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This is a nonrandomized, multinational, open-label trial of pembrolizumab (MK-3475) in subjects with metastatic cas-tration-resistant prostate cancer (mCRPC) previously treated with docetaxel-based chemotherapy. The trial will be conducted in conformance with Good Clinical Practices. Approximately 250 subjects will be enrolled into one of three cohorts based on programmed death-ligand 1 (PD-L1) status and RECIST 1.1 measurability. Each of these two characteristics will be centrally confirmed. The enroll-ment cohorts will be:
(Cohort 1) subjects with PD-L1 positive, RECIST 1.1-measurable disease (n≈100)
(Cohort 2) subjects with PD-L1 negative, RECIST 1.1-measurable disease (n≈100)
(Cohort 3) subjects with bone-metastases, RECIST 1.1 non-measurable (n≈50)
Bone metastases must be radiographically evident by whole body bone scintigraphy. Subjects will be enrolled in the study and will receive pembrolizumab 200 mg every 3 weeks (Q3W) regardless of PD-L1 expression status; however, PD-L1 expression status will determine cohort assignment. Participation in this trial will be dependent upon subjects supplying tumor tissue from a newly obtained biopsy and/or an archival specimen. Adequacy of these specimens for PDL1 biomarker analysis will be evaluated by a central laboratory prior to enrollment. Please refer to Section 7.1.2.7 for tissue sample collection requirements by cohort. Cohorts 1 and 2 will begin enrolling irrespective of PD-L1 expression status; however, PDL1 expression status will be monitored. Enrollment of Cohort 2 is expected to complete more quickly than Cohort 1 based on the low anticipated prevalence of subjects with PD-L1 positive tumors in this population. After approximately 100 PD-L1 negative subjects have been enrolled, enrollment of Cohort 2 will stop. Subjects will be enrolled into Cohort 3 irrespective of PD-L1 status. All subjects will undergo radi-ologic imaging assessments to evaluate response to treatment at regular intervals. On study imaging will be assessed every 9 weeks for approximately one year and every 12 weeks thereafter. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 will be adapted per the con-sensus guidelines of the Prostate Cancer Clinical Trials Working Group 2 (PCWG3) as described in Section 7.1.2.6.2 to account for the tumor response and progres-sion patterns seen in bone metastases in prostate cancer. Adverse events (AEs) will be monitored throughout the trial and graded in severity according to the guidelines outlined in the National Cancer Institute (NCI) Common Terminolo-gy Criteria for Adverse Events (CTCAE) version 4.0 (See Appendix 12.6). Treatment with pembrolizumab will contin-ue until documented confirmed disease progression, unac-ceptable AEs, intercurrent illness that prevents further ad-ministration of treatment, Investigator’s decision to withdraw the subject, subject discontinuation from the study, noncompliance with trial treatment or procedure require-ments, subject receives 35 administrations of pembroli-zumab (approximately 2 years), or administrative reasons requiring the cessation of treatment. Subjects who attain an Investigator-determined confirmed complete response (CR) may receive up to 35 infusions of treatment. Subjects who discontinue after 35 infusions for reasons other than disease progression or intolerability, or who discontinue after attaining a CR [and had at least 8 administrations of pembrolizumab and at least 2 treatments beyond initial CR] may be eligible for up to 17 additional infusions (ap-proximately one year) after they have experienced radio-graphic disease progression. The decision to retreat will be at the discretion of the Investigator only if no cancer treat-ment was administered since the last dose of pembroli-zumab, the subject still meets the safety parameters listed in the Inclusion/Exclusion criteria, and the trial remains open (refer to Section 7.1.5.2.1 for further details). After the end of treatment, each subject will be followed for 30 days for AE monitoring (serious AEs will be collected for 90 days after the end of treatment or 30 days after the end of treatment if the subject initiates new anticancer therapy, whichever is earlier). Subjects who discontinue treatment for reasons other than disease progression will stay on study and continue to undergo study-related disease as-sessments until disease progression, initiation of a non-study cancer treatment, withdrawal of consent, or becom-ing lost to follow-up. All subjects will be followed by tele-phone contact for overall survival until death, withdrawal of consent or the end of the study, whichever comes first. Specific procedures to be performed during the trial, as well as their prescribed times and associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each procedure are provided in Section 7.0 – Trial Procedures.