Patient-reported outcomes (PRO) from a dose-escalation and expansion trial of fractionated and multiple-cycle PSMA-targeted alpha radionuclide ²²⁵ Ac-J591.

Abstract

208 Background: A prior phase I dose-escalation study demonstrated encouraging safety and efficacy of single administration of anti-PSMA antibody J591 linked to α-emitter 225 Ac, with or without prior 177Lu-PSMA exposure. We subsequently performed a dose-escalation/expansion trial (NCT04886986) in two parallel cohorts: fractionated (dose-dense) and multiple-cycle (q6 weeks). Here, we report protocol-specified secondary endpoint of health-related quality of life (HRQoL). Methods: Patients with metastatic, hormone-resistant PC received escalating doses of 225 Ac-J591 in either a fractionated (D1 and D15) or multiple-cycle (q6 weeks × up to 4) regimen. HRQoL was assessed using the validated FACT-P (39-item, 5-domain instrument for prostate cancer) and, in an amended protocol, the FACT-RNT (novel, 15-item questionnaire evaluating symptoms and toxicities specific to targeted RNT). Both instruments were administered at baseline and at multiple follow-up time points. Descriptive statistics and mixed-effects modeling evaluated longitudinal HRQoL changes and dose–time interactions. Results: 60 patients were enrolled (fractionated n=42; multiple-cycle n=18), median age 73 years. Prior therapies: ≥2 ARPI in 32 (53%), chemotherapy in 43 (72%), radium-223 in 7 (12%), sipuleucel-T in 17 (34%), and 177Lu-PSMA in 11 (18%). Metastatic sites: bone (88%), lymph nodes (62%), and viscera (26%); 53% were Halabi high-risk. A ≥50% PSA decline was achieved in 68% (fractionated) and 28% (multiple-cycle). The RP2D was 60 KBq/kg ×2 for fractionated dosing; multiple-cycle dosing was not advanced due to thrombocytopenia-related delays. At cutoff, 95% (fractionated) and 100% (multiple-cycle) completed ≥1 FACT-P, and 31% (13/42) completed ≥1 FACT-RNT. In the multiple-cycle arm, median FACT-P declined from 106 to 74 at Day 85, with most pronounced decreases in physical (–13) and functional (–8) well-being. In contrast, the fractionated cohort showed stable or improved HRQoL: median FACT-P rose from 116 to 123 (+14; p=0.2), with no significant dose–time interaction. FACT-RNT total scores remained stable (median 49), showing no meaningful deterioration across timepoints or dose levels. Conclusions: 225Ac-J591 was well tolerated with preserved HRQoL, particularly in the fractionated regimen. FACT-P demonstrated maintained or modest improvement in QoL, while FACT-RNT confirmed stability of treatment-related symptom burden across dose levels. Together, these results suggest that 225 Ac-J591 preserves quality of life during therapy without significant physical or emotional decline. On-going follow up with larger sample size is needed to clarify long-term HRQoL trends. Clinical trial information: NCT04506567 .