Pembrolizumab in Metastatic Castration Resistant Prostate Cancer (mCRPC) With or Without DNA Damage Repair Defects

Inclusion Criteria

• Documented histology of adenocarcinoma of the prostate.
• Metastatic castration resistant prostate cancer with castrate-level testosterone ( 2.0 ng/mL and rising PSA by at least 2 consecutive measurements a minimum of 1-week apart.
• Soft tissue progression as defined by RECIST v1.1 criteria.
• Bone disease progression as defined by Prostate Cancer Clinical Trials Working Group 3 (PCWG3).
• Have received prior secondary hormonal therapy including abiraterone, enzalutamide and/or apalutamide.
• Be taking prednisone at a dose of ≤ 10mg/day, 7 days prior to starting treatment (Cycle 1, Day 1).
• Be willing and able to provide written informed consent/assent for the trial.
• Be >= 18 years of age on day of signing informed consent.
• Patients must agree to have a tumor tissue biopsy at baseline, and there must be a lesion that can be biopsied with acceptable clinical risk as judged by the investigator.
• Patients with inconclusive DNA damage repair status testing on this baseline biopsy must have one of the following (per the investigator's discretion): (i) Sufficient archival tissue, or (ii) An additional biopsy attempt.
• Patients with previously identified homozygous deletion or deleterious germline or somatic mutation(s) in DNA damage repair gene(s) (such as BReast CAncer gene 1 (BRCA1) , BReast CAncer gene 2 (BRCA2), and ATM) identified in a Clinical Laboratory Improvement Amendments of 1988 (CLIA)-certified laboratory are allowed in Group 2. (i) Somatic mutation(s) in DNA damage repair gene(s) needs to be identified on the biopsy of a castration-resistant tumor site (ii) Archival FFPE tissue will be requested for determination of MSI (if not already assessed by gene sequencing) signature status.(iia) A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or at least 10 slides containing unstained, freshly cut, serial sections must be available along with an associated pathology report before study enrollment. (iii) If archival FFPE tissue is unable to be obtained or is insufficient, patients will be required to undergo tumor tissue biopsy if feasible for determination of MSI signature status.
• Patients with germline mutation(s) in mismatch repair (MMR) gene(s) (i.e. Lynch syndrome),or have previously identified Microsatellite instability (MSI)-high tumor by Polymerase chain reaction (PCR) or MMR deficient tumor by Immunohistochemistry (IHC) are also allowed in Group 2. (i) Archival FFPE tissue will be requested for determination of Fanconi anaemia (FA)/BRCA signature status. (ia) A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or at least 10 slides containing unstained, freshly cut, serial sections must be available along with an associated pathology report before study enrollment. (ii) If archival FFPE tissue is unable to be obtained or is insufficient, patients will be required to undergo tumor tissue biopsy if feasible for determination of FA/BRCA signature status.
• If group 1 is not filled, patients may proceed onto treatment without the completion of tests for DNA repair status. Once group 1 is filled, patients cannot be enrolled onto the study or start treatment until DNA damage repair status is successfully determined for study group placement.

a. Patients will be replaced if they have tissues that are not evaluable for DNA repair mutations

• Patients must be willing to provide archival tissue from prior biopsy or surgery for prostate cancer, if available.

a. A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or at least 10 slides containing unstained, freshly cut, serial sections must be available along with an associated pathology report before study enrollment.

• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
• Patients must discontinue antiandrogen therapy (i.e. bicalutamide, flutamide, nilutamide) at