Impact of early vs. delayed metastasis-directed therapy on clinical outcomes in high Gleason score metastatic prostate cancer: long-term results of a landmark cohort study (PROMPT-G)

PURPOSE/OBJECTIVE(S): For patients who have received standard systemic treatment during the metastatic hormone-sensitive prostate cancer (mHSPC) stage, the optimal timing of radiotherapy (RT) is still not clear. We compared the efficacy and safety of early RT (≤ 6 months after systemic therapy initiation) versus delayed RT (> 6 months) in high Gleason Score patients. MATERIALS/METHODS: Patients with high Gleason Score prostate cancer receiving standard systemic therapy in the metastatic hormone-sensitive phase followed by metastasis-directed radiotherapy (MDT, RT to all detectable lesions) from 2018 to 2025 were included. Patients were categorized into early RT (≤ 6 months) and delayed RT (> 6 months) groups. Inverse probability of treatment weighting (IPTW) balanced baseline characteristics. The primary endpoint was castration-resistant prostate cancer-free survival (CRPCFS) analyzed by IPTW-weighted Cox models. RESULTS: Among 196 patients, 190 were analyzed (65 early RT, 125 delayed RT). IPTW achieved generally good balance in measured baseline covariates. Median follow-up was 33.1 months. Early RT significantly improved CRPCFS (HR 0.172, 95% CI 0.063-0.469, P = 0.001), with 5-year CRPCFS rates of 71.1% vs. 44.0%. Results were consistent in multivariable and competing risk analyses. Early RT also improved PFS (P = 0.007), PSAPFS (P = 0.002), and OS (P = 0.018), with benefits consistent across tumor volume subgroups (P-interaction = 0.191). Sensitivity analyses confirmed robustness. CONCLUSION: Earlier RT was associated with improved CRPCFS, with favorable signals in secondary outcomes. These findings warrant prospective evaluation of RT timing in high Gleason score mHSPC.