Primary resistance to androgen receptor (AR)-directed therapies in metastatic castration-resistant prostate cancer (mCRPC) is poorly understood. We randomized 202 patients with treatment-naïve 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.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); 444-57. ©2018 AACR.See related commentary by Jayaram et al., p. 392This article is highlighted in the In This Issue feature, p. 371.
Cancer discovery. 2018 Jan 24 [Epub]
Matti Annala, Gillian Vandekerkhove, Daniel Khalaf, Sinja Taavitsainen, Kevin Beja, Evan W Warner, Katherine Sunderland, Christian Kollmannsberger, Bernhard J Eigl, Daygen Finch, Conrad D Oja, Joanna Vergidis, Muhammad Zulfiqar, Arun A Azad, Matti Nykter, Martin E Gleave, Alexander W Wyatt, Kim N Chi
Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada., British Columbia Cancer Agency, Vancouver Centre, Vancouver, British Columbia, Canada., Faculty of Medicine and Life Sciences and Biomeditech Institute, University of Tampere, Tampere, Finland., British Columbia Cancer Agency, Southern Interior Centre, Kelowna, British Columbia, Canada., British Columbia Cancer Agency, Fraser Valley Centre, Vancouver, British Columbia, Canada., British Columbia Cancer Agency, Vancouver Island Centre, Victoria, British Columbia, Canada., British Columbia Cancer Agency, Abbotsford Centre, Vancouver, British Columbia, Canada., Monash University, Monash, Australia., Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada. .