Phase II Multicenter Study of Enzalutamide in Metastatic Castration-Resistant Prostate Cancer to Identify Mechanisms Driving Resistance.

Autor:	McKay RR; University of California San Diego, San Diego, California.; Dana-Farber Cancer Institute, Boston, Massachusetts., Kwak L; Dana-Farber Cancer Institute, Boston, Massachusetts., Crowdis JP; Dana-Farber Cancer Institute, Boston, Massachusetts., Sperger JM; Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin., Zhao SG; Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin., Xie W; Dana-Farber Cancer Institute, Boston, Massachusetts., Werner L; Dana-Farber Cancer Institute, Boston, Massachusetts., Lis RT; Dana-Farber Cancer Institute, Boston, Massachusetts., Zhang Z; Dana-Farber Cancer Institute, Boston, Massachusetts., Wei XX; Dana-Farber Cancer Institute, Boston, Massachusetts., Lang JM; Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin., Van Allen EM; Dana-Farber Cancer Institute, Boston, Massachusetts., Bhatt RS; Beth Israel Deaconess Medical Center, Boston, Massachusetts., Yu EY; University of Washington, Seattle, Washington.; Fred Hutchinson Cancer Research Center, Seattle, Washington., Nelson PS; University of Washington, Seattle, Washington.; Fred Hutchinson Cancer Research Center, Seattle, Washington., Bubley GJ; Beth Israel Deaconess Medical Center, Boston, Massachusetts., Montgomery RB; University of Washington, Seattle, Washington.; Fred Hutchinson Cancer Research Center, Seattle, Washington., Taplin ME; Dana-Farber Cancer Institute, Boston, Massachusetts. mtaplin@partners.org.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2021 Jul 01; Vol. 27 (13), pp. 3610-3619. Date of Electronic Publication: 2021 Apr 13.
DOI:	10.1158/1078-0432.CCR-20-4616
Abstrakt:	Purpose: Enzalutamide is a second-generation androgen receptor (AR) inhibitor that has improved overall survival (OS) in metastatic castration-resistant prostate cancer (CRPC). However, nearly all patients develop resistance. We designed a phase II multicenter study of enzalutamide in metastatic CRPC incorporating tissue and blood biomarkers to dissect mechanisms driving resistance. Patients and Methods: 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: A total of 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 vs. 53.9% at baseline) and BRCA2 alterations (64.7% at progression vs. 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 the importance of serial tumor sampling in CRPC. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu