Targeted Alpha Therapy: Exploring the Clinical Insights into [225Ac]Ac-PSMA and Its Relevance Compared with [177Lu]Lu-PSMA in Advanced Prostate Cancer Management.

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 ([225Ac]Ac-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 [225Ac]Ac-PSMA radioligand therapy (RLT), emphasising its efficacy, safety profile, and position relative to beta-emitter therapy with lutetium-177 ([177Lu]Lu-PSMA). Data from compassionate-use programs and small clinical trials demonstrate that [225Ac]Ac-PSMA produces significant biochemical and imaging responses, including > 50% declines in prostate-specific antigen (PSA) and lesion regression on [68Ga]Ga-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 [177Lu]Lu-PSMA, [225Ac]Ac-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 [225Ac]Ac-PSMA RLT and its evolving role in advanced prostate cancer management.