Purpose: Enzalutamide is a second-generation androgen receptor (AR) inhibitor which has improved overall survival (OS) in metastatic castration resistant prostate cancer (CRPC). However, nearly all patients develop resistance. We designed a phase 2 multicenter study of enzalutamide in metastatic CRPC incorporating tissue and blood biomarkers to dissect mechanisms driving resistance. Experimental Design: Eligible patients with metastatic CRPC underwent a baseline metastasis biopsy and then initiated enzalutamide 160 mg daily. A repeat metastasis biopsy was obtained at radiographic progression from the same site when possible. Blood for circulating tumor cell (CTC) analysis was collected at baseline and progression. The primary objective was to analyze mechanisms of resistance in serial biopsies. Whole exome sequencing was performed on tissue biopsies. CTC samples underwent RNA sequencing. Results: 65 patients initiated treatment, of whom 22 (33.8%) had receiv ed prior abiraterone. Baseline biopsies were enriched for alterations in AR (mutations, amplifications) and tumor suppression genes (PTEN, RB1, and TP53) which were observed in 73.1% and 92.3% of baseline biopsies, respectively. Progression biopsies revealed increased AR amplifications (64.7% at progression versus 53.9% at baseline) and BRCA2 alterations (64.7% at progression versus 38.5% at baseline). Genomic analysis of baseline and progression CTC samples demonstrated increased AR splice variants, AR regulated-genes, and neuroendocrine markers at progression. Conclusions: Our results demonstrate that a large proportion of enzalutamide-treated patients have baseline and progression alterations in the AR pathway and tumor suppressor genes. We demonstrate an increased number of BRCA2 alterations post-enzalutamide highlighting importance of serial tumor sampling in CRPC.
No comments:
Post a Comment