Targeted alpha therapy (TAT) has recently emerged as a highly promising approach for the management of metastatic castration-resistant prostate cancer (mCRPC), especially in patients with disease progression despite standard treatments. Among alpha-emitter radiopharmaceuticals, actinium-225-labelled prostate-specific membrane antigen (225AcAc-PSMA) has shown remarkable potential due to its high linear energy transfer (LET), short path length, and ability to induce potent, localised cytotoxic effects. This review summarises current clinical evidence regarding 225AcAc-PSMA radioligand therapy (RLT), emphasising its efficacy, safety profile, and position relative to beta-emitter therapy with lutetium-177 (177LuLu-PSMA). Data from compassionate-use programs and small clinical trials demonstrate that 225AcAc-PSMA produces significant biochemical and imaging responses, including > 50% declines in prostate-specific antigen (PSA) and lesion regression on 68GaGa-PSMA PET/CT, even in heavily pre-treated mCRPC cohorts. Xerostomia, renal toxicity, and haematological adverse effects remain the main safety challenges, necessitating optimisation of patient selection, dosing strategies, and salivary gland protection protocols. Compared with 177LuLu-PSMA, 225AcAc-PSMA appears effective even in cases of beta-refractory disease, highlighting its complementary role rather than a competitive alternative. However, limited availability, high production costs, and the lack of large-scale, randomised trials hinder widespread clinical adoption. Future directions include combination protocols, improved radiopharmaceutical design, and trials evaluating its use in earlier disease stages. This review provides a comprehensive overview of the clinical aspects of 225AcAc-PSMA RLT and its evolving role in advanced prostate cancer management.
Jalloul et al. (Mon,) studied this question.