Evolution of Castration-Resistant Prostate Cancer in ctDNA during Sequential Androgen Receptor Pathway Inhibition
Matti Annala1,2, Sinja Taavitsainen2, Daniel J Khalaf3
1Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, British Columbia, Canada.
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.
Insights
Androgen receptor (AR) signaling inhibitors face cross-resistance in metastatic castration-resistant prostate cancer (mCRPC). Genomic analysis reveals evolving AR genotypes drive acquired resistance to sequential therapies.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) poses significant treatment challenges.
- Cross-resistance to androgen receptor (AR) signaling inhibitors limits therapeutic options.
Purpose of the Study:
- To identify acquired genomic alterations contributing to cross-resistance in mCRPC.
- To understand the evolution of AR signaling pathways under sequential inhibition.
Main Methods:
- Deep targeted and whole-exome sequencing of 458 serial plasma cell-free DNA samples from 202 mCRPC patients.
- Analysis of circulating tumor DNA (ctDNA) at baseline and progression during sequential AR inhibitor therapy.
Main Results:
- ctDNA abundance correlated with therapy response and survival.
- Shifts in somatic populations, particularly AR gene alterations, occurred in 53% of patients post-treatment.
- Increased AR copy number, altered AR mutations, and AR ligand binding domain truncating rearrangements were observed.
Conclusions:
- The AR genotype evolves under sequential AR inhibition in mCRPC.
- This evolution of AR signaling is a key driver of acquired treatment resistance.
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