Cross-resistance renders multiple lines of androgen receptor (AR) signaling inhibitors increasingly futile in metastatic castration-resistant prostate cancer (mCRPC). We sought to determine acquired genomic contributors to cross-resistance.
We collected 458 serial plasma cell-free DNA samples at baseline and progression timepoints from 202 mCRPC patients receiving sequential AR signaling inhibitors (abiraterone and enzalutamide) in a randomized phase II clinical trial (NCT02125357). We utilized deep targeted and whole exome sequencing to compare baseline and post-treatment somatic genomic profiles in circulating tumor DNA (ctDNA).
Patient ctDNA abundance was correlated across plasma collections and independently prognostic for sequential therapy response and overall survival. Most driver alterations in established prostate cancer genes were consistently detected in ctDNA over time. However, shifts in somatic populations after treatment were identified in 53% of patients, particularly after strong treatment responses. Treatment-associated changes converged upon the AR gene, with an average 50% increase in AR copy number, changes in AR mutation frequencies, and a 2.5-fold increase in the proportion of patients carrying AR ligand binding domain truncating rearrangements.
Our data show that the dominant AR genotype continues to evolve during sequential lines of AR inhibition and drives acquired resistance in patients with mCRPC.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021 Jun 03 [Epub ahead of print]
Matti Annala, Sinja Taavitsainen, Daniel J Khalaf, Gillian Vandekerkhove, Kevin Beja, Joonatan Sipola, Evan W Warner, Cameron Herberts, Amanda Wong, Simon Fu, Daygen L Finch, Conrad D Oja, Joanna Vergidis, Muhammad Zulfiqar, Bernhard J Eigl, Christian K Kollmansberger, Matti Nykter, Martin E Gleave, Kim N Chi, Alexander W Wyatt
Faculty of Medicine and Health Technology, Tampere University and Tays Cancer Centre., Faculty of Medicine and Health Technology; Tays Cancer Centre, Tampere University., Vancouver Centre, British Columbia Cancer Agency., Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia., Urologic Sciences, Vancouver Prostate Centre., Oncology, University of Auckland., Southern Interior Centre, BCCA CSI., Fraser Valley Centre, British Columbia Cancer Agency., Vancouver Island Centre, British Columbia Cancer Agency., Abbotsford Centre, British Columbia Cancer Agency., Medical Oncology, BC Cancer, Vancouver Centre., Faculty of Medicine and Health Technology, Tampere University., Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia .