Abstract There is an urgent need to develop novel biomarkers of treatment response for precision medicine in prostate cancer, particularly in the setting of localized, non-indolent disease, which represents the vast majority of cases at initial clinical presentation. The Canadian Prostate Cancer Genome Network (CPC-GENE) - a member of the International Cancer Genome Consortium - aims to identify multi-modal prognostic and predictive signatures of therapeutic outcome based on intrinsic tumour genomics, transcriptomics, and epigenomics, which are being incorporated into novel clinical trials of treatment escalation/de-escalation for image-guided radiotherapy and/or radical prostatectomy. Herein we report the results of the largest prostate cancer whole-genome sequencing study to date, consisting of 194 patients and whole-exome sequencing of 479 patients with localized, potentially curable disease; a sample size that allows for saturating discovery of genes mutated at ≥1% frequency. We show that tumours treated by curative local therapy have a paucity of clinically-actionable mutations relative to high-risk localized or metastatic disease, but instead harbor a significant number of recurrent non-coding aberrations and genomic rearrangements, including a novel inversion - and an associated reduction in gene expression - of the PTEN tumour suppressor gene on chromosome 10. The median tumour contains three distinct driver mutations, with >86% of tumours possessing at least one known driver. Importantly, multiple driver aberrations are associated with patient outcome, including copy number aberrations and methylation events, but notably excluding well-described recurrent events such as TMPRSS2:ERG fusions and SPOP point mutations. Localized hypermutation events (e.g. kataegis) were detected in >20% of tumours, and were strongly enriched for aggressive disease. Taken together, these data provide a comprehensive analysis of the genomic landscape of localized, non-indolent prostate cancer. Moreover, our results strongly suggest that specific molecular aberrations may serve as useful biomarkers for improved pre-treatment stratification of patients with localized, low/intermediate risk disease into escalation/de-escalation protocols, and support the development of clinical trials to assess this hypothesis, based on patient-specific molecular profiles. Citation Format: Michael E. Fraser, Theodorus van der Kwast, John McPherson, Colin C. Collins, Yves Fradet, Bernard Tetu, Alain Bergeron, Rob G. Bristow, Paul C. Boutros. A comprehensive profile of the genomic architecture of curable prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 118.