Pathological Predictors of Limited Salvage Radiotherapy Efficacy After Radical Prostatectomy: Central Review of JCOG0401

Background/Objectives: The multicenter randomized trial JCOG0401 showed that initial salvage radiotherapy (SRT) before salvage hormonal therapy (SHT) significantly prolonged time to treatment failure (TTF) compared with SHT alone. This central pathology analysis aimed to explore pathological features potentially associated with reduced relative benefit from SRT, while distinguishing prognostic from predictive effects. Methods: We re-analyzed 167 patients from JCOG0401 (SHT: 81, SRT ± SHT: 86). Prostatectomy specimens were re-evaluated, focusing on tertiary Gleason pattern (GP) 5 and intraductal carcinoma of the prostate (IDC-P). Cox proportional hazards models assessed exploratory interaction effects between pathological features and the treatment effect of bicalutamide on TTF. Pathological subgroups in which SRT failed to improve TTF over SHT alone were defined as having reduced benefit from SRT. Results: Adverse pathological features associated with shorter TTF with limited SRT included Gleason score (≥8), GP5, tertiary GP5, IDC-P, positive surgical margins, lymphovascular invasion, and advanced pathological T stage. Exploratory Interaction analyses suggested that IDC-P and tertiary GP5 may be associated with reduced relative benefit from SRT. Among patients without IDC-P, SRT significantly improved TTF (HR 0.330, 95%CI 0.161–0.673), whereas no significant benefit was observed in those with IDC-P (HR: 0.771, 95% CI: 0.446–1.332). Similarly, the absence of tertiary GP5 was associated with a marked benefit from SRT (HR: 0.099, 95% CI: 0.021–0.466), whereas this effect was not observed with tertiary GP5 (HR: 0.760, 95% CI: 0.400–1.443). Conclusions: IDC-P and tertiary GP5 may represent pathological features associated with reduced relative benefit from SRT after radical prostatectomy. These findings are exploratory and hypothesis-generating and require prospective validation in independent cohorts. Careful pathological evaluation may help identify patients who could benefit from treatment intensification or alternative postoperative strategies.