Defining the Position of [177Lu]Lu-PSMA Radioligand Therapy in the Treatment Landscape of Metastatic Castration-Resistant Prostate Cancer: A Meta-analysis of Clinical Trials

Background: In recent years, theranostics has become a promising approach for treating metastatic castration-resistant prostate cancer (mCRPC), with trials investigating targeted radioligand therapy, particularly using prostate-specific membrane antigen labeled with lutetium-177 ([177Lu]Lu-PSMA). The proper position of [177Lu]Lu-PSMA in the therapeutic algorithm of mCRPC is yet to be identified. Design, Setting, and Participants: We conducted a systematic review and meta-analysis of phase II/III randomized controlled trials to assess the efficacy of [177Lu]Lu-PSMA in treating mCRPC. Study endpoints included radiographic progression-free survival (rPFS), prostate-specific antigen-PFS, objective response rate, and overall survival. Outcome Measurements and Statistical Analysis: Data were extracted according to the PRISMA statement. Summary hazard ratios (HRs) were calculated using random- or fixed-effects models. Statistical analyses were performed with RevMan software (v.5.2.3). Results: [177Lu]Lu-PSMA reduced the risk of rPFS (HR 0.55; 95% confidence interval [CI] 0.43–0.71; p < 0.00001) and prostate-specific antigen-PFS (HR 0.53; 95% CI 0.41–0.67; p < 0.00001), and improved the objective response rate compared with control therapies (response rate 3.55; 95% CI 1.91–6.60; p < 0.0001), whereas no significant cumulative effect on overall survival was documented (HR 0.92; 95% CI 0.65–1.31; p = 0.63). Notably, in a dedicated subanalysis, comparable effects on rPFS were observed when [177Lu]Lu-PSMA was compared with active therapy. Conclusion: [177Lu]Lu-PSMA has a favorable impact on the radiographic and biochemical control of mCRPC and represents a potential treatment in a scenario where other valuable options are available. Further efforts are required to identify clinical and molecular markers necessary for proper patient stratification.