervention