Background: In previously treated adenocarcinoma metastatic castration-resistant prostate cancer (mCRPC), approximately 20% of patients develop t-NE PC, which is aggressive with short overall survival (OS). t-NE PC treatment includes platinum-containing chemotherapy because of t-NE’s histologic, biologic, and clinical similarity to small cell/NE lung cancer. In the open-label, multicohort, phase 1b/2 KEYNOTE-365 study (NCT02861573), pembrolizumab, when combined with several agents for treatment of adenocarcinoma mCRPC, showed clinical activity and acceptable safety. To identify new treatment options for t-NE mCRPC, cohort I will help to evaluate platinum-containing chemotherapy alone or combined with pembrolizumab for patients with t-NE. Methods: Cohort I of the KEYNOTE-365 study will enroll patients with t-NE (≥1% neuroendocrine cells in a recent biopsy specimen confirmed by central histology review) and prior docetaxel treatment for mCRPC. Prior treatment with ≤2 next-generation hormonal agents (NHAs) for metastatic hormone-sensitive prostate cancer (mHSPC) or mCRPC and 1 other chemotherapy for mCRPC is permitted. Additionally, enrollment in cohort I requires previous prostate cancer progression within 6 months of starting an NHA (mHSPC or mCRPC) and within < 6 cycles of docetaxel for mCRPC. Each arm will enroll 40-100 patients with Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0 or 1. Eligible patients will be randomly assigned 1:1 to receive pembrolizumab 200 mg IV on day 1 of each cycle every 3 weeks + carboplatin AUC of 5 IV on day 1 + etoposide 100 mg/m² IV on days 1, 2, and 3 of each 21-day cycle for 4 cycles (arm 1) or the same chemotherapy regimen without pembrolizumab (arm 2). Pembrolizumab treatment will continue for up to 2 years until disease progression, unacceptable toxicity, or withdrawal of consent. Patients will be stratified by ECOG PS score (0 vs 1). Primary end points are safety and tolerability, prostate-specific antigen (PSA) response rate, and objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR). Secondary end points include time to PSA progression; duration of response (DOR) and disease control rate (DCR) per RECIST v1.1 by BICR; ORR, DOR, DCR, and radiographic progression-free survival per Prostate Cancer Working Group 3–modified RECIST v1.1 by BICR; and OS. End points will be summarized for each arm without formal hypothesis testing. This cohort of KEYNOTE-365 is enrolling in Australia, Germany, New Zealand, Spain, and the United States. Clinical trial information: NCT02861573.