Background: Lesions in mCRPC are typically immunologically cold. AMG 160 binds to PSMA on cancer cells and CD3 on T cells, leading to T-cell infiltration, activation, expansion, and tumor cell killing. In a first-in-human study, AMG 160 has demonstrated a manageable safety profile with preliminary efficacy in heavily pretreated patients. Enzalutamide and abiraterone are novel hormonal therapies (NHTs) that improve survival in mCRPC and may enhance T-cell responses, but resistance occurs. Combination therapy with AMG 160 may help overcome hormonal therapy resistance and broaden use for earlier line mCRPC. Preclinical data have demonstrated enhanced activity when AMG 404, an anti-PD-1 that can overcome T-cell exhaustion, and AMG 160 are combined. The safety and efficacy of AMG 160 combinations will be evaluated. Methods: NCT04631601 will enroll ∼100 men with histologically or cytologically confirmed adenocarcinoma of the prostate. The protocol consists of 3 subprotocols. Subprotocols A and B are phase 1b, multicenter, open-label studies; subprotocol C is a phase 1b/2 study. Therapeutic combinations include AMG 160 + enzalutamide (A), AMG 160 + abiraterone (B), and AMG 160 + AMG 404 vs AMG 404 monotherapy (C). Patients who received prior PSMA radionuclide therapy may be eligible. Patients must not have received prior PSMAxCD3 bispecific therapy, prior taxane treatment (unless approved by the sponsor) across subprotocols, and prior NHT specific to the subprotocol. In subprotocol C, patients must have progressive disease on an NHT to be eligible. Patients with CNS metastases, leptomeningeal disease, or active autoimmune disease will be excluded. AMG 160 will be administered intravenously (IV). Dexamethasone (or other corticosteroids) will be administered before AMG 160 administration in cycle 1 and possibly subsequent cycles. Enzalutamide or abiraterone will be administered per label. AMG 404 will be administered IV. Primary objectives are to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of AMG 160 combinations. Subprotocol C will also evaluate the preliminary antitumor activity of AMG 404 monotherapy. Secondary objectives are to assess preliminary antitumor activity and characterize pharmacokinetics. MTD/RP2D will be established in the dose-escalation phase, and the safety and tolerability of the MTD/RP2D will be confirmed in the expansion phase. Evaluation of preliminary antitumor activity will be based on RECIST 1.1 with Prostate Cancer Working Group 3 modifications, prostate-specific antigen (PSA) response, circulating tumor cell response, progression-free survival (radiographic, PSA, clinical), overall survival, and ⁶⁸Ga-PSMA-11 and ¹⁸F-FDG PET/CT imaging. The study is currently recruiting patients. Clinical trial information: NCT04631601