[$^{225}$Ac]Ac-PSMA for the treatment of metastatic castration-resistant prostate cancer: A systematic review and meta-analysis

Background: Approximately 10%-20% of prostate cancers progress to metastatic and castration-resistant forms (mCRPC). Radioligand (RLT) therapy with [$^{177}$Lu]Lu-prostate-specific membrane antigen (PSMA) is an approved treatment for metastasized mCRPC. Moreover, Actinium-225 ($^{225}$Ac), an alpha-emitter isotope, has also been used to label PSMA and, recently, to treat mCRPC patients with encouraging results. However, robust clinical data on [$^{225}$Ac]Ac-PSMA therapy and its comparison with [$^{177}$Lu]Lu-PSMA are still limited. Our aim was to evaluate the role of [$^{225}$Ac]Ac-PSMA in treating mCRPC and compare it with conventional [$^{177}$Lu]Lu-PSMA therapy. Methods: A systematic search was performed in PubMed, Web of Science, Scopus and the Cochrane Register of Controlled Trials from June 2023 to January 2024. This work was conducted in accordance with PRISMA guidelines. Results: After screening and study selection according to PRISMA guidelines, 11 studies were included, 9 of which focused on [$^{225}$Ac]Ac-PSMA only and two on tandem therapy ([$^{225}$Ac]Ac-PSMA/[$^{177}$Lu]Lu-PSMA). Overall, the pooled proportion of PSA decline in patients was .85 (95% CI: .79-.91, p < .001); patients pretreated with [$^{177}$Lu]Lu-PSMA achieved a pooled proportion of PSA decline of .90 (95% CI: .82-.97, p < .001). In patients treated with tandem therapy, PSA decline was observed in approximately 90% of them, while PSA response rates above 50% ranged from 53.3% to 65%. Xerostomia was the most frequently reported side effect, along with anaemia, thrombocytopenia and nephrotoxicity. Conclusions: Overall, the main results of our study showed that [$^{225}$Ac]Ac-PSMA-617 had a significant therapeutic effect on mCRPC with an acceptable toxicity level. The latter, however, appears greater than with [$^{177}$Lu]Lu-PSMA-617. In future studies, an adequate analysis of the incidence of side effects associated with [$^{225}$Ac]Ac-PSMA should be performed to evaluate the role of cumulative toxicity of earlier treatments and the higher frailty of heavily pretreated patients.