Evolution of AR and Non-AR Alterations in ctDNA of Patients with Metastatic Prostate Cancer Treated in the Phase III Alliance A031201 Trial.

Androgen receptor pathway inhibitors (ARPI), such as enzalutamide and abiraterone, are standard treatments for metastatic castration-resistant prostate cancer (mCRPC). However, a subset of patients display primary resistance and most eventually acquire secondary resistance. This study aimed to define genomic features of ARPI resistance using longitudinal ctDNA analysis. We used the targeted AR-ctDETECT cell-free DNA (cfDNA) sequencing assay to profile tumor-derived genomic alterations in plasma samples collected at baseline and progression from patients with mCRPC enrolled in the phase III Alliance A031201 trial of first-line enzalutamide with or without abiraterone. Analysis focused on 327 patients with paired samples available from both time points. Progression plasma samples displayed elevated cfDNA levels and increased ctDNA positivity. AR was the most frequently altered gene at baseline and at progression. AR copy-number gains and AR genomic structural rearrangements (AR-GSR) increased at progression, along with copy-number losses of FANCA, POLD1, RAD54L, CDKN2A, ZNRF3, and ETS2. An AR extrachromosomal DNA signature was enriched at progression and was associated with AR-GSRs predicted to truncate the AR ligand-binding domain. Stratification by two extre mes of radiographic progression-free survival revealed preferential accumulation of AR alterations in patients with delayed progression and a higher burden of non-AR alterations in patients with rapid progression. AR alterations in ctDNA accumulate at progression in patients with mCRPC treated with ARPIs, especially in those with initially durable responses. These findings support the use of liquid biopsy to serially track resistance mechanisms and inform precision therapy in advanced prostate cancer. See related commentary by Chauhan et al., p. 2323.