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

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.