5010 Background: Pembro has activity as monotherapy in pts with pretreated advanced mCRPC. A phase 2 study suggested that pembro + enza after progression on enza may have clinical activity. Data from cohort C (pembro + enza) of KEYNOTE-365 (NCT02861573), a phase 1b/2 umbrella study to test combinations in mCRPC, are presented. Methods: Pts who were unsuccessful with or became intolerant to ≥4 weeks of abi in the prechemotherapy mCRPC state, with either PSA or radiologic progression within 6 mo before screening were included. Pts received pembro 200 mg IV Q3W with enza 160 mg/day orally. Primary end points were safety and PSA response rate (confirmed PSA decrease ≥50%). Key secondary end points were investigator-assessed ORR (RECIST v1.1), disease control rate (DCR: CR+PR+SD ≥6 mo), time to PSA progression, rPFS, and OS. Results: 69 pts began treatment (median age, 69 y; visceral disease, 26%; measurable disease, 36%). Median (95% CI) follow-up was 9 (7-13) mo. Efficacy is outlined in the table. Treatment-related AEs occurred in 63 (91%) pts; most frequent (≥20%) were fatigue (30%), rash (23%), and nausea (22%). Grade 3/4 treatment-related AEs occurred in 28 (41%) pts; most common was rash (10%); no deaths were from treatment-related AEs. Conclusions: The pembro + enza combination showed sustained activity in abi-pretreated chemotherapy-naive mCRPC. AEs were considered tolerable for the treatment combination; incidence of rash resolved with standard-of-care treatment. Clinical trial information: NCT02861573. [Table: see text]