Background: Pts with mCRPC who progress on docetaxel and new hormonal agents (NHAs) have few therapeutic options. In the CARD study of cabazitaxel, 35.7% of pts had PSA responses and 36.5% of pts had tumor responses. While immune checkpoint inhibitors have limited single-agent activity in mCRPC, the combination of the adenosine 2A receptor antagonist, AZD4635, with durvalumab may improve response to chemotherapy. This study assessed AZD4635 in combination with durvalumab (Arm A) or with durvalumab + cabazitaxel (Arm B) in pts with mCRPC. We report interim analysis results from Arm B (Arm A to be reported elsewhere). Methods: Eligible pts had histologically confirmed mCRPC, disease progression ≤6 months prior to enrollment, and were previously treated with docetaxel and 1 NHA. Pts received AZD4635 75 mg PO QD + durvalumab 1500 mg IV Q3W + cabazitaxel Q3W (dosed per locally approved label) for up to 10 cycles. The primary endpoint was radiographic progression-free survival (rPFS), by RECIST v1.1 (soft tissue) or PCWG3 (bone). Secondary endpoints included safety, pharmacokinetics, confirmed PSA₅₀ response, and objective response rate by RECIST v1.1. A futility analysis was planned based on PSA₅₀ responses (confirmed + unconfirmed) after approximately 30 pts were treated. Results: As of August 10, 2021, 28 pts received AZD4635 + durvalumab + cabazitaxel, and 21 pts were still on treatment. Most common adverse events (AEs) possibly related to treatment were nausea (50.0%), diarrhea (46.4%), asthenia, and vomiting (each 28.6%). Treatment-related febrile neutropenia occurred in 7.1% pts. Twelve (42.9%) pts had a serious AE possibly related to treatment. One AE possibly related to treatment led to death (myositis). Exposures of cabazitaxel and/or durvalumab did not change when combined with AZD4635. Median rPFS was 4.4 months (95% CI: 4.2–not calculable) with low percent maturity. Of 28 PSA-evaluable pts, 8 (28.6%) had PSA₅₀ responses (4 confirmed). There were 5 unconfirmed partial responses by RECIST v1.1. Conclusions: Although efficacy data are immature, enrollment was stopped for futility. Safety of the combination was consistent with the known safety profiles of the individual agents. Clinical trial information: NCT04089553.