Evaluating the spectrum of disease within Gleason grade group 3: Results from a large institutional cohort.

361 Background: A biopsy diagnosis of Gleason Grade Group (GG) 3 prostate cancer (PCa), also known as Gleason 4+3, automatically risk stratifies patients into at least unfavorable intermediate-risk by major guidelines including the AUA and NCCN, for which definitive treatment such as surgery or radiation is warranted. We hypothesized that GG3 prostate cancers represent a spectrum of disease, and that there may be GG3 PCa patients with lower risk of disease that may benefit from more conservative management. Methods: The Urologic Outcomes Database (UODB) at the University of California San Francisco (UCSF) was queried for men with localized, non-metastatic PCa diagnosed after 2000 who underwent radical prostatectomy (RP). Pre-biopsy clinicodemographic factors and biopsy and surgical pathology data were obtained, and Cancer of the Prostate Risk Assessment (CAPRA) and post-surgical CAPRA (CAPRA-S) scores were calculated. Outcomes were recurrence after surgery, defined as either biochemical failure (two PSA ≥0.2 ng/ml) or second treatment, and development of new metastasis. Multivariable Cox proportional hazards regression models were used to calculate associations with risk of recurrence and development of metastases, adjusting for year of diagnosis, age at diagnosis, percentage of positive biopsy cores (PPC), PSA density (PSAD), PSA before RP, Gleason pattern 4 histology, genomic risk score, prostate MRI findings, with or without CAPRA-S. Results: 5262 men from the UODB database who underwent RP were included in the study. Of these, 904 (17%) men were diagnosed with GG3 on diagnostic biopsy. The number of GG3 diagnoses over time increased from 8.5% between 2000-2004 to 27% between 2020-2023. Among patients with initial diagnoses of GG3, pathologic GG after RP showed an increasing proportion of patients with upgrade to ≥GG4 and a decreasing proportion of patients with downgrade to <GG3 over time. Post-RP CAPRA-S scores overall increased over time, but remained broadly distributed. On multivariable analysis, favorable biopsy Gleason pattern 4 histology was strongest pre-operative factor associated with decreased recurrence after RP (HR 0.54, 95% CI 0.35-0.85, p<0.01). Increased PPC was the only factor associated with risk of metastasis after RP (HR 1.13, 95% CI 1.00-1.27, p=0.04). Conclusions: Patients with GG3 on diagnostic biopsy are a heterogenous group, with post-surgical grade and risk scores both broadly distributed and increasing over time. These data suggest that certain GG3 patients, such as those with favorable biopsy histology and lower PPC, may not be as unfavorable as guidelines suggest and may benefit from more conservative management.