Efficacy of Lu-PSMA–based treatment strategies in metastatic hormone-sensitive prostate cancer: A systematic review and meta-analysis.

Abstract

e17114 Background: Lutetium-177-PSMA-617 (Lu-PSMA) has demonstrated significant survival benefit in metastatic castration-resistant prostate cancer; however, its role in metastatic hormone-sensitive prostate cancer (mHSPC) remains under investigation. This systematic review and meta-analysis aim to assess the efficacy of early integration of Lu-PSMA in high-volume mHSPC. Methods: Following PRISMA guidelines, a systematic search of PubMed/MEDLINE, Embase, CENTRAL, and ClinicalTrials.gov was conducted from inception through January 1, 2026, using MeSH terms and keywords related to Lu-PSMA, PSMA radioligand therapy, mHSPC, and randomized trials. Randomized phase II trials comparing Lu -PSMA-based therapy with standard treatment in high-volume mHSPC and reporting progression-free survival (PFS) were included. Hazard ratios (HR) and 95% confidence intervals (CI) were pooled using a random-effects model. Pooled estimates were derived using the Freeman–Tukey transformation with Knapp–Hartung adjustment, implemented in R (version 4.5.2). Results: Two randomized phase II trials comprising 160 patients (Lu-PSMA n = 78; control n = 82) were included. In the post-docetaxel consolidation trial, 30 patients with synchronous high-volume mHSPC and residual disease after ADT plus docetaxel were randomized. Median age was 69 vs 68 years; ECOG performance status ranged from 0–2; and all patients had completed 6 prior docetaxel cycles. Lu-PSMA consolidation resulted in higher objective response rates (53% vs 7%) and greater achievement of undetectable PSA at 6 months (60% vs 13%), with no grade ≥3 toxicity. In the upfront sequential trial, 130 patients with de novo high-volume mHSPC received Lu-PSMA followed by docetaxel or docetaxel alone with ADT. The median age was 69 years; 91% had high-volume disease by conventional imaging, and 8% had visceral metastases. Undetectable PSA at 48 weeks was more frequent with Lu-PSMA (41% vs 16%), and Lu-PSMA was associated with longer PSA progression-free survival and radiographic progression-free survival. Grade ≥3 adverse events were similar between arms (29% vs 27%) and largely attributable to docetaxel. In pooled analyses, Lu-PSMA-based strategies significantly improved PSA progression-free survival (HR 0.60; 95% CI, 0.40–0.90; I² = 0%; τ² = 0) and radiographic progression-free survival (HR 0.55; 95% CI, 0.34–0.92; I² = 0%; τ² = 0). Conclusions: Lu-PSMA-based strategies demonstrate promising clinical activity in patients with mHSPC, with consistent improvements in both biochemical and radiologic PFS across different treatment settings. These findings provide rationale for ongoing and future phase III trials of Lu-PSMA-based intensification strategies in this subset of patients.