Efficacy, safety, and quality of life outcomes of [177Lu] Lu-PSMA radioligand therapy in metastatic castration-resistant prostate cancer: a GRADE-assessed systematic review, meta-analysis and trial sequential analysis.

BACKGROUND AND OBJECTIVE: Lutetium-177-PSMA radioligand therapy ([177Lu] Lu-PSMA) is an emerging targeted treatment for metastatic castration-resistant prostate cancer (mCRPC). We evaluated the comparative efficacy, safety, and quality-of-life (QoL) impact of [177Lu] Lu-PSMA versus contemporary standard-of-care (SOC) regimens in mCRPC. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). Adult participants with PSMA-positive mCRPC (n = 2113) randomized to [177Lu] Lu-PSMA or SOC were included. Primary outcomes were overall survival (OS) and radiographic progression-free survival (rPFS). Secondary outcomes included PSA response, QoL (FACT-P), and adverse events. Treatment effects were pooled using random-effects models. KEY FINDINGS AND LIMITATIONS: Six RCTs were analyzed. Primary intention-to-treat analysis did not demonstrate a statistically significant overall survival improvement (HR 0.81; 95% CI 0.62-1.06); however, sensitivity analysis adjusting for control-arm crossover suggested a survival benefit (HR 0.76; 95% CI 0.59-0.96). [1⁷⁷Lu] Lu-PSMA significantly improved rPFS (HR 0.55; 95% CI 0.43-0.71), PSA response (RR 2.33; 95% CI 1.38-3.93), and delayed QoL deterioration (HR 0.58; 95% CI 0.51-0.66). The intervention increased low-grade xerostomia and grade ≥ 3 thrombocytopenia, though overall severe adverse events were comparable to SOC. Limitations include inter-trial heterogeneity, control-arm crossover diluting ITT estimates, and imaging-based selection bias. CONCLUSIONS AND CLINICAL IMPLICATIONS: [177Lu] Lu-PSMA improves rPFS, biochemical response, and QoL in mCRPC, with an OS benefit apparent after accounting for crossover. These findings support integrating [177Lu] Lu-PSMA into clinical practice. Additional trials are required to determine optimal treatment sequencing and efficacy in taxane-naïve populations. PROSPERO REGISTRATION: The protocol of this systematic review and meta-analysis is registered under PROSPERO, having ID CRD420251151366.