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

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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 or Death (TFST) [ Time Frame: Up to approximately 29 months ]
   Time from randomization to initiation of the first subsequent anticancer therapy or death, whichever occurs first
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 from randomization to the first SSRE. SSRE is defined as radiation to prevent or relieve skeletal symptoms, occurrence of new symptomatic pathological fracture, spinal cord compression, or surgery to bone
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 from randomization to radiographic soft tissue progression per PCWG-modified RECIST 1.1
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 ]
   Time from randomization to pain progression. In this study, pain progression will be assessed by participant responses to Item 3 of the BPI-SF and participant AQA Scores
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

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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 prior 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)
• 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

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

Locations

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United States, Nebraska
Nebraska Cancer Specialists ( Site 0034)	Recruiting
Omaha, Nebraska, United States, 68130
Contact: Study Coordinator 402-691-6971
United States, South Carolina
Carolina Urologic Research Center ( Site 0070)	Recruiting
Myrtle Beach, South Carolina, United States, 29572
Contact: Study Coordinator 8434491010257
France
C.H.U. Lyon Sud ( Site 0436)	Recruiting
Pierre Benite, France, 69310
Contact: Study Coordinator +33478864324
Israel
Hadassah Ein Kerem Medical Center ( Site 0546)	Recruiting
Jerusalem, Israel, 9112001
Contact: Study Coordinator +972505172315
Rabin Medical Center ( Site 0545)	Recruiting
Petach-Tikwa, Israel, 4941492
Contact: Study Coordinator +97239378074
Korea, Republic of
Chonnam National University Hwasun Hospital ( Site 0174)	Recruiting
Hwasun Gun, Jeollanam Do, Korea, Republic of, 58128
Contact: Study Coordinator +82613798015
Asan Medical Center ( Site 0171)	Recruiting
Seoul, Korea, Republic of, 05505
Contact: Study Coordinator +82216887575
Samsung Medical Center ( Site 0172)	Recruiting
Seoul, Korea, Republic of, 06351
Contact: Study Coordinator +82215993114
Spain
Hospital Quiron Madrid ( Site 0325)	Recruiting
Pozuelo de Alarcon, Madrid, Spain, 28223
Contact: Study Coordinator +34917567850
Hospital Josep Trueta ( Site 0321)	Recruiting
Girona, Spain, 17007
Contact: Study Coordinator +349722258284028
Taiwan
Taipei Veterans General Hospital ( Site 0135)	Recruiting
Taipei, Taiwan, 112
Contact: Study Coordinator 886228757519306

Sponsors and Collaborators

Merck Sharp & Dohme Corp.

Investigators

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Study Director:	Medical Director	Merck Sharp & Dohme Corp.

More Information

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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 )
First Posted:	February 8, 2019
Last Update Posted:	May 16, 2019
Last Verified:	May 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

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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:

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Prostatic Neoplasms; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Pembrolizumab; Prednisone; 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