Genomic analysis of circulating cell-free DNA (cfDNA) to investigate mechanisms of primary and acquired resistance to enzalutamide (ENZ) in metastatic castration-resistant prostate cancer (mCRPC).

5015 Background: ENZ is a potent androgen receptor (AR) antagonist that prolongs survival in mCRPC patients (pts). However, factors driving resistance to ENZ are incompletely understood. Genomic analysis of cfDNA is a promising, minimally invasive approach for interrogating mechanisms of therapeutic resistance in mCRPC. Methods: Baseline plasma samples were collected from 57 mCRPC pts commencing ENZ. In 37 pts, additional samples at 12-weeks +/- end-of-treatment were obtained. DNA was extracted and subjected to array Comparative Genomic Hybridization (aCGH) for chromosome copy number (CN) analysis and AR gene (exon 2-8) sequencing (MiSeq) for mutation analysis. Endpoints were i) PSA50 or PSA30 response rates (RR) (PSA decline ≥ 50% or 30% for ≥ 3 weeks); and ii) radiographic/clinical progression-free survival (PFS). Results: On aCGH, the most frequent CN changes in baseline samples (n = 57) were 8p loss (25%), 8q gain (35%), MYC gain (26%) and AR gain/amp (33%). Compared to pts with no AR gain/amp, pts wi...