Actinium-225-PSMA versus lutetium-177-PSMA radioligand therapy for metastatic castration-resistant prostate cancer: results of an observational study

Background Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) with Lutetium-177 ( 177 Lu) and Actinium-225 ( 225 Ac) is increasingly used in metastatic castration-resistant prostate cancer (mCRPC), but head-to-head prospective data remain limited. Methods We conducted an observational study of mCRPC patients treated with 177 Lu-PSMA (n=116; 2022–2023) or 225 Ac-PSMA (n=43; 2023). Primary outcomes were PSA response (≥50% decline) and overall survival (OS); secondary outcomes included hematologic toxicity. Treatments were given every 8 ± 2 weeks (1–6 cycles; median 2) with administered activity typically 5–10 GBq (median 7.5 GBq) alongside standard androgen-deprivation therapy; concurrent chemotherapy was not allowed. Results Median follow-up was 9 months ( 177 Lu-PSMA) and 10 months ( 225 Ac-PSMA). Median OS was 13.0 months (95% CI 9.5–18.3) for 177 Lu-PSMA and 11.8 months (95% CI 7.0–NR) for 225 Ac-PSMA, with no significant difference between groups. A ≥50% PSA decline occurred in 42.2% ( 177 Lu-PSMA) and 40.5% ( 225 Ac-PSMA). Receiving 2 RLT courses was associated with longer OS in both cohorts ( 177 Lu-PSMA: 18.3 vs 7.3 months; 225 Ac-PSMA: OS not reached vs 5.2 months). Trends toward worse outcomes were observed in patients with visceral (especially hepatic) metastases and in those previously exposed to taxanes. Hematologic toxicity was frequent but mostly grade 1–2: anemia 66% ( 177 Lu-PSMA) vs 58% ( 225 Ac-PSMA), leukopenia 59% vs 57%, thrombocytopenia 47% vs 48%; treatment-related deaths were not observed. Conclusions In this observational experience, 225 Ac-PSMA and 177 Lu-PSMA achieved comparable survival and PSA response with predominantly mild-to-moderate hematologic toxicity. Greater treatment exposure (2 cycles) correlated with improved survival. Randomized trials are warranted to refine sequencing and patient selection for PSMA-RLT.