Background: Docetaxel is an established treatment for pts with mCRPC. Pembro, a PD-1 inhibitor, showed single-agent antitumor activity in mCRPC. In the phase 1b/2 KEYNOTE-365 study (NCT02861573), docetaxel + pembro and prednisone showed activity in pts treated with abi or enza for mCRPC, warranting further evaluation. Methods: KEYNOTE-921 (NCT03834506) is a phase 3 trial to evaluate efficacy and safety of pembro + docetaxel and prednisone in chemotherapy-naive pts who progressed with enza or abi therapy for mCRPC. An estimated 1000 pts will be randomly assigned 1:1 to receive docetaxel 75 mg/m² IV every 3 weeks (Q3W) + prednisone/prednisolone orally 5 mg twice daily (BID) and pembrolizumab 200 mg IV Q3W or docetaxel 75 mg/m² IV Q3W + prednisone/prednisolone 5 mg orally BID + placebo IV Q3W. Treatment will be stratified by previous next-generation hormone agent (abi or enza) and metastases location (bone only, liver, other). Adults (≥18 years) with histologically or cytologically confirmed mCRPC who progressed with androgen deprivation therapy (or postbilateral orchiectomy) ≤6 months of screening, have ECOG PS 0 or 1, and have adequate organ function are eligible. Pts must have experienced either progression after ≥8 weeks (≥14 weeks for bone progression) or intolerance after ≥4 weeks of abi or enza (but not both) in a chemotherapy-naive mCRPC state. Pts will be required to provide tissue for biomarker analysis. Responses will be assessed by CT or MRI and radionuclide bone imaging per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST v1.1 by blinded independent central review (BICR) Q9W during the first year and Q12W thereafter. Treatment will continue with docetaxel and prednisone for up to 10 cycles and with pembro for up to 35 cycles or until disease progression, unacceptable toxicity, or consent withdrawal. Primary end points are rPFS by BICR and OS. Secondary end points are time to initiation of subsequent anticancer therapy or death, PSA response rate, time to PSA progression, ORR and DOR per PCWG3-modified RECIST v1.1 assessed by BICR, and safety. Accrual began May 2, 2019. Clinical trial information: NCT03834506