Prostate cancer is the most common cancer and the second leading cause of cancer death among men, with an estimated 300,000 new cases diagnosed in 2024 within the United States alone.1 Fortunately, approximately 80% of men are diagnosed with localized disease amenable to curative intent treatment.2 Of those, however, 15% present with high risk localized disease, which portends worse prognosis due to increased risk of locoregional recurrence and distant spread.3

Currently, the primary treatment strategies for high-risk localized prostate cancer include radical prostatectomy (RP) and definitive radiotherapy (RT) given with hormonal-based therapies including androgen depravation therapy (ADT). Although both RP and definitive RT-based treatments have existed for several decades, randomized evidence comparing modalities is lacking. The currently accruing Scandinavian Prostate Cancer Group (SPCG)-15 trial is a prospective randomized trial comparing RP and RT for the management of locally advanced prostate cancer.4 Preliminary reports have suggested adequate accrual of patients and thus SPCG-15 holds promise to provide valuable evidence to guide treatment recommendations for these patients.5 However, results from this trial are not expected to be initially reported until approximately 2030. At present, clinicians therefore must synthesize other existing sources of evidence in order to provide optimal treatment recommendations aimed at maximizing patient quality and quantity of life.

Here, we comprehensively appraise current knowledge and existing data regarding various treatment strategies for high-risk localized prostate cancer. Further, we argue that the optimal initial management approach for most men is definitive RT and ADT. We focus specifically on differences in oncologic outcomes and toxicities affecting patient quality of life between modalities, including a discussion of the impact of evolving radiotherapy techniques in optimizing the therapeutic ratio. We conclude with a proposal of practical recommendations for management of these cancers, focusing particularly on patient selection for RT-based treatment approaches.