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Study of Pembrolizumab (MK-3475) Plus Olaparib Versus Abiraterone Acetate or Enzalutamide in Metastatic Castration-resistant Prostate Cancer (mCRPC) (MK-7339-010/KEYLYNK-010)

NCT03834519

Description:

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)

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Study of Pembrolizumab (MK-3475) Plus Olaparib Versus Abiraterone Acetate or Enzalutamide in Metastatic Castration-resistant Prostate Cancer (mCRPC) (MK-7339-010/KEYLYNK-010)
  • Official Title: A Phase 3, Randomized Open-label Study of Pembrolizumab (MK-3475) Plus Olaparib Versus Abiraterone Acetate or Enzalutamide in Participants With Metastatic Castration-resistant Prostate Cancer (mCRPC) Who Are Unselected for Homologous Recombination Repair Defects and Have Failed Prior Treatment With One Next-generation Hormonal Agent (NHA) and Chemotherapy (KEYLYNK-010)

Clinical Trial IDs

  • ORG STUDY ID: 7339-010
  • SECONDARY ID: 2018-004118-16
  • SECONDARY ID: MK-7339-010
  • SECONDARY ID: KEYLYNK-010
  • SECONDARY ID: 194832
  • NCT ID: NCT03834519

Conditions

  • Prostatic Neoplasms

Interventions

DrugSynonymsArms
PembrolizumabMK-3475, KEYTRUDA®Pembrolizumab + Olaparib
OlaparibMK-7339, AZD-2281, LYNPARZA®Pembrolizumab + Olaparib
Abiraterone acetateZYTIGA®, CB-7630, JNJ-212082Abiraterone + Prednisone or Enzalutamide
PrednisoneAbiraterone + Prednisone or Enzalutamide
EnzalutamideXTANDI®, MDV-3100, ASP-9785Abiraterone + Prednisone or Enzalutamide

Purpose

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)

Trial Arms

NameTypeDescriptionInterventions
Pembrolizumab + OlaparibExperimentalParticipants receive olaparib 600 mg as two 150 mg oral tablets twice daily (BID) continuously until progression PLUS on Day 1 of each 21-day cycle, pembrolizumab 200 mg by intravenous (IV) infusion for up to 35 cycles (approximately 2 years).
  • Pembrolizumab
  • Olaparib
Abiraterone + Prednisone or EnzalutamideActive ComparatorParticipants receive abiraterone acetate (participants previously treated with enzalutamide) 1000 mg as two 500 mg or four 250 mg oral tablets once daily (QD) PLUS prednisone 10 mg as one 5 mg tablet BID until progression OR Participants receive enzalutamide (participants previously treated with abiraterone acetate) 160 mg as four 40 mg oral tablets or capsules QD until progression.
  • Abiraterone acetate
  • Prednisone
  • Enzalutamide

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 prior to 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 prior to randomization

          -  Must agree to refrain from donating sperm during the intervention period and for at
             least 180 days thereafter PLUS Be abstinent from heterosexual intercourse OR Agree to
             use contraception unless confirmed to be azoospermic AND Also agree to use a male
             condom when engaging in any activity that allows passage of ejaculate to another
             person of any sex

          -  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) prior to 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) prior to 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 prior to 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 180 days after the last dose of study intervention
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:Up to approximately 29 months
Safety Issue:
Description:Time from randomization to death due to any cause

Secondary Outcome Measures

Measure:Time to Initiation of the First Subsequent Anticancer Therapy (TFST)
Time Frame:Up to approximately 29 months
Safety Issue:
Description:Time from randomization to initiation of the first subsequent anticancer therapy
Measure:Objective Response Rate (ORR) 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
Time Frame:Up to approximately 29 months
Safety Issue:
Description:Percentage of participants in the analysis population who have a best overall response of either confirmed Complete Response (CR) or a confirmed Partial Response (PR) per PCWG-modified RECIST 1.1
Measure:Duration of Response (DOR) 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
Time Frame:Up to approximately 29 months
Safety Issue:
Description:Time from first documented evidence of confirmed Complete Response (CR) or a confirmed Partial Response (PR) per PCWG-modified RECIST 1.1 until disease progression or death from any cause, whichever occurs first
Measure:Time to Prostate-Specific Antigen (PSA) Progression
Time Frame:Up to approximately 29 months
Safety Issue:
Description:Time from randomization to PSA progression. PSA progression date is defined as the date of ≥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 ≥25% increase and ≥2 ng/mL increase from baseline beyond 12 weeks if there is no PSA decline from baseline
Measure:Time to First Symptomatic Skeletal-Related Event (SSRE)
Time Frame:Up to approximately 29 months
Safety Issue:
Description:Time to first SSRE: the time from randomization to the first symptomatic skeletal-related event, defined as: First 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
Measure:Time to Radiographic Soft Tissue Progression Per Soft Tissue Rules of 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
Time Frame:Up to approximately 29 months
Safety Issue:
Description:Time to radiographic soft tissue progression: the time from randomization to radiographic soft tissue progression
Measure:Time to Pain Progression (TTPP) as Assessed by Brief Pain Inventory-Short Form (BPI-SF) Item 3 ("Worst Pain in 24 Hours") and Opiate Analgesic Use (Analgesic Quantification Algorithm [AQA] Score)
Time Frame:Up to approximately 29 months
Safety Issue:
Description:TTPP: the time from randomization to pain progression as determined by Item 3 of the Brief Pain Inventory Short Form (BPI-SF) and by the Analgesic Quantification Algorithm (AQA) score
Measure:Number of Participants Who Experience an Adverse Event (AE)
Time Frame:Up to approximately 29 months
Safety Issue:
Description:An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment
Measure:Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)
Time Frame:Up to approximately 29 months
Safety Issue:
Description:The number of participants who discontinue study treatment due to an AE will be presented

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Merck Sharp & Dohme Corp.

Trial Keywords

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

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