High-Risk Prostate Cancer Treated with Radiation Therapy: Favorable Outcomes in Men with PSA > 20 as the Sole High-Risk Factor

<b>Background/Objectives:</b> The National Comprehensive Cancer Network (NCCN) classifies prostate cancer with PSA > 20 ng/mL as high risk; however, outcomes within this group are heterogeneous. Emerging data suggest that men with PSA > 20 ng/mL as the sole high-risk feature may have more favorable disease biology. We evaluated outcomes of men with prostate cancer treated with definitive radiation therapy (RT), focusing on the prognostic significance of individual high-risk factors. <b>Methods:</b> We analyzed 742 men with prostatic adenocarcinoma treated with curative-intent RT between 2005 and 2021, including 282 meeting traditional NCCN high-risk criteria. Treatment consisted of dose-escalated RT (median 78 Gy), with androgen deprivation therapy (ADT) administered to 94% (median duration 28 months). Primary endpoints were freedom from biochemical failure (FFBF) and distant metastasis (FFDM). Outcomes were assessed using Kaplan-Meier methods and Cox proportional hazards modeling. <b>Results:</b> At 5 years, high-risk patients demonstrated FFBF of 83% and FFDM of 89%, with significantly worse outcomes among very high-risk subgroups. Men with PSA > 20 ng/mL as their only high-risk feature (n = 49) achieved superior outcomes compared with other high-risk patients (5-year FFBF 94% vs. 74%; FFDM 97% vs. 82%; both <i>p</i> = 0.05), comparable to intermediate-risk disease. On multivariable analysis, Gleason score and clinical T-stage independently predicted poorer outcomes, whereas PSA > 20 alone did not. <b>Conclusions:</b> PSA > 20 ng/mL as an isolated high-risk feature is associated with favorable outcomes following definitive RT and appears to be the weakest NCCN high-risk criterion. These findings support refined risk stratification and raise the possibility of treatment de-escalation in select patients.