ORIGINAL RESEARCH article
Front. Oncol.
Sec. Radiation Oncology
Actinium-225-PSMA versus Lutetium-177-PSMA radioligand therapy for metastatic castration-resistant prostate cancer: results of an observational study
Provisionally accepted
Tatiana Yu. Kochetova1
Mikhail B. Potievskiy1*
Lidia A. Nekrasova2Valeriy V. Krylov1Peter V. Shegai1Sergei A. Ivanov1Andrei D. Kaprin1- 1National Medical Research Center of Radiology, Ministry of Health (Russia), Moscow, Russia
- 2Moscow City Oncological Hospital №. 62, Moscow, Russia
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Background: Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) with Lutetium-177 (¹⁷⁷Lu) and Actinium-225 (²²⁵Ac) 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 ¹⁷⁷Lu-PSMA (n=116; 2022–2023) or ²²⁵Ac-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 (¹⁷⁷Lu-PSMA) and 10 months (²²⁵Ac-PSMA). Median OS was 13.0 months (95% CI 9.5–18.3) for ¹⁷⁷Lu-PSMA and 11.8 months (95% CI 7.0–NR) for ²²⁵Ac-PSMA, with no significant difference between groups. A ≥50% PSA decline occurred in 42.2% (¹⁷⁷Lu-PSMA) and 40.5% (²²⁵Ac-PSMA). Receiving >2 RLT courses was associated with longer OS in both cohorts (¹⁷⁷Lu-PSMA: 18.3 vs 7.3 months; ²²⁵Ac-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% (¹⁷⁷Lu-PSMA) vs 58% (²²⁵Ac-PSMA), leukopenia 59% vs 57%, thrombocytopenia 47% vs 48%; treatment-related deaths were not observed. Conclusions: In this observational experience, ²²⁵Ac-PSMA and ¹⁷⁷Lu-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.
Keywords: actinium-225-PSMA, hematological toxicity, Lutetium-177-PSMA, metastatic castration-resistant prostate cancer, overall survival, Radioligand Therapy
Received: 11 Nov 2025; Accepted: 02 Feb 2026.
Copyright: © 2026 Kochetova, Potievskiy, Nekrasova, Krylov, Shegai, Ivanov and Kaprin. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Mikhail B. Potievskiy
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