Hypofractionated Dose Escalation Radiotherapy for High-Risk Prostate Cancer: the survival analysis of the Prostate Cancer Study-5 (PCS-5), a GROUQ-led phase III trial

Background and objective Prostate Cancer Study 5 (PCS5) compared conventional fractionated radiotherapy (CFRT) with hypofractionated radiotherapy (HFRT) in high-risk prostate cancer (PCa) patients, hypothesizing similar toxicity and survival outcomes. This report presents the efficacy analysis. Methods PCS5 is a Canadian multicenter, open-label, phase 3 randomized control trial. Men with histologically proven, clinically localized PCa with one or more high-risk features (T3/T4, Gleason score >= 8, and prostate-specific antigen >20) were eligible. Patients were randomized 1:1 to CFRT (76 Gy/38 fractions [Fx] to the prostate and 46 Gy/23 Fx to the pelvic lymph nodes [PLNs]) or HFRT (68 Gy/25 Fx to the prostate and 45 Gy/25 Fx to the PLNs) and 28 mo of androgen suppression. The primary endpoint was toxicity; secondary endpoints included survival outcomes. Key findings and limitations Of 329 patients, 164 were randomized to HFRT and 165 to CFRT, with 159 in the HFRT arm and 160 in the CFRT arm included in survival analyses. At the 5-yr median follow-up, there were no significant differences in overall survival (OS; 90.3% vs 89.7%; risk ratio [RR]: 1.01; 95% confidence interval [CI]: 0.93-1.09), PCa-specific survival (PCSS; 97.4% vs 97.5%; RR: 1.00; 95% CI: 0.93-1.07), biochemical recurrence-free survival (BCRFS; 85.2% vs 85.2%; RR: 1.00; 95% CI: 0.91-1.10), or distant metastasis-free survival (DMFS; 87.1% vs 87.1%; RR: 1.00; 95% CI: 0.92-1.09). Hazard ratios were 0.92 (95% CI: 0.56-1.53) for OS, 1.31 (95% CI: 0.46-3.78) for PCSS, 0.85 (95% CI: 0.56-1.30) for BCRFS, and 0.90 (95% CI: 0.56-1.43) for DMFS. Sample size was a limiting factor. Conclusions and clinical implications There were no differences in survival outcomes between HFRT (68 Gy/25 Fx) and CFRT (76 Gy/38 Fx). HFRT, including PLN radiotherapy and long-term androgen deprivation therapy, should be considered a new standard of care for high-risk PCa patients undergoing external beam radiotherapy. (c) 2024 Published by Elsevier B.V. on behalf of European Association of Urology.