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 (Lu) and Actinium-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 Lu-PSMA (n=116; 2022-2023) or 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 (Lu-PSMA) and 10 months (Ac-PSMA). Median OS was 13.0 months (95% CI 9.5-18.3) for Lu-PSMA and 11.8 months (95% CI 7.0-NR) for Ac-PSMA, with no significant difference between groups. A ≥50% PSA decline occurred in 42.2% (Lu-PSMA) and 40.5% (Ac-PSMA). Receiving >2 RLT courses was associated with longer OS in both cohorts (Lu-PSMA: 18.3 vs 7.3 months; 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% (Lu-PSMA) vs 58% (Ac-PSMA), leukopenia 59% vs 57%, thrombocytopenia 47% vs 48%; treatment-related deaths were not observed.

[CONCLUSIONS] In this observational experience, Ac-PSMA and 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.