By any classification system used, patients with “high-risk” prostate cancer face substantial risks of recurrence and metastatic progression despite initial local therapy. This risk category represents a disease state in which 2 conditions are possible but whose true status is not known at the time of decision-making: (1) the cancer is localized but treatment may fail to eradicate it, and/or (2) occult disseminated cancer exists at the time of diagnosis, rendering local treatment ineffective. The probabilities of these events are estimated by prognostic systems directed at endpoints including disease recurrence, metastasis, and overall survival.1, 2, 3, 4 Risk groupings comprised of clinical features including prostate specific antigen (PSA) level, Gleason grade group (GG), clinical stage, and the number of involved biopsy cores offer definitions used in clinical practice. For example, the National Comprehensive Cancer Network (NCCN) risk groupings define high-risk prostate cancer as patients with one or more of the following features: cT3-cT4, Grade Group 4 or Grade Group 5 disease, or PSA > 20 ng/mL.5 Multivariable risk assessment tools integrating various clinical and pathologic data enhance prognostic accuracy.46 Depending on the classification system used, approximately one quarter of patients diagnosed with prostate cancer are categorized as high-risk, and this proportion is likely to continue changing with improvements in screening, diagnosis, and staging paradigms.7, 8, 9

The risks of disease progression are highly varied among those with high-risk disease. For example, those with International Staging Collaboration for Prostate Cancer (STAR-CAP) stage group IIIA (11-12 points) have a predicted 10-year prostate cancer specific mortality estimate of 11.7% while those categorized as group IIIC (17-18 points) possess a predicted 10-year PCMS risk of 40%.6 An appreciation of the heterogeneity in cancer outcome within the high-risk subset underscores the need for personalized decision-making in this group to also emphasize considerations of preference, health-related quality of life (HRQoL), and life expectancy.

The population meeting criteria for high-risk localized prostate cancer continues to change with the widespread use of molecular imaging, specifically prostate specific membrane antigen positron emission tomography (PSMA-PET).10, 11, 12 As a consequence of more accurate imaging, a growing number of individuals with occult metastatic disease may now be correctly classified and spared inadequate local treatment alone. As a result, the emerging subset of patients with high-risk, localized prostate cancer appears to be more accurately classified, and in theory stands to benefit more from locoregional therapy. However, this assumption remains to be empirically demonstrated.13 In this debate we will consider the index patient with high clinical risk features, with a greater than 5-year life expectancy, and without any radiographic evidence of regional (N1) or distant (M1) disease based on PSMA-PET. At the time of writing, clinical practice guidelines recommend either radiation therapy (RT) combined with ADT or radical prostatectomy (RP) as the course of initial therapy. There is a lack of level 1 evidence comparing the efficacy of these treatment modalities in the setting of high-risk disease. The active SPCG-15 randomized trial comparing RP with primary RT combined with ADT in men with nonmetastatic, locally advanced prostate cancer seeks to address this unresolved question but has not yet reported. Given the current absence of randomized clinical evidence to guide primary treatment choice, patients often experience high levels of decisional uncertainty and regret.1415 With equipoise regarding comparative efficacy, decision-making remains driven largely by patient preference. In this perspective, we present 5 evidence-based arguments (Table 1) that commonly motivate the use of RP in appropriate surgical candidates.