Beyond [177Lu]Lu-PSMA: a meta-analysis of safety and efficacy of emerging PSMA radioligand therapy agents

Abstract Background This systematic review and meta-analysis evaluates the safety and efficacy of emerging prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) agents used beyond [¹⁷⁷Lu]Lu-PSMA in metastatic castration-resistant prostate cancer (mCRPC). Methods Systematic searches of PubMed, Web of Science, and Scopus were performed from inception until November 3, 2025. Studies reporting objective response rate (ORR), disease control rate (DCR), and/or toxicity outcomes were included. Meta-analytic pooling, assessment of publication bias, heterogeneity analyses, and subgroup evaluations were conducted using Stata software. Results A total of 33 studies published between 2017 and 2025 met inclusion criteria, encompassing 3625 therapy cycles administered to 1525 patients. The pooled DCR was 86% (95% CI: 82–90%), and the pooled ORR was 57% (95% CI: 50–63%). [²²⁵Ac]Ac-PSMA monotherapy, evaluated in 17 studies, achieved pooled DCR and ORR values of 88% and 62%. Eight studies assessing [¹⁷⁷Lu]Lu/[²²⁵Ac]Ac-PSMA tandem therapy reported pooled DCR and ORR values of 84% and 51%. Five studies on [¹⁶¹Tb]Tb-PSMA demonstrated pooled DCR and ORR values of 81% and 46%. [¹³¹I]PSMA therapy, reported in three studies, resulted in a pooled DCR of 75% and pooled ORR of 48%. Adverse events were documented in 32 studies, with a pooled incidence of 26%. Most events were low-grade and reversible. Xerostomia and anemia were the most frequently reported toxicities, with xerostomia particularly associated with [²²⁵Ac]Ac-PSMA–containing regimens. Conclusion These findings underscore the promising therapeutic potential of emerging PSMA RLT agents beyond [¹⁷⁷Lu]Lu-PSMA, with favorable biochemical responses and manageable safety profiles. Future large-scale prospective studies are essential to define optimal therapeutic roles and expand treatment opportunities for patients with mCRPC.