Study of Pembrolizumab (MK-3475) in Participants With Metastatic Castration-Resistant Prostate Cancer (mCRPC)(MK-3475-199/KEYNOTE-199)

Phase 2

Completed

Conditions: Metastatic Castration-resistant Prostate Cancer

Interventions: Biological: Pembrolizumab

Registration Number: NCT02787005

Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary: This is a study of pembrolizumab (MK-3475) in participants with metastatic castration-resistant prostate cancer (mCRPC). Participants will be enrolled into one of five cohorts: Cohort 1 (participants with programmed cell death ligand 1 \[PD-L1\]-positive, measurable disease), Cohort 2 (participants with PD-L1 negative, measurable disease), Cohort 3 (participants with bone-metastases and non-measurable disease) post-chemotherapy, Cohort 4 (participants with Response Evaluation Criteria in Solid Tumors version 1.1- \[RECIST 1.1\]-measureable disease) and Cohort 5 (participants with bone metastases only or bone-predominant disease) pre-chemotherapy.

Detailed Description: Participants with mCRPC previously treated with docetaxel-based chemotherapy in Cohorts 1 to 3 will receive monotherapy with pembrolizumab. Chemotherapy-naïve subjects with mCRPC either having failed or showing signs of failure with enzalutamide in Cohorts 4 and 5 will receive pembrolizumab monotherapy in addition to their current regimen of enzalutamide. In all cohorts, pembrolizumab administration will occur on Day 1 of each 3-week dosing cycle and will continue for a maximum of 35 cycles (approximately 2 years) unless specific withdrawal/discontinuation criteria are met. Participants who discontinue after 35 infusions of pembrolizumab for reasons other than disease progression or intolerability, or who discontinue after attaining a complete response may be eligible for up to 17 additional infusions (approximately 1 year) after they have experienced disease progression.

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 388

Inclusion Criteria

Has histologically- or cytologically-confirmed adenocarcinoma of the prostate without small cell histology. Disease must be either metastatic or locally confined inoperable disease that cannot be treated with definitive intent (no chance for a curative intervention).
Has supplied tumor tissue from a newly obtained biopsy or a biopsy obtained ≤12 months prior to study start and an archival specimen, if available, from a site not previously irradiated. Participants in Cohorts 1, 2, and 4 with visceral/measurable lesions must provide a newly obtained biopsy performed after the last line of systemic therapy or a biopsy obtained ≤12 months prior to study start and an archival specimen, if available. Participants in Cohorts 3 and 5 must at least provide an archival specimen.

For Cohorts 1, 2, and 3 only:

Has been treated with:
At least 1 targeted endocrine therapy (defined as second generation antiandrogen therapies that include but are not limited to abiraterone acetate with prednisone, enzalutamide, and next generation targeted agents such as ARN-509).
At least 1 regimen/line of chemotherapy that contained docetaxel.
No more than 2 chemotherapy regimens.
No more than 3 regimens/lines of the aforementioned treatments (having failed/progressed on chemotherapy and targeted endocrine therapy).

For Cohorts 4 and 5 only:

Failing or showing early signs of failure on current pre-chemotherapy enzalutamide treatment as defined by Prostate Cancer Working Group 3 (PCWG3) guidelines. Participants can have failed prior abiraterone treatment before current enzalutamide treatment. Participants must have had a clinically meaningful response to enzalutamide treatment. Enzalutamide must have been initiated no less than 4 weeks prior to the first dose of trial treatment and be continued throughout the study.

For All Cohorts:

Has documented prostate cancer progression within 6 months prior to screening, as determined by the Investigator, by means of one of the following: 1) PSA progression as defined by a minimum of 3 rising PSA levels with an interval of ≥1 week between each assessment where the PSA value at screening should be ≥2 ng/mL, OR, 2) Radiographic disease progression in soft tissue or bone with or without PSA progression
Has ongoing androgen deprivation with total serum testosterone <50 ng/dL (<2.0 nM).
Participants receiving bone resorptive therapy (including but not limited to bisphosphonate or Receptor activator of nuclear factor kappa-B ligand [RANK-L inhibitor]) must have been on stable doses for ≥4 weeks prior to first dose of study drug.
Has a performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale
Participants of reproductive potential must agree to use an adequate method of contraception, starting with the first dose of study drug through at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception after the last dose of enzalutamide is 30 days.
Demonstrates adequate organ function.

Exclusion Criteria

For All Cohorts:

Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of study drug.
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to the first dose of study drug or who has not recovered (i.e., ≤ Grade 1 or at Baseline) from AEs due to mAbs administered more than 4 weeks earlier.
Has had prior chemotherapy, targeted small molecule therapy, or external beam radiation therapy within 4 weeks prior to the first dose of study drug or who has not recovered (i.e., ≤ Grade 1 or at Baseline) from AEs due to a previously administered agent.
Has a known additional malignancy that has had progression or has required active treatment in the last 3 years. Exceptions include basal cell carcinoma of the skin and squamous cell carcinoma of the skin that has undergone potentially curative therapy.
Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
Has evidence of interstitial lung disease and/or a history of (non-infectious) pneumonitis that required steroids, or current pneumonitis.
Has an active infection requiring systemic therapy.
Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
Has previously participated in any other pembrolizumab (MK-3475) trial, or received prior therapy with an anti-programmed cell death 1 (anti-PD-1, anti-PD ligand 1 [anti-PD-L1], and anti-PD-L2 [including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways]).
Has a known history of Human Immunodeficiency Virus (HIV).
Has known active Hepatitis B or Hepatitis C.
Has received a live vaccine within 30 days of planned start of study drug. Any licensed coronavirus disease 2019 (COVID-19) vaccine (including for Emergency use) in a particular country is allowed in the study as long as they are messenger ribonucleic acid (mRNA) vaccines, adenoviral vaccines, or inactivated vaccines. Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not allowed.

For Cohorts 4 and 5 only:

Has received prior chemotherapy (e.g., docetaxel) for mCPRC.
Has any condition (cardiac, neurologic, absorption) other than clinically failing or showing early signs of failure on enzalutamide treatment that would require imminent discontinuation of enzalutamide treatment.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 5: Bone metastases only or bone-predominant disease	Pembrolizumab	Participants with bone metastases only or bone-predominant disease receive pembrolizumab 200 mg via intravenous infusion on Day 1 of every 3-week cycle for up to 2 years.
Cohort 1: PD-L1 positive with measurable disease	Pembrolizumab	Participants with programmed cell death ligand 1 (PD-L1)-positive, measurable disease receive pembrolizumab 200 mg via intravenous infusion on Day 1 of every 3-week cycle for up to 2 years.
Cohort 2: PD-L1 negative with measurable disease	Pembrolizumab	Participants with PD-L1 negative, measurable disease receive pembrolizumab 200 mg via intravenous infusion on Day 1 of every 3-week cycle for up to 2 years.
Cohort 3: Bone metastases with non-measurable disease	Pembrolizumab	Participants with bone metastases and non-measurable disease receive pembrolizumab 200 mg via intravenous infusion on Day 1 of every 3-week cycle for up to 2 years.
Cohort 4: RECIST 1.1-measureable disease	Pembrolizumab	Participants with Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1)-measureable disease receive pembrolizumab 200 mg via intravenous infusion on Day 1 of every 3-week cycle for up to 2 years.

Primary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (Cohort 1, Cohort 2, Cohort 4 and Cohorts 1 and 2 Combined)	Up to ~52 months	ORR was defined as the percentage of participants who experienced a complete response (CR; disappearance of all target lesions) or a partial response (PR; at least a 30% decrease in the sum of diameters of target lesions) and was assessed using RECIST 1.1 by central imaging vendor. Per protocol, analysis for this outcome measure was conducted in Cohorts 1 and 2 combined, as well as in Cohorts 1, 2, and 4 separately for the first course of treatment.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants Who Experienced an Adverse Event (AE)	Up to ~52 months	An AE was defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. The percentage of participants that experienced at least one AE for the first course of treatment was reported.
Time to PSA Progression (By Each Cohort, Cohorts 1 and 2 Combined, Cohorts 1, 2, and 3 Combined and Cohorts 4 and 5 Combined)	Up to ~52 months	Time to PSA progression was defined as the time from first day of study treatment to the date of PSA progression. Participants without PSA progression were censored at the last PSA assessment date. PSA progression was defined as the date that an increase of 25% or more and an absolute increase of 2 ng/mL or more from the nadir were documented. For participants who had a decline in PSA during treatment, PSA progression must have been confirmed by a second value 3 or more weeks later increased with respect to the nadir PSA. Per protocol, analysis for this outcome measure was conducted in Cohorts 1 and 2 combined, Cohorts 1,2, and 3 combined, Cohorts 4 and 5 combined well as in Cohorts 1 to 5 separately for the first course of treatment.
Disease Control Rate (DCR) (By Each Cohort, Cohorts 1 and 2 Combined, Cohorts 1, 2, and 3 Combined, Cohorts 4 and 5 Combined)	Up to ~52 months	Percentage of participants who had CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions)or stable disease (SD; Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease) for at least 6 months, by central imaging vendor where progressive disease (PD) in bone-only tumors were determined by radionuclide bone scan using Prostate Cancer Working Group (PCWG3) criteria and PD for all other tumors was determined using RECIST 1.1. Per protocol, analysis for this outcome measure was conducted in Cohorts 1 and 2 combined, Cohorts 1,2, and 3 combined, Cohorts 4 and 5 combined well as in Cohorts 1 to 5 separately for the first course of treatment.
Percentage of Participants Who Discontinued Study Treatment Due to an AE	Up to ~52 months	An AE was defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. The percentage of participants who discontinued study treatment during the first course of treatment due to an AE was reported.
Duration of Response (DOR) Per PCWG3-modified RECIST 1.1 (Cohort 1, Cohort 2, Cohort 4 and Cohorts 1 and 2 Combined)	Up to ~52 months	DOR was defined as the time from first documented evidence of complete response (CR; disappearance of all target lesions) or partial response (PR; ≥30% decrease in the sum of diameters of target lesions) until progressive disease (PD) assessed by central imaging where PD was determined by radionuclide bone scan using Prostate Cancer Working Group (PCWG3)-modified RECIST 1.1 criteria and PD for all other tumors was determined using RECIST 1.1 or death due to any cause, whichever occurred first. Per protocol, analysis for this outcome measure was conducted in Cohorts 1, 2 and 4 separately, well as in Cohorts 1 and 2 combined for the first course of treatment.
Duration of PSA Response (Cohorts 4 and 5 by Cohort and Combined)	Up to ~52 months	Duration of PSA response was defined as the time from PSA response, when the PSA value first declined by at least 50% of the baseline (must have been confirmed by a second value), to the date of PSA progression at which there was an increase of 25% or more from the nadir PSA, provided the absolute increase from the nadir PSA was at least 2 ng/mL. Per protocol, analysis for this outcome measure was conducted in Cohorts 4 and 5 separately and combined for the first course of treatment.
DOR- Per RECIST 1.1 (Cohort 1, Cohort 2, Cohort 4 and Cohorts 1 and 2 Combined)	Up to ~52 months	DOR was defined as the time from first documented evidence of complete response (CR; disappearance of all target lesions) or partial response (PR; ≥30% decrease in the sum of diameters of target lesions) ) until progressive disease (PD) assessed by central imaging where PD was determined by radionuclide bone scan using RECIST 1.1 and PD for all other tumors was determined using RECIST 1.1 or death due to any cause, whichever occurred first. Per protocol, analysis for this outcome measure was conducted in Cohorts 1, 2 and 4 separately, well as in Cohorts 1 and 2 combined for the first course of treatment.
Prostate-specific Antigen (PSA) Response Rate (By Each Cohort, Cohorts 1 and 2 Combined, Cohorts 1, 2, and 3 Combined and Cohorts 4 and 5 Combined)	Up to ~52 months	Percentage of participants who had PSA response defined as at least 50% decline from baseline measured twice at least 3 weeks apart. Per protocol, analysis for this outcome measure was conducted in Cohorts 1 and 2 combined, Cohorts 1, 2, and 3 combined, Cohorts 4 and 5 combined well as in Cohorts 1 to 5 for the first course of treatment.
Radiographic Progression-free Survival (rPFS) - Per PCWG3-modified RECIST 1.1 (By Each Cohort, Cohorts 1 and 2 Combined, Cohorts 1, 2, and 3 Combined, and Cohorts 4 and 5 Combined)	Up to ~52 months	rPFS was defined as the time from first day of study treatment to the documented disease progression by central imaging vendor where PD in bone-only tumors was determined by radionuclide bone scan using PCWG3 criteria and PD for all other tumors were determined using RECIST 1.1 or death due to any cause, whichever occurs first. Per protocol, analysis for this outcome measure was conducted in Cohorts 1 and 2 combined, Cohorts 1,2, and 3 combined, Cohorts 4 and 5 combined well as in Cohorts 1 to 5 separately for the first course of treatment.
Overall Survival (OS) (By Each Cohort, Cohorts 1 and 2 Combined, Cohorts 1, 2, and 3 Combined, Cohorts 4 and 5 Combined)	Up to ~52 months	OS was defined as the time from first day of study treatment to the time of death. Participants without documented death were censored at the date of the last follow up. The OS was calculated using the product-limit (Kaplan-Meier) method for censored data. Per protocol, analysis for this outcome measure was conducted in Cohorts 1 and 2 combined, Cohorts 1,2, and 3 combined, Cohorts 4 and 5 combined well as in Cohorts 1 to 5 separately for the first course of treatment.
Time to Initiation of Cytotoxic Chemotherapy (Cohorts 4 and 5 by Cohort and Combined)	Up to ~52 months	Time to initiation of cytotoxic chemotherapy was defined as the time from first day of study treatment to the time of initiation of cytotoxic chemotherapy for prostate cancer. The median time was calculated using the Kaplan-Meier method for censored data. Per protocol, analysis for this outcome measure was conducted in Cohorts 4 and 5 separately and combined for the first course of treatment.
Time to First Skeletal-related Event (Cohorts 4 and 5 By Cohort and Combined)	Up to ~52 months	Time to initiation of first skeletal-related event was defined as the time from first day of study treatment to the first skeletal-related event, which was defined as radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression, or change or antineoplastic therapy to treat bone pain. Per protocol, analysis for this outcome measure was conducted in Cohorts 4 and 5 separately and combined for the first course of treatment.
Time to New-Anticancer Therapy (Cohorts 4 and 5 By Cohort and Combined)	Up to ~52 months	Time to new-anticancer therapy was defined as the time from first day of study treatment to the time of new-anticancer therapy for prostate cancer. The median time was calculated using the Kaplan-Meier method for censored data. Per protocol, analysis for this outcome measure was conducted in Cohorts 4 and 5 separately and combined for the first course of treatment.