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)
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| ClinicalTrials.gov Identifier: NCT03834519 |
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Recruitment Status :
Active, not recruiting
First Posted : February 8, 2019
Last Update Posted : October 18, 2022
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Sponsor:
Merck Sharp & Dohme LLC
Information provided by (Responsible Party):
Merck Sharp & Dohme LLC
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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:
- Overall Survival (OS) and
- 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 Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 793 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 |
| Actual Primary Completion Date : | March 14, 2022 |
| Estimated Study Completion Date : | September 29, 2023 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Prostate cancer
MedlinePlus related topics:
Prostate Cancer
| Arm | Intervention/treatment |
|---|---|
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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).
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Biological: Pembrolizumab
IV infusion
Other Names:
Drug: Olaparib Oral tablets
Other Names:
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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 OR two 80 mg tablets QD until progression.
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Drug: Abiraterone acetate
Oral tablets
Other Names:
Drug: Prednisone Oral tablets Drug: Enzalutamide Oral tablets or oral capsules
Other Names:
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Primary Outcome Measures :
- Overall Survival (OS) [ Time Frame: Up to approximately 40 months ]Overall survival (OS) is defined as the time from randomization to death due to any cause.
- Radiographic Progression-Free Survival (rPFS) [ Time Frame: Up to approximately 40 months ]rPFS defined as the time from randomization to the first documented disease progression or death due to any cause, whichever occurs first per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). rPFS as assessed by BICR will be presented.
Secondary Outcome Measures :
- Time to Initiation of the First Subsequent Anticancer Therapy (TFST) [ Time Frame: Up to approximately 40 months ]TFST is defined as the time from randomization to initiation of the first subsequent anticancer therapy or death.
- Objective Response Rate (ORR) [ Time Frame: Up to approximately 40 months ]ORR is defined as the percentage of participants with Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. The percentage of participants who experience CR or PR as assessed by BICR will be presented.
- Duration of Response (DOR) [ Time Frame: Up to approximately 40 months ]DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death. Per PCWG-modified RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD. DOR as assessed by BICR will be presented.
- Time to Prostate-Specific Antigen (PSA) Progression [ Time Frame: Up to approximately 40 months ]
Time to PSA progression is defined as the 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.
- Time to First Symptomatic Skeletal-Related Event (SSRE) [ Time Frame: Up to approximately 40 months ]
SSRE is defined as 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.
- Time to Radiographic Soft Tissue Progression [ Time Frame: Up to approximately 40 months ]Time to radiographic soft tissue progression is defined as the time from randomization to radiographic soft tissue progression per soft tissue rule of PCWG-modified RECIST 1.1. Progression is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. Time to radiographic soft tissue progression as assessed by BICR will be presented.
- Time to Pain Progression (TTPP) [ Time Frame: Up to approximately 40 months ]
TTPP is defined as 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.
Pain progression is defined as:
- For participants who are asymptomatic at baseline, a ≥2-point change from baseline in the average (4-7 days) BPI-SF item 3 score OR initiation of opioid use for pain
- For participants who are symptomatic at baseline (average BPI-SF Item 3 score >0 and/or currently taking opioids), a ≥2-point change from baseline in the average BPI-SF Item 3 score and an average worst pain score ≥4 and no decrease in average opioid use (≥1-point decrease in AQA score from a starting value of 2 or higher) OR any increase in opioid use at 2 consecutive follow-up visits.
- Number of Participants Who Experience an Adverse Event (AE) [ Time Frame: Up to approximately 40 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.
- Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE) [ Time Frame: Up to approximately 40 months ]The number of participants who discontinue study treatment due to an AE will be presented.
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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 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)
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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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03834519
Locations
Show 193 study locations
Sponsors and Collaborators
Merck Sharp & Dohme LLC
Investigators
| Study Director: | Medical Director | Merck Sharp & Dohme LLC |
Additional Information:
| Responsible Party: | Merck Sharp & Dohme LLC |
| ClinicalTrials.gov Identifier: | NCT03834519 |
| Other Study ID Numbers: |
7339-010 MK-7339-010 ( Other Identifier: Merck Protocol Number ) KEYLYNK-010 ( Other Identifier: Merck ) 194832 ( Registry Identifier: JAPIC-CTI ) 2018-004118-16 ( EudraCT Number ) |
| First Posted: | February 8, 2019 Key Record Dates |
| Last Update Posted: | October 18, 2022 |
| Last Verified: | October 2022 |
| 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 LLC:
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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) |
Additional relevant MeSH terms:
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Prostatic Neoplasms Genital Neoplasms, Male Urogenital Neoplasms Neoplasms by Site Neoplasms 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 |