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

• Sponsor: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Merck Sharp & Dohme Corp.

Study Description

Brief 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)

Condition or disease	Intervention/treatment	Phase
Prostatic Neoplasms	Biological: Pembrolizumab; Drug: Olaparib; Drug: Abiraterone acetate; Drug: Prednisone; Drug: Enzalutamide	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 780 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: May 2, 2019
• Estimated Primary Completion Date: October 12, 2021
• Estimated Study Completion Date: September 30, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Pembrolizumab + Olaparib; Participants 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).	Biological: Pembrolizumab; IV infusion; Other Names: MK-3475; KEYTRUDA®; Drug: Olaparib; Oral tablets; Other Names: MK-7339; AZD-2281; LYNPARZA®
Active Comparator: Abiraterone + Prednisone or Enzalutamide; Participants 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.	Drug: Abiraterone acetate; Oral tablets; Other Names: ZYTIGA®; YONSA®; CB-7630; JNJ-212082; Drug: Prednisone; Oral tablets; Drug: Enzalutamide; Oral tablets or oral capsules; Other Names: XTANDI®; MDV-3100; ASP-9785

Outcome Measures

Primary Outcome Measures :

1. Overall Survival (OS) [ Time Frame: Up to approximately 29 months ]
   Time from randomization to death due to any cause
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 [ Time Frame: Up to approximately 29 months ]
   Time from randomization to radiographic progression, or death due to any cause, whichever occurs first

Secondary Outcome Measures :

1. Time to Initiation of the First Subsequent Anticancer Therapy (TFST) [ Time Frame: Up to approximately 29 months ]
   Time from randomization to initiation of the first subsequent anticancer therapy
2. 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 ]
   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
3. 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 ]
   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
4. Time to Prostate-Specific Antigen (PSA) Progression [ Time Frame: Up to approximately 29 months ]

   Time from randomization to PSA progression. PSA progression date is 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
5. Time to First Symptomatic Skeletal-Related Event (SSRE) [ Time Frame: Up to approximately 29 months ]

   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
6. 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 ]
   Time to radiographic soft tissue progression: the time from randomization to radiographic soft tissue progression
7. 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 ]
   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
8. Number of Participants Who Experience an Adverse Event (AE) [ Time Frame: Up to approximately 29 months ]
   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
9. Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) [ Time Frame: Up to approximately 29 months ]
   The number of participants who discontinue study treatment due to an AE will be presented

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

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 disease that progressed during or after treatment with abiraterone acetate OR enzalutamide, but not both, for mCRPC
• Has received no more than 1 previous chemotherapy regimen for mCRPC and have had PD during treatment
• 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 severe (≥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 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

Contacts and Locations

Contacts

Contact: Toll Free Number; 1-888-577-8839; Trialsites@merck.com

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Sponsors and Collaborators

Merck Sharp & Dohme Corp.

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme Corp.

More Information

• Responsible Party: Merck Sharp & Dohme Corp.
• ClinicalTrials.gov Identifier: NCT03834519 History of Changes
• Other Study ID Numbers: 7339-010; 2018-004118-16 ( EudraCT Number ); MK-7339-010 ( Other Identifier: Merck Protocol Number ); KEYLYNK-010 ( Other Identifier: Merck ); 194832 ( Registry Identifier: JAPIC-CTI )
• First Posted: February 8, 2019
• Last Update Posted: August 21, 2019
• Last Verified: August 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Merck Sharp & Dohme Corp.:

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

Additional relevant MeSH terms:

Prostatic Neoplasms; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Prednisone; Pembrolizumab; Olaparib; Abiraterone Acetate; Antineoplastic Agents, Immunological; Antineoplastic Agents; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Poly(ADP-ribose) Polymerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Steroid Synthesis Inhibitors; Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors