Background: Novel therapeutic options to extend disease control and survival for pts with mCRPC whose disease progressed after docetaxel chemotherapy remain a clinical need. The anti-TIGIT (T-cell immunoreceptor with immunoglobulin and ITIM domain) antibody vibostolimab is well tolerated and has antitumor activity in advanced solid tumors as monotherapy and in combination with the PD-1 inhibitor pembrolizumab. In cohort G of the phase 1b/2 KEYNOTE-365 study (NCT02861573), the safety and efficacy of a coformulation of pembrolizumab and vibostolimab were evaluated in pts with docetaxel-pretreated mCRPC. Methods: Eligible pts were aged ≥18 years with confirmed mCRPC, an ECOG PS of 0 or 1, and prior treatment with docetaxel for mCRPC. Prior treatment for mCRPC with 1 other chemotherapy and ≤2 next-generation hormonal manipulations were allowed. Pts received a coformulation of pembrolizumab 200 mg plus vibostolimab 200 mg IV Q3W for ≤35 cycles. Primary end points were prostate-specific antigen (PSA) response rate, objective response rate (ORR) per RECIST v1.1 by blinded independent central review (BICR), and safety. Secondary end points included duration of response (DOR) and disease control rate (DCR; CR and PR of any duration and SD or non-CR/non-PD of ≥6 months) per RECIST v1.1 by BICR, radiographic progression-free survival (rPFS) per PCWG3-modified RECIST v1.1 by BICR, and overall survival (OS). Results: A total of 40 pts received pembrolizumab plus vibostolimab. The median age was 72 years (range, 50-83), 73% had RECIST v1.1–measurable disease per BICR, and 68% had an ECOG PS of 1. Median time from first dose to data cutoff date (January 25, 2023) was 10.2 months (range, 8.6-15.7). As of data cutoff date, 90% of pts had discontinued study treatment (60% due to PD); 10% were continuing treatment. Confirmed PSA response was 18% (7/40 pts; 95% CI, 7-33) for pts with a baseline PSA measurement. ORR for pts with RECIST v1.1–measurable disease was 7% (95% CI, 1-23; 1 CR, and 1 PR, both ongoing for ≥6 months). DCR for all pts was 13%. Median rPFS was 2.1 months (95% CI, 2.0-4.0); estimated 12-month rPFS rate was 10%. Median OS was 8.6 months (95% CI, 7.1-NR); estimated 12-month OS rate was 48%. A total of 63% of pts had an any-grade treatment-related adverse event (TRAE), most commonly (≥10%) pruritus (25%) and nausea (10%); 23% of pts had a grade 3-5 TRAE, most commonly (≥5%) pyrexia (5%) and rash (5%). Three deaths occurred because of an AE (pulmonary sepsis, cardiac arrest, pulmonary embolism); 1 was considered treatment related (pulmonary embolism). Conclusions: The coformulation of pembrolizumab and vibostolimab had limited antitumor activity in pts with mCRPC previously treated with docetaxel. The safety profile was manageable and generally consistent with the individual profiles of each agent. Clinical trial information: NCT02861573.