Evolution of castration-resistant prostate cancer in ctDNA during sequential androgen receptor pathway inhibition

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

Research output: Contribution to journalArticleScientificpeer-review

1 Citation (Scopus)

Abstract

Purpose: 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. Experimental Design: We collected 458 serial plasma cell-free DNA samples at baseline and progression timepoints from 202 patients with mCRPC 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 posttreatment somatic genomic profiles in circulating tumor DNA (ctDNA). Results: 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)4610-4623
Number of pages14
JournalClinical Cancer Research
Volume27
Issue number16
DOIs
Publication statusPublished - Aug 2021
Publication typeA1 Journal article-refereed

Publication forum classification

  • Publication forum level 2

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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