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We randomized 202 patients with treatment-na\u00efve mCRPC to abiraterone or enzalutamide and performed whole-exome and deep targeted 72-gene sequencing of plasma cell-free DNA prior to therapy. For these agents, which have never been directly compared, time to progression was similar. Defects in BRCA2 and ATM were strongly associated with poor clinical outcomes independently of clinical prognostic factors and circulating tumor DNA abundance. Somatic alterations in TP53, previously linked to reduced tumor dependency on AR signaling, were also independently associated with rapid resistance. Although detection of AR amplifications did not outperform standard prognostic biomarkers, AR gene structural rearrangements truncating the ligand binding domain were identified in several patients with primary resistance. These findings establish genomic drivers of resistance to first-line AR-directed therapy in mCRPC and identify potential minimally invasive biomarkers.<\/jats:p>\n                  <jats:p>Significance: Leveraging plasma specimens collected in a large randomized phase II trial, we report the relative impact of common circulating tumor DNA alterations on patient response to the most widely used therapies for advanced prostate cancer. Our findings suggest that liquid biopsy analysis can guide the use of AR-targeted therapy in general practice. Cancer Discov; 8(4); 444\u201357. \u00a92018 AACR.<\/jats:p>\n                  <jats:p>See related commentary by Jayaram et al., p. 392.<\/jats:p>\n                  <jats:p>This article is highlighted in the In This Issue feature, p. 371<\/jats:p>","DOI":"10.1158\/2159-8290.cd-17-0937","type":"journal-article","created":{"date-parts":[[2018,1,24]],"date-time":"2018-01-24T20:20:10Z","timestamp":1516825210000},"page":"444-457","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":472,"title":["Circulating Tumor DNA Genomics Correlate with Resistance to Abiraterone and Enzalutamide in Prostate Cancer"],"prefix":"10.1158","volume":"8","author":[{"given":"Matti","family":"Annala","sequence":"first","affiliation":[{"name":"1Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada."},{"name":"2Faculty of Medicine and Life Sciences and Biomeditech Institute, University 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