225AcAc‐PSMA for the treatment of metastatic castration‐resistant prostate cancer: A systematic review and meta‐analysis

Abstract Background Approximately 10%–20% of prostate cancers progress to metastatic and castration‐resistant forms (mCRPC). Radioligand (RLT) therapy with 177 LuLu‐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 AcAc‐PSMA therapy and its comparison with 177 LuLu‐PSMA are still limited. Our aim was to evaluate the role of 225 AcAc‐PSMA in treating mCRPC and compare it with conventional 177 LuLu‐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 AcAc‐PSMA only and two on tandem therapy ( 225 AcAc‐PSMA/ 177 LuLu‐PSMA). Overall, the pooled proportion of PSA decline in patients was .85 (95% CI: .79–.91, p < .001); patients pretreated with 177 LuLu‐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 AcAc‐PSMA‐617 had a significant therapeutic effect on mCRPC with an acceptable toxicity level. The latter, however, appears greater than with 177 LuLu‐PSMA‐617. In future studies, an adequate analysis of the incidence of side effects associated with 225 AcAc‐PSMA should be performed to evaluate the role of cumulative toxicity of earlier treatments and the higher frailty of heavily pretreated patients.