A Phase I Dose-Escalation/Expansion Study of Fractionated-Dose and Multiple-Cycle Anti-PSMA-Targeted α-Emitter 225Ac-J591 in Patients with Prostate Cancer.

In 30 seconds

This phase I dose-escalation and expansion study evaluated fractionated and repeated-cycle 225Ac-J591 in patients with progressive metastatic prostate cancer resistant to androgen pathway modulation. The fractionated regimen was given on days 1 and 15, while the multiple-cycle regimen was repeated every 6 weeks for up to four cycles. Three patients had dose-limiting toxicities with fractionated dosing, and the recommended phase II dose was 60 KBq/kg twice. A prostate-specific antigen decline greater than 50% was the best response in 60% of patients across fractionated cohorts; repeated-cycle dosing was not recommended for further development.

Key findings

• Three patients had dose-limiting toxicities with fractionated dosing; the recommended phase II dose was 60 KBq/kg twice.
• Seven patients had dose-limiting toxicities in the multiple-cycle regimen, which was not recommended for further development.
• A PSA decline greater than 50% was the best response in 60% of patients across fractionated cohorts, with or without prior 177Lu-PSMA.
• Temporary hematologic toxicity was common: thrombocytopenia occurred in 93% (32% grade >3), neutropenia in 65% (13% grade ≥3), and anemia in 63% (20% grade ≥3).

Why it matters

The study provides early safety and activity data for PSMA-targeted alpha-emitter therapy in patients with advanced prostate cancer, including some previously treated with 177Lu-PSMA. The contrast between the fractionated and repeated-cycle regimens is relevant to further clinical development, while the frequent hematologic adverse events underscore the need to assess toxicity alongside PSA responses.

What to keep in mind

This was a phase I study focused primarily on dose-limiting toxicity and dose selection; the abstract does not report a comparative efficacy assessment.