AcTION: Phase 1 study of 225 AcAc-PSMA-617 ( 225 Ac-PSMA-617) in men with metastatic castration-resistant prostate cancer (mCRPC) with or without prior 177 LuLu-PSMA ( 177 Lu-PSMA) radioligand therapy (RLT).

5010 Background: AcTION is the first prospective dosage escalation study of 225 Ac-PSMA-617, an alpha-emitting, PSMA-targeted RLT in patients (pts) with mCRPC (NCT04597411). Methods: This study enrolled pts with progressive, PSMA-positive mCRPC in 3 groups (Gps). Gp A: prior chemotherapy (ChT) and an androgen receptor pathway inhibitor (ARPI) but no prior 177 Lu-PSMA RLT; Gp B: no prior ChT, ARPI, or 177 Lu-PSMA RLT (ChT/ARPI-naive); Gp C: prior 177 Lu-PSMA RLT. Dosage escalation of 225 Ac-PSMA-617 used a Bayesian logistic regression model with administered activities of 4, 6, 8 or 10 MBq given intravenously for ≤6 cycles every 8 weeks. Primary objective was to identify the recommended phase 2 dosage (RP2D), based on dosage-limiting toxicities (DLTs) within the first 6 weeks of 225 Ac-PSMA-617 administration. This analysis includes all 101 treated pts per 13 Nov 2025. Results: Gp A pts had a median of 3 prior systemic therapies and median baseline BL PSA 73.4 (range 1-3320) ng/mL. At a median follow-up FU of 7.46 months (mos), PSA50 response rate (PSA50) was 20/34 (58.8%; 95% CI 40.7, 75.4) and PSA90 was 15/34 (44.1%; 95% CI 27.2, 62.1). Gp B pts had BL PSA 223.4 (5-12308) ng/mL. At a FU of 13.24 mos, PSA50 was 23/27 (85.2%; 95% CI 66.3, 95.8) and PSA90 was 22/27 (81.5%; 95% CI 61.9, 93.7). Gp C pts had 5 prior systemic therapies and BL PSA 85.5 (5-1760) ng/mL. At a FU of 8.57 mos, PSA50 was 21/40 (52.5%; 95% CI 36.1, 68.5) and PSA90 was 7/40 (17.5%; 95% CI 7.3, 32.8). Across all 3 Gps, there were no DLTs and a maximum tolerated dosage was not reached. No Grade G 4/5 TRAEs occurred. No dosage-dependent safety signals were observed. Dry mouth (G1/2 only) was the most common treatment-related (TR) adverse event (AE), observed in > 90% of pts across all Gps and mostly reported as not resolved at data cut off. Two TRAEs led to treatment discontinuation (G2 dry mouth at 8 MBq, and G3 anemia at 10 MBq; both occurring in Gp C). The RP2D for all 3 Gps was 10 MBq. Additional efficacy data will be presented. Conclusions: 225 Ac-PSMA-617 demonstrated an acceptable safety profile and promising anti-tumor activity up to 10 MBq in pts with mCRPC regardless of prior 177 Lu-PSMA RLT. Two phase 3 trials, AcTFirst (NCT06855277) and PSMAcTION (NCT06780670), are currently recruiting. Clinical trial information: NCT04597411 . Overall pts A: Prior ChT + ARPI; N=34 B: ChT/ARPI-naive; N=27 C: Prior 177 Lu-PSMA RLT; N=40 Selected AEs regardless of study dose, n (%): All Gs / G ≥3 Dry mouth 33 (97.1) / 0 26 (96.3) / 0 36 (90.0) / 0 Fatigue 18 (52.9) / 0 4 (14.8) / 0 27 (67.5) / 0 Anemia 9 (26.5) / 6 (17.6) 4 (14.8) / 4 (14.8) 16 (40.0) / 6 (15.0) Thrombocytopenia 2 (5.9) / 0 2 (7.4) / 1 (3.7) 5 (12.5) / 0 Renal impairment 1 (2.9) / 1 (2.9) 0 / 0 3 (7.5) / 1 (2.5) Anti-tumor activity, n (%) 95% CI PSA50 20 ( 58.8% ) 40.7, 75.4 23 ( 85.2% ) 66.3, 95.8 21 ( 52.5% ) 36.1, 68.5 PSA90 15 ( 44.1% ) 27.2, 62.1 22 ( 81.5% ) 61.9, 93.7 7 ( 17.5% ) 7.3, 32.8