Background: PC is a radiosensitive disease. PSMA is selectively overexpressed in advanced PC with upregulation by androgen receptor (AR) pathway dysregulation; limited expression exists in other organs. Prior studies of beta-emitting radiolabeled anti-PSMA antibody J591 demonstrated accurate targeting, efficacy with dose-response effect, and safety with predictable dose-limiting myelosuppression. Recent prospective trials have shown efficacy and safety of ¹⁷⁷Lu-PSMA-617 in mCRPC. Studies demonstrate different binding sites of J591 and PSMA-617 and co-administration leads to non-competitive additive binding and delivery of payloads to PSMA+ cells. As the pharmacokinetics and biodistribution of the 2 agents is mostly non-overlapping (other than tumor) and given our prior dose-response data, we hypothesize that delivery of the combination will yield higher tumor delivery with less off-target toxicity (i.e. better responses without increased toxicity). Methods: Men with progressive mCRPC following at least 1 potent AR-targeted agent (e.g. abi/enza) and docetaxel (or unfit/refuse chemo) with metastatic disease on CT/MRI or bone scan without limit of # prior therapies (excluding bone-targeted beta-emitting radioisotopes) provided adequate organ function will be enrolled. Pre-treatment ⁸⁸Ga-PSMA-11 will be performed, but results are not used for eligibility. Treatment includes fractionated ¹⁷⁷Lu-J591 at a fixed moderate dose with escalating doses of ¹⁷⁷Lu-PSMA-617 (7.4 – 18.5 GBq per cycle, fractionated D1 and D15) in a 3+3 dose-escalation study. Dose-limiting toxicity (DLT) is defined as attributable grade > 3 heme toxicity or grade > 2 non-heme toxicity. Following determination of recommended phase 2 dose (RP2D), the phase 2 portion will enroll in a 2-stage design. Primary endpoints: DLT and RP2D (ph 1) and PSA decline proportion (ph 2). Secondary endpoints include toxicity, radiographic response, PFS, rPFS, OS, CTC count changes. Correlatives include baseline/follow up PSMA imaging, whole body distribution of ¹⁷⁷Lu, tissue and circulating genomic assessment, immunologic assessment, and patient reported outcomes (FACT-P and BPI-SF). Clinical trial information: NCT03545165