Background: Pembro has antitumor activity as monotherapy in pretreated advanced mCRPC (KEYNOTE-028; KEYNOTE-199). A study has suggested that pembro + enza after progression on enza may have clinical activity. KEYNOTE-365 (NCT02861573) is a phase 1b/2 umbrella study testing combinations in mCRPC; we report early results from cohort C combining pembro + enza in mCRPC. Methods: Patients who failed or became intolerant to ≥4 weeks of abi in the pre-chemotherapy mCRPC state were included. Pts also had to have progressed within 6 months prior to screening as determined by either PSA progression or radiologic progression in bone or soft tissue. Pts received pembro 200 mg intravenously Q3W with enza 160 mg per day orally, and response was evaluated by PSA levels Q3W and imaging Q9W for the first year and Q12W thereafter. Primary end points were safety and PSA response rate (confirmed PSA decline ≥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 initiated treatment (median age 69 years; PD-L1+ 30%; visceral disease 26%; measurable disease 36%). Median (95% CI) follow-up was 9 (7-13) mo. See efficacy outcomes in 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; no deaths were due to treatment-related AEs. Conclusions: Early results from the pembro + enza combination show sustained activity in abi-pretreated frontline mCRPC. Observed safety profile for the combination treatment was consistent with the known safety profiles of pembro and enza. Clinical trial information: NCT02861573