Background: The role of immune checkpoint inhibition (ICI) in prostate cancer remains undefined outside of the subset with mismatch repair. Several studies have suggested that ICI combined with androgen receptor signaling inhibitors (ARSI) or kinase inhibitors may result in improved and/or more durable response in a proportion of men with mCRPC. While not yet proven, addition of external beam radiation to ICI may improve outcomes (for instance Kwon et al Lancet Oncol 2014, Fizazi K et al, Eur Urol 2020). PSMA targeted therapy with 177Lu-PSMA-617 improves survival in men with CRPC, has been combined with ICI in early phase studies, and we have previously demonstrated the benefit of PSMA targeted therapy using radiolabeled mAb J591. PSMA-targeted alpha-emitters have a very high potency and the potential to generate immune response. Based upon i) ARSI may increase PSMA expression, ii) ARSI may radiosensitize tumors, iii) ARSI resistance may lead to increased PD-L1 expression, and iv) alpha emitters may generate an immune response, we hypothesize that the addition of an alpha-emitting radionuclide (²²⁵Ac) targeting prostate cancer (i.e PSMA+ tumors targeted with J591) will lead to double-stranded DNA breaks, cell death, and subsequent release of neoantigens, and thus will increase the response proportion to pembrolizumab plus ARSI resulting in more durable response. Methods: Key eligibility criteria include progressive mCRPC by PCWG3 on at least 1 prior AR pathway inhibitor and no prior chemotherapy for mCRPC. A phase I dose-finding study will first test safety of the triplet combination of pembrolizumab, an ARSI of physician choice, and 2 different doses of ²²⁵Ac-J591 (one with minimal and one with moderate single-agent toxicity). Following determination of the optimal dose, a randomized phase II trial will treat subjects with a fixed dose of pembrolizumab 400 mg every 6 weeks (for up to 2 years) plus a standard ARSI (until progression or intolerance) with or without ²²⁵Ac-J591. The primary endpoint of the study will test the hypothesis that the addition of a PSMA-targeted alpha emitter increases the composite of RECIST measurable disease, PSA, and CTC count response to immuno-hormonal therapy with 90% power. Key secondary clinical endpoints include 1-year progression-free survival, duration of response, and overall survival. Exploratory objectives include assessment of immunogenic cell death, immune serologic and host microbiome changes, plasma ctDNA, serial PSMA PET, and patient reported outcomes (FACT-P, BPI, EQ-5D-5L). The phase I portion of this DOD-funded study was activated in summer 2021 with the randomized phase II portion expected to open at PCCTC sites in 2022. Clinical trial information: NCT04946370.