Background: PSMA may be targeted by antibodies (mAb) or small molecules (SML), with different kinetics and biodistribution. mAb with longer circulation time and marrow exposure, but decreased access to luminal PSMA expression (e.g. salivary glands, intestine, kidney). SML diffuse to all sites of PSMA expression and then excreted. Alpha radionuclides emit more energy over shorter range vs beta. Pre-clinical data combining mAb and SML supports synergy, with enhanced uptake and retention of SML. Here, we present phase I dose-escalation results of a phase I/II trial investigating combo ²²⁵Ac-J591 with ¹⁷⁷Lu-PSMA-I&T (aka PNT2002). Methods: Eligibility criteria include progressive mCRPC, ≥1 prior AR pathway inhibitor (ARPI), prior chemo (or unfit/refuse), ≥1 lesion with SUVmax >liver. Doses: ¹⁷⁷Lu-PSMA-I&T (6.8 GBq); ²²⁵Ac-J591 (30, 35, or 40 KBq/kg), up to 2 doses of combo TRT 8 weeks (wks) apart with ¹⁷⁷Lu SPECT following each dose. Primary objectives: dose-limiting toxicity (DLT) and recommended phase II dose; phase II will test the proportion of patients (pts) obtaining >50% PSA decline (PSA50). DLT defined as G4 myelosuppression lasting >1 wk, Gr>2 non-hematologic adverse event (AE), any Gr attributed AE delaying therapy >3 wks. Additional endpoints include progression-free and overall survival, radiographic response rate, safety, circulating tumor cell (CTC) changes, pt reported outcomes, PSMA imaging, blood/tissue correlatives. Results: 18 pts treated (6 at each dose level); 3 did not receive the 2nd dose due to progressive disease or withdrawal. Median age 70 (range 54-86), PSA 54.4 (2.43-9614). 13 (72%) with bone, 9 (50%) lymph node, 2 (11%) liver, 2 (11%) lung mets. 10 (56%) pts CALGB risk category high, 7 (39%) intermediate, 1 low. Previous therapies: 11 (61%) with >1 ARPI, 12 (67%) chemo, 5 (28%) sip-T, 3 (17%) radium-223. 2 of 6 pts with DLT at 40 KBq/Kg (Gr 2 or 3 thrombocytopenia delaying cycle 2 by >3 wk); no DLT observed in other cohorts. As submission, 7 pts (39%) remain on study, including 1 without progression at 16 months and another with undetectable PSA at 10 months. With follow up ongoing, 17 (94%) with PSA decline, 9 (50%) with PSA50. Of those with paired CTC counts, 4 of 5 (80%) converted from unfavorable to favorable CTC count, 4 of 8 (50%) from detectable to undetectable, 1 of 2 (50%) remained undetectable. AEs include 3 (17%) neutropenia (all Gr <2), 12 (67%) thrombocytopenia (3 Gr 3), 10 (56%) anemia (3 Gr 3), 10 (56%) pain flare (1 Gr3 in pt with cord compression), 12 (67%) xerostomia (one Gr2), 11 (61%) nausea (all Gr 1), 9 (50%) fatigue (all Gr 1). Conclusions: The combination of dual-PSMA targeting with mAb + SML and alpha + beta is feasible with follow up ongoing. Efficacy will formally be tested in the upcoming phase II portion of the study with ²²⁵Ac-J591 at 35 KBq/Kg and ¹⁷⁷Lu-PSMA I&T at 6.8 GBq. Clinical trial information: NCT04886986.