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.
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.
65 patients initiated treatment, of whom 22 (33.8%) had received 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.
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.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021 Apr 13 [Epub ahead of print]
Rana R McKay, Lucia Kwak, Jett Crowdis, Jamie M Sperger, Shuang G Zhao, Wanling Xie, Lillian Werner, Rosina T Lis, Zhenwei Zhang, Xiao X Wei, Joshua M Lang, Eliezer M Van Allen, Rupal S Bhatt, Evan Y Yu, Peter S Nelson, Glenn J Bubley, Bruce Montgomery, Mary-Ellen Taplin
Medicine, University of California, San Diego., Dana-Farber Cancer Institute., Department of Medicine, University of Wisconsin–Madison., Department of Human Oncology, University of Wisconsin–Madison., Biostatistics and Computational Biology, Dana-Farber Cancer Institute., Department of Medical Oncology, Dana-Farber Cancer Institute., Medical Oncology, Dana-Farber Cancer Institute., Carbone Cancer Center and Department of Medicine, University of Wisconsin–Madison., Division of Hematology-Oncology, Beth Israel Deaconess Medical Center., Medicine (Oncology), University of Washington and Fred Hutchinson Cancer Research Center., Division of Clinical Research, Fred Hutchinson Cancer Research Center., Division of Hematology and Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School., Medicine, University of Washington., GU Oncology, Dana-Farber Cancer Institute .