e17500 Background: IT heterogeneity (ITH) is well recognised in prostate cancer (PC), but its role in high-risk disease and patient outcomes are uncertain. Methods: This was a prospective, single-arm, translational study using targeted multi-region prostate biopsies to study genomic and T-cell ITH in clinically high-risk PC aiming to identify drivers and potential therapeutic strategies. A pre-defined exploratory objective was to evaluate the association of ITH, median inflammatory infiltrate (MII), total, clonal and neoantigens, with overall survival (OS) and time-to-next-line of therapy (TTNL). Results: 49 men with elevated prostate-specific antigen (PSA) and multiparametric-magnetic resonance imaging (MRI) detected PC underwent image-guided multiregion transperineal biopsy. 79 tumour regions from 25 patients (pts) with PC underwent sequencing, analysis of mutations, copy number and neoepitopes combined with tumour infiltrating T-cell subset quantification. The median follow-up was 60 months (m) with 10 death events. For %ITH, MII, total, clonal and subclonal neoantigens, patients were split by the median. Conclusions: The PROGENY study provides a diagnostic platform suitable for studying tumour ITH and has the potential to identify poor outcome subgroups in PC. Larger sample numbers in prospective trials are warranted to further investigate this hypothesis. [Table: see text]