Efficacy, safety, and quality of life outcomes of 177Lu-PSMA-617 in metastatic castration-resistant prostate cancer: A GRADE-assessed systematic review, meta-analysis, and trial sequential analysis of randomized controlled trials.

5062 Background: 177Lu-PSMA-617 radioligand therapy (RLT) offers a targeted approach for metastatic castration-resistant prostate cancer (mCRPC). However, its consolidated impact on survival, patient-reported outcomes, and safety requires rigorous validation. We conducted a systematic review, meta-analysis, and trial sequential analysis (TSA) to evaluate the robustness of evidence regarding efficacy, toxicity, and quality of life (QoL). Methods: We systematically searched PubMed, Cochrane, and Embase for prospective randomized controlled trials (RCTs) comparing 177Lu-PSMA-617 versus standard-of-care (SOC) in mCRPC. Primary outcomes included overall survival (OS), radiographic progression-free survival (rPFS), and PSA response. Secondary outcomes included QoL (FACT-P scores, pain intensity) and adverse events (AEs). TSA was performed to assess the conclusiveness of the cumulative evidence. Data were pooled using a random-effects model. Results: Six prospective RCTs comprising 2,113 patients (1,263 Lu-PSMA; 850 SOC) were included. Lu-PSMA significantly improved overall survival (HR 0.76; P = 0.02) and radiographic progression-free survival (HR 0.55; P < 0.00001) compared to SOC. QoL metrics significantly favored Lu-PSMA, including mean difference in QoL scores (MD 2.93; P < 0.00001), time to deterioration of FACT-P (RR 0.58; P < 0.00001), and worsening of pain intensity (OR 0.61; P = 0.002). TSA demonstrated conclusive evidence for PSA response (RR 2.33; P = 0.001), as the Z-curve crossed the monitoring boundary. However, TSA for ORR and PFS remained inconclusive despite favorable point estimates. Regarding safety, Lu-PSMA was associated with higher risks of Grade 1-2 dry mouth (RR 9.75), Grade ≥3 thrombocytopenia (RR 6.20), and Grade 1-2 dry eyes (RR 6.66). Conclusions: 177Lu-PSMA-617 demonstrates a significant survival benefit and conclusively improves PSA response rates in mCRPC. Crucially, it preserves quality of life by delaying the deterioration of physical function and pain. While effective, the therapy carries specific toxicity risks, notably xerostomia and high-grade thrombocytopenia, necessitating careful patient monitoring. Outcome Effect Estimate (95% CI) P-Value I² TSA Status Overall Survival HR 0.76 (0.59–0.96) 0.02 68% - Radiographic PFS HR 0.55 (0.43–0.71) <0.00001 67% Inconclusive PSA Response Rate RR 2.33 (1.38–3.93) 0.001 93% Conclusive Objective Response Rate RR 2.94 (1.55–5.55) 0.0009 72% Inconclusive Quality of Life (MD) MD 2.93 (1.80–4.07) <0.00001 20% - Time to Det. FACT-P RR 0.58 (0.51–0.66) <0.00001 0% - Worsening Pain Score OR 0.61 (0.44–0.84) 0.002 81% - Dry Mouth (Grade 1-2) RR 9.75 (6.85–13.88) <0.00001 91% - Thrombocytopenia (G≥3) RR 6.20 (2.18–17.65) 0.0006 0% - Dry Eyes (Grade 1-2) RR 6.66 (2.79–15.91) <0.0001 0% -