Alternate definitions of adverse pathology to predict a very high risk of metastasis in men with intermediate- and low-risk prostate cancer.

Background: Adverse pathology (AP) is often used as an intermediate end point for long-term outcomes in men with prostate cancer (PCa) who are active surveillance candidates. The association between a commonly used AP definition and long-term outcomes was tested, which identified definitions more strongly linked to a high risk of metastasis.

Methods: Data were reviewed from the Shared Equal Access Regional Cancer Hospital cohort of men undergoing radical prostatectomy (RP) from 1988 to 2020 at nine Veterans Affairs hospitals. Men meeting National Comprehensive Cancer Network low-risk and favorable intermediate-risk criteria were included. Men with and without AP were compared; men with AP were defined as having grade groups 3-5 or pathological stage ≥pT3a or pN1 at RP (definition 1). Sensitivity analyses were performed for six alternative definitions (definitions 2-7) and their association with biochemical recurrence (BCR), metastasis, PCa-specific mortality (PCSM), and castrate-resistant PCa (CRPC).

Results: A total of 2175 men were included: 711 had AP by definition 1. In univariable analyses, all AP definitions were associated with the risk of BCR, metastasis, and PCSM. All but one definition were associated with CRPC. In definitions 1-6, the 10-year event rate for metastasis in those with AP ranged from 3.0% (definition 1) to 7.9% (definition 5). Only in definition 7 was the 10-year event rate for metastasis >10%. However, only 0.5% of patients (11 of 2175) met definition 7.

Conclusions: AP was statistically associated with relatively worse outcomes. However, in all but the most stringent definitions, met by <1% of patients, the absolute event rate of metastasis in men with AP was low. This challenges the clinical usefulness of AP as an intermediate end point in men with intermediate- to low-risk PCa.