Background: The STAMPEDE trial recruits men with high risk prostate cancer commencing first line systemic therapy. In a pilot study to ascertain the feasibility of tNGS and the prevalence of common genomic aberrations, we tested a commercial clinically-accredited assay on tumor blocks and present data obtained in the largest cohort of treatment-naïve M1 CSPC to date. Methods: Archival FFPE blocks were retrieved from trial participants and a single block submitted for sequencing by a Foundation Medicine. Inc. tNGS assay that includes 395 genes. Results: We successfully obtained tNGS data on 115 (62%) of 186 patients enrolled between Nov-2011 and April-2017 at 15 UK participating centers. The median age was 70 years (IQR 44-85); 97% had de novo M1 disease and 83% Gleason score ≥8. We observed PTEN deficiency (34%) due to copy-number loss (25%) or mutation (9%); TP53 mutation or loss (33%) and aberrations in PI3K signaling (16%), genes involved in DNA repair (14%), Wnt signaling (14%) and cell cycle control (6%). In total, these aberrations were observed in 76% of patients, with 35% harboring two or more. No androgen receptor (AR) mutations were detected. Conclusions: The prevalence of PTEN deficiency is comparable with that observed in mCRPC consistent with this being a feature of metastatic disease. In contrast, AR mutations are not observed in this treatment-naïve group. The prevalence of DNA repair deficiency is less than observed in mCRPC but more than reported in prostatectomy cohorts. Although it is possible to use FFPE biopsies for tNGS, the test failure-rate poises challenges to evaluating treatments in low prevalence biomarker-defined groups. These data will inform the design and conduct of biomarker-directed trials.