Background: PG5 (5+5 and 5+4) PCa is historically associated with poor clinical outcomes such as progression to metastatic disease, poor response to androgen deprivation therapy (ADT) and short survival. To characterize the clinical features and biology of this aggressive type of PCa, we studied patients with PG5 who underwent a RP. Methods: Patients with surgical PG5 who underwent RP for localized PCa at Johns Hopkins Hospital were retrospectively studied. Pathological staging, tumor genomic data by Next Generation Sequencing (NGS), and PTEN and TP53 by IHC were correlated with clinical outcomes, such as biochemical relapse (BCR), metastasis-free survival (MFS), time to castration-resistance (TCR) and overall survival (OS). Fisher’s test and Kaplan-Meier were used for statistical analysis. Results: 60 pts, 90% pT3-4, 26% pN1, 46% R+, 90% seminal vesicle invasion (SVI) had a median follow up of 9 years. Overall median survival estimates: BCR: 17.4 months (m), MFS:86.4m and OS:111m. 26 patients developed metastasis (bone 77%, visceral 31%) with a median time to metastasis of 21.8m and TCR of 12m. On multivariate analysis, ductal/intraductal histology (HR 4.5, p<0.01) and SVI (HR 4.4, p<0.01) were associated with poor prognosis. Of 49 pts with NGS, 22% had Homologous recombination (HR) and 12% mismatch repair (MMR) alterations. In addition, 32% had TP53 mutation and 51% PTEN loss. Genomic event frequencies and outcomes are in Table. Conclusions: Patients with PG5 have adverse pathological features, short BCR, MFS and resistance to ADT, but outcomes are variable, suggesting heterogeneity. TP53 mutations and PTEN loss are associated with poor outcomes in univariate analysis, while ductal/intraductal and SVI are associated with poor outcomes in multivariate analysis. Although genomic data were not independently associated with outcomes, the high incidence of HR and MMR alterations provides the rationale for the design of adjuvant clinical trials.