All modern randomized controlled trials for patients with mCRPC have included a backbone of continuous medical or surgical castration in control and experimental arms. Unfortunately, continuous medical castration virtually guarantees ongoing side effects that are predictably detrimental to quality of life. Theoretical rationales notwithstanding, there is no definitive empirical evidence that maintaining castrate levels of testosterone is required during ongoing treatment of patients with mCRPC. In fact, modern prospective data strongly suggests that (1) ongoing medical castration therapy is likely not required if patients are receiving active non-AR directed therapy, and (2) restoration of physiologic testosterone investigated in combination with such therapy will improve quality of life. Most mCRPCs over-express PSMA which is amenable to PSMA targeted radiopharmaceuticals that deliver beta-particle radiation selectively to PSMA positive cells and their immediate surroundings. Metastasis directed SBRT enables safe and accurate precision delivery of ablative doses of ionizing radiation to metastatic lesions independent of PSMA expression. Comprehensive systemic targeted radiopharmaceutical therapy combined with metastasis directed ablative tumor directed therapy might not only delay progression, but also create a critical window of opportunity to restore physiologic levels of testosterone and thereby potentially enable Veterans time with normal vitality, hormonal function, and even sexual function. We propose: a Phase II Trial Of TargetEd Radiation with No CastraTion for mCRPC (POTENT-C). By leveraging advances in non-AR directed active therapy for mCRPC, our proposal promises to improve treatment efficacy and quality of life for Veterans with mCRPC. Specifically, we hypothesize that comprehensive non- hormonal therapy in the form of PSMA targeted radioligand therapy combined with metastasis directed SBRT, followed by physiologic restoration of testosterone will (1) improve efficacy of therapy for Veterans with mCRPC while simultaneously (2) improving quality of life. POTENT-C is a single arm Phase II clinical trial of PSMA targeted radiopharmaceutical therapy and comprehensive metastasis directed therapy followed by palliative testosterone replacement therapy (TRT) in Veterans with mCRPC who have progressed on at least one prior second generation anti-AR therapy. We hypothesize that this therapeutic approach will both improve clinical outcomes and quality of life for Veterans. Planned therapeutic interventions include two cycles of Lu-177 PSMA PNT2002 separated by 8 weeks with intervening metastasis directed SBRT to all visible sites of disease. Four weeks after this planned therapy, Veterans are re-imaged and those without suspicion of radiographic progression are planned for symptomatic palliation with testosterone replacement therapy (TRT). • The primary endpoint is six-month radiographic progression free survival per PCWG3 criteria. Second...