A recent clinical trial of the AR inhibitor enzalutamide in patients with TNBC included an exploratory endpoint using RNA sequencing to identify a genomic signature of patients likely to respond to treatment. Tumor samples were collected from all patients enrolled in the single-arm, open-label phase 2 trial. The primary endpoint was clinical benefit rate at 16 weeks (CBR16). Samples were assayed by whole transcriptome RNA-sequencing and divided into a training and blinded validation cohort for model development and evaluation. The gene expression model of enzalutamide sensitivity demonstrated strong association with progression free survival (HR = 0.40, Wald p = 0.0001). This signature is being used to select patients enrolling in a phase 3 trial of enzalutamide in patients with advanced TNBC. Biological associations and translation of the assay for clinical use will highlighted.