Comparator-dependent evidence for earlier PSMA-targeted radioligand therapy in prostate cancer: a systematic review and meta-analysis of randomized trials

Background PSMA-targeted radioligand therapy (PSMA-RLT) is moving from post-taxane metastatic castration-resistant prostate cancer (mCRPC) into earlier disease settings, but the context in which this migration is justified remains uncertain. We synthesized randomized evidence. Methods PubMed/MEDLINE, Cochrane CENTRAL, Scopus, Web of Science, ClinicalTrials.gov, and meeting proceedings were searched through May 17, 2026. Randomized PSMA-RLT trials were included; conference reports were incorporated in sensitivity analyses. Random-effects models pooled hazard ratios (HRs) and risk ratios (RRs) within prespecified strata. Treatment-effect interactions and risk of bias were assessed. Results Twelve trials involving 3,767 patients were included. In late-line mCRPC, PSMA-RLT improved progression outcomes (HR, 0.51; 95% CI, 0.32–0.80), with overall survival benefit established in VISION. In taxane-naive mCRPC after androgen receptor pathway inhibitor (ARPI) progression, radiographic progression-free survival also improved (HR, 0.59; 95% CI, 0.41–0.84), with no attenuation versus late-line use (P for interaction = 0.624), although overall survival was not improved. Comparator type significantly modified benefit: efficacy was weaker against docetaxel than against ARPI switch (ratio of HRs, 1.69; 95% CI, 1.06–2.70; P for interaction = 0.026), and docetaxel-comparator trials showed no progression advantage (HR, 1.00; 95% CI, 0.77–1.30). ENZA-p provided a distinct first-line combination signal, improving PSA progression-free survival (HR, 0.43; 95% CI, 0.29–0.63) and overall survival (HR, 0.55; 95% CI, 0.36–0.84). In metastatic hormone-sensitive prostate cancer, progression outcomes improved (HR, 0.69; 95% CI, 0.57–0.84), whereas overall survival remained immature. Oligometastatic or oligorecurrent disease showed a strong but heterogeneous exploratory signal (HR, 0.17; I² = 90.5%). Available grade 3 or higher adverse-event data favored PSMA-RLT in taxane-naive mCRPC (RR, 0.73; 95% CI, 0.59–0.90) but indicated a modest increase with hormone-sensitive intensification (RR, 1.17; 95% CI, 1.04–1.33). Conclusions PSMA-RLT treatment migration is comparator-dependent rather than simply line-dependent. Randomized evidence supports its use after ARPI progression and before taxane therapy, without detectable loss of progression benefit versus late-line use, but does not support replacing docetaxel. Earlier hormone-sensitive use is promising but awaits mature survival data.