Abstract CT305: Fractionated (dose dense) and multiple dose PSMA-targeted alpha emitter 225Ac-J591 for advanced prostate cancer: Final primary and secondary outcomes

Abstract Background: 225Ac-J591 delivers the potent alpha emitter actinium-225 to PSMA+ cells via monoclonal antibody J591 via vasculature, with different kinetics and biodistribution than small molecules such as PSMA-617 (J Clin Oncol 2024). Dose fractionation is a method of administering targeted radionuclides in a dose dense fashion; cycles of radionuclides at longer fixed intervals (multiple cycles) is a standard approach. We performed parallel dose-escalation studies of each regimen with expansion of the fractionated regimen. Methods: Entry criteria: ECOG PS 0-2, intact organ function, progressive mCRPC after ARPI and chemo (or unfit/refuse). PSMA PET performed, not used for eligibility. In fractionated cohort, 1 dose-dense cycle D1 and D15; in MD cohort, 225Ac-J591 q6 wks up to 4 cycles. 1o objectives: DLT and RP2D; expansion to further define safety and prelim efficacy (PSA, PFS, OS) with PSMA PET and patient reported outcome (PRO) correlatives. Results: 60 pts treated: 42 fractionated (22 dose-escalation 45-65 KBq/Kg/dose with/without prior 177Lu-PSMA, 12 expansion, 8 additional post-177Lu after initial dose-escalation) ; 18 in multiple cycle escalation (45-65 Kbq/Kg/dose). Median age 73. 5, PSA 68. 8; 53% CALGB (Halabi) high risk, 38% intermediate risk. 88% bone, 61% node, 13% lung, 13% liver mets. 60% ≥2 prior ARPI, 70% ≥1 chemo, 13% PARPi, 12% 223Ra, 20% 177Lu-PSMA. RP2D in fractionated was 60 KBq/Kg x2, multiple cycles q6 wks not recommended due to Gr 1-3 AEs delaying subsequent cycles. PSA response (p=0. 005), PFS (p=0. 009), and OS (p=0. 003) was better with fractionated regimen. With fractionated dose regimen (regardless of prior 177Lu), 68% with 50% PSA decline, 61% with CTC count (CellSearch) decline (36% conversion), PFS 5. 2 mo, OS 15. 4 mo; PFS and OS better at RP2D. Gr 3/4 AEs: thrombocytopenia (26%), neutropenia and anemia (16. 7%), fatigue and AST elevation (4. 8%), pain (2. 4%). Despite AEs, PRO as measured by FACT-P and FACT-RNT remained stable. Pain as measured by BPI-SF tended to improve. Baseline 68Ga-PSMA-11 small molecule PET parameters SUVmax, SUVmean, total tumor volume (TTV) without clear association with response, PFS, or OS, but clinical parameters (CALGB nomogram) associated with outcome (p=0. 013, 0. 015, 0. 001, respectively). All median PSMA PET parameters improved following treatment for the cohorts. Conclusions: 225Ac-J591 administered in a fractionated (dose-dense) regimen has demonstrated safety with preliminary efficacy. Multiple doses q6 weeks not recommended given timing of blood count nadir, delaying subsequent cycles. Pain may be improved with treatment and overall quality of life stabilizes despite AEs. Small molecule PSMA PET is not associated with outcome from antibody-delivered alpha emitters, but improves after treatment. Following our academic studies, a multicenter pharma study is underway to validate fractionated results with or without prior 177Lu-PSMA NCT06549465. Citation Format: Scott T. Tagawa, Charlene Thomas, Valentina Marulanda Corzo, Jones Nauseef, Abdul Baseet Arham, Maham Fatima, Sandra Huicochea Castellanos, Elisabeth O'Dwyer, Sarah Yuan, Cora N. Sternberg, Ana Molina, Amie Patel, Vasilios Avlonitis, Shankar Vallabhajosula, David M. Nanus, Neil H. Bander, Joseph Osborne. Fractionated (dose dense) and multiple dose PSMA-targeted alpha emitter 225Ac-J591 for advanced prostate cancer: Final primary and secondary outcomes abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr CT305.