Salvage radiotherapy with or without hormonal therapy for biochemical recurrence after radical prostatectomy: A systematic review and meta-analysis

Abstract Background Salvage radiotherapy (SRT) is the standard of care for patients with biochemical recurrence (BCR) after radical prostatectomy (RP). Several randomized trials have evaluated the addition of hormonal therapy (HT), including androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs), to SRT; however, differences in patient selection, treatment duration, and endpoints have led to inconsistent results. We performed an updated systematic review and meta-analysis to clarify the clinical benefit of adding HT to SRT in this setting. Methods A comprehensive literature search of PubMed/MEDLINE, EMBASE, the Cochrane Library, ClinicalTrials.gov, and ASCO and ESMO meeting abstracts was conducted through April 2025. Randomized phase II-III trials enrolling patients with confirmed BCR after RP and comparing SRT with or without HT were included. Five trials (GETUG-AFU 16, RTOG 9601, RTOG 0534/SPPORT, RADICALS-HD, and SALV-ENZA), comprising 4536 patients, met the eligibility criteria. Hazard ratios (HRs) and 95% confidence intervals (CIs) for metastasis-free survival (MFS), progression-free survival (PFS), biochemical progression-free survival (bPFS), and overall survival (OS) were pooled using fixed- or random-effects models according to heterogeneity. Analyses were stratified by HT duration (short-term vs. long-term), and subgroup analyses were performed based on pathological features. Results Short-term HT combined with SRT significantly improved bPFS (HR = 0.57; 95% CI: 0.46–0.71, p < 0.00001), PFS (HR = 0.58; 95% CI: 0.49–0.69; p < 0.00001), and MFS (HR = 0.82; 95% CI: 0.69–0.96; p = 0.02). Long-term HT was also associated with improved MFS (HR = 0.76; 95% CI: 0.61–0.94; p = 0.01). No statistically significant OS benefit was observed with either short-term or long-term HT. Subgroup analyses showed a significant MFS benefit in patients with positive surgical margins (HR = 0.68; 95% CI: 0.47–0.98; p = 0.04), whereas no clear benefit was detected in patients with Gleason score ≥8 or negative margins. Conclusions The addition of HT to SRT improves disease control outcomes in patients with BCR after RP, particularly in those with positive surgical margins, although no overall survival benefit was demonstrated. These findings support a tailored approach to treatment intensification in the salvage setting.