Genomic alterations in cell-free DNA and enzalutamide resistance in castration-resistant prostate cancer

The molecular landscape underpinning response to the AR-antagonist enzalutamide in metastatic castration-resistant prostate cancer (mCRPC) is unclear. Since mCRPC tissue biopsies are frequently impractical, we collected temporal circulating cell-free DNA (cfDNA) samples from 65 mCRPC patients receiving enzalutamide and performed integrated genomic profiling. AR mutations were robustly detected in 23% of baseline samples and were not associated with primary resistance, except in patients with ≥2 mutations. We observed temporal AR heterogeneity, and persistence of abiraterone-associated L702H positive clones at progression, potentially driven by continued administration of glucocorticoids. Interestingly, AR amplification was linked to poor outcomes, despite hypothesized inhibition by enzalutamide. RB1 loss was also associated with adverse outcomes. At the time of progression we identified mutations or copy number changes in all patients tested, including clinically-actionable alterations in DNA repair and PI3K genes and a high frequency of activating CTNNB1 mutations. These data demonstrate that clinically-informative genomic profiling of cfDNA is feasible in nearly all mCRPC patients and provides important insights into treatment resistance.