Phase I/II Trial of Pembrolizumab and Androgen-receptor Inhibitor With or Without 225Ac-J591 for Progressive Metastatic Castration Resistant Prostate Cancer

Inclusion Criteria: * Male participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of prostate adenocarcinoma. * A male participant must agree to use a contraception during the treatment period and for at least 4 months after the last dose of study treatment and refrain from donating sperm during this period. * Documented progressive metastatic CRPC based on Prostate Cancer Working Group 3 (PCWG3) criteria, which includes at least one of the following criteria: PSA progression, Objective radiographic progression in soft tissue, New bone lesions * Evaluable for response with at least one of the following: * Measurable disease by RECIST 1.1 * Detectable (\>0) CTC by CellSearch * PSA of at least 2 ng/dL * ECOG performance status of 0-1 * Have serum testosterone ≤ 50 ng/dL. Subjects must continue primary androgen deprivation with an LHRH/GnRH analogue (agonist/antagonist) if they have not undergone orchiectomy. * Have previously been treated with at least one of the following in any disease state: Androgen receptor inhibitor (ARI, such as enzalutamide, apalutamide or darolutamide), CYP 17 inhibitor (such as abiraterone acetate). These drugs may have been initiated in the metastatic hormone sensitive (i.e. non-castrate) or non-metastatic (M0) CRPC setting provided they meet criteria for progressive mCRPC at study entry. * Age ≥ 18 years * Patients must have normal organ and marrow function as defined: Abs…