Ninatti, GaiaScilipoti, PietroPini, CristianoBarletta, FrancescoLongoni, MattiaGelardi, FabriziaSollini, MartinaGandaglia, GiorgioSathekge, Mike MachabaMontorsi, FrancescoChiti, ArturoBriganti, Alberto2025-03-272025-03-272025-02Ninatti, G., Scilipoti, P., Pini, C. et al. 2025, 'Time for action : actinium-225 PSMA-targeted alpha therapy for metastatic prostate cancer – a systematic review and meta-analysis', Theranostics, vol. 15, no. 8, pp. 3386-3399, doi : 10.7150/thno.106574.1838-7640 (online)10.7150/thno.106574http://hdl.handle.net/2263/101763DATA AVAILABILITY : Data relevant to the study derive from original papers included for analysis in this systematic review and are available upon request.RATIONALE : Metastatic prostate cancer in the castration-resistant (mCRPC) setting remains challenging to treat. Prostate-specific membrane antigen (PSMA)-targeted alpha therapy (TAT) is emerging as a promising option. We aimed to systematically review the efficacy and safety of PSMA-TAT in patients with prostate cancer. METHODS : A comprehensive search of PubMed/MEDLINE and EMBASE databases was conducted up to October 2024, adhering to the PRISMA guidelines. Selected studies were original research articles evaluating the efficacy and/or safety of PSMA-TAT including at least 10 patients. The outcomes measured included any prostate-specific antigen (PSA) response, ≥50% PSA reduction (PSA50), progression-free survival (PFS), overall survival (OS), and adverse events. PSA50 was pooled using a random-effects model, incorporating individual patient data on PSA50 and previous lines of treatment. RESULTS : Eighteen studies involving 1,155 patients met the inclusion criteria. The majority included heavily pre-treated patients. The most commonly employed radiopharmaceutical was [225Ac]Ac-PSMA-617, in 15 studies. The pooled PSA50 response rate was 65% [95% Confidence interval (CI), 57-72%] with a moderate level of heterogeneity (I² = 81.17%, p < 0.001). Pooled response rates in patients who received none, one, and more than one prior line of treatment were 82% (95% CI, 73-90%), 72% (95% CI, 56-85%), and 55% (95% CI, 48-63%), respectively. PFS varied from 3 to 15 months, and OS from 8 to 31 months. Adverse events were predominantly mild (grades 1-2); severe adverse events (≥ grade 3) included anaemia (11%) and thrombocytopenia (6%). CONCLUSION : PSMA-TAT holds promising efficacy and an acceptable safety profile for treating metastatic prostate cancer. Randomised controlled trials are needed to optimise treatment protocols toward the implementation of PSMA-TAT into clinical practice.en© The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/)Metastatic prostate cancer in the castration-resistant (mCRPC)Prostate-specific membrane antigen (PSMA)Targeted alpha therapy (TAT)PSMA-TATProstate cancerProstate-specific antigen (PSA)PSA responseSDG-03: Good health and well-beingArticle