Debate 1: High-Risk Localized Prostate Cancer: Why Combination Hormone Therapy and Radiotherapy is the Optimal Treatment Strategy for Most Men

Abstract

Prostate cancer is the most commonly diagnosed malignancy among men in the United States, with high-risk localized disease accounting for approximately 15% of new cases. High-risk cancer portends increased risk of locoregional recurrence and distant metastases. Despite the longstanding use of radical prostatectomy (RP) and definitive radiotherapy (RT) with androgen deprivation therapy (ADT) as primary treatment options, there remains a lack of randomized data directly comparing these modalities. The ongoing SPCG-15 trial may eventually provide such evidence but its results are not expected until 2030. In the interim, clinicians must rely on existing observational studies to guide treatment selection. This review synthesizes current evidence comparing RP and RT+ADT for high-risk localized prostate cancer, highlighting oncologic outcomes, treatment-related toxicities, and patient-reported quality of life in survivorship. RT+ADT may offer biological advantages in addressing occult micrometastases with radiobiological foundations for synergy between modalities. Further, although observational data comparing RP and RT+ADT are heterogeneous and often methodologically limited, recent analyses using modern causal inference frameworks suggest improved distant metastatic control with RT+ADT. Toxicity profiles also differ significantly between modalities, with RT+ADT associated with fewer early and long-term urinary side effects, and less treatment regret but transient hormone-related and bowel symptoms during treatment. Here, we propose that under the shared-decision-making model RT+ADT will be the preferred first-line treatment for most men with high-risk localized prostate cancer, offering favorable oncologic control while preserving quality of life, particularly with modern advances in radiotherapy techniques.