Background: Metastatic NEPC is an aggressive form of prostate cancer that can occur de novo or as a result of androgen deprivation therapy (ADT). Treatment-emergent NEPC (t-NE) or de novo NEPC is often treated with platinum-based chemotherapy; however, no standard of care for these patients exists. Pembro, a PD-1 inhibitor, has shown antitumor activity and manageable safety in subsets of patients with metastatic castration-resistant prostate cancer (mCRPC). Cohort I of the multicohort, open-label, phase 1b/2 KEYNOTE-365 study (NCT02861573) will assess efficacy and safety of pembro + platinum/etoposide for metastatic NEPC. Methods: Eligible patients are aged ≥18 years, have metastatic NEPC (t-NE or de novo NEPC) defined by ≥1% of neuroendocrine (NE) cells in discrete regions of a recent biopsy specimen from a metastasis, and have experienced disease progression within 6 months prior to screening. NE histology must be confirmed by central review according to Epstein 2014 criteria. A limited number of patients with metastatic de novo NEPC can enroll. Patients with NEPC must have an ECOG PS of 0 or 1 and have received prior treatment with ADT for metastatic disease; ≤2 chemotherapies for mCRPC and ≤2 prior NHAs are permitted. Docetaxel for metastatic hormone sensitive prostate cancer or mCRPC is permitted. Patients will be randomly assigned 1:1 to receive carboplatin (AUC5 IV day 1) + etoposide (100 mg/m² IV days 1-3) in cycles 1-4 Q3W plus pembro 200 mg IV Q3W for ≤35 cycles or the same combination chemotherapy without pembro. Randomization will be stratified by ECOG PS (0 vs 1). Approximately 40 to 100 patients will be enrolled in each treatment arm. Imaging assessments (computed tomography/magnetic resonance imaging, and bone scans) will be performed Q9W through week 54 and Q12W thereafter, at treatment discontinuation, and during follow-up. PSA will be measured Q3W until treatment discontinuation. Adverse events (AEs) will be monitored and assessed by investigators per NCI Common Terminology Criteria for Adverse Events v4.0 throughout the study for 30 days (90 days for serious AEs or 30 days if new anticancer therapy is initiated, whichever occurs first) after last dose of study treatment. Primary end points are safety and tolerability, PSA response rate, and ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary end points include PSA progression; OS; rPFS, ORR, DOR and DCR per PCWG3-modified RECIST v1.1 by BICR and DOR and DCR per RECIST v1.1 by BICR. Efficacy and safety will be analyzed in all allocated patients who received ≥1 dose of study treatment. No formal hypothesis testing will be performed. PSA response rates, ORR, and DCR will be estimated using the Clopper-Pearson method. Kaplan-Meier method will estimate DOR, time to PSA progression, rPFS, and OS. AEs will be summarized descriptively. Recruitment is ongoing. Clinical trial information: NCT02861573.