Background: Despite recent advances, treatment (tx) of metastatic triple-negative breast cancer (TNBC) remains an important unmet clinical need. Activation of the glucocorticoid receptor (GR) initiates cell survival pathways, leading to chemotherapy resistance. Furthermore, high GR expression is a negative prognostic marker in early-stage, hormone receptor negative breast cancer. We hypothesized that GR antagonism with mifepristone (mif) prior to the administration of cytotoxic chemotherapy would improve efficacy by blocking the potent anti-apoptotic signals mediated by GR activation. Methods: We conducted a phase II, randomized, placebo-controlled, multi-center study of nab-paclitaxel (nab-pac) with or without mif in patients (pts) with locally advanced, unresectable or metastatic TNBC (NCT02788981). Prior tx with nab-pac was not allowed. Two prior chemotherapies allowed in the metastatic setting. Pts were randomized to receive nab-pac 100mg/m² on day 1, 8, and 15 of a 28-day cycle with mif 300mg or placebo the day prior and day of each dose of nab-pac. The primary endpoint was progression free survival (PFS). Secondary endpoints included objective response rate (ORR), overall survival (OS), and safety and tolerability. Results: 29 patients were enrolled from September 2017 to July 2021; 16 patients were randomized to nab-pac+placebo and 13 patients to nab-pac+mif. The mean age was 53 years (range 32-73) and 34% of pts were self-reported Black. The median PFS was 3.0 and 3.0 months (mos) in the nab-pac alone and combination arms respectively (hazard ratio [HR] 0.87, 95% CI 0.37 – 2.01, p=0.739]. ORR in the nab-pac and combination arms were 31.5% and 23%, respectively; both arms had 1 complete response (CR). Median OS with nab-pac alone was 6.0 mos and in the combination arm was 9.0 mos (HR=0.67, 95% CI 0.29 – 1.16, p=0.350]. The pt on the mif arm who achieved a CR completed 50 cycles and ultimately died of a non-cancer, non-tx related event. Tx was generally well-tolerated, with a safety profile comparable with nab-pac monotherapy. The most common treatment-related adverse events (TRAEs) were fatigue (50%), neuropathy (42%), and neutropenia (42%); the most common grade 3 TRAE was neutropenia. Grade 3 neutropenia occurred more frequently in pts receiving nab-pac+mif (69% vs 13%). Conclusions: This study did not achieve the desired statistical power due to poor accrual attributed to the COVID-19 pandemic and the approval of checkpoint inhibitors in advanced TNBC. Nonetheless, in this subset of patients, the addition of mif to nab-pac did not significantly improve PFS compared to nab-pac alone. There was a trend towards improvement in OS, primarily driven by one long-term responder. GR activation remains relevant in advanced TNBC. Further investigation of this pathway and other strategies to target chemotherapy resistance are needed. Clinical trial information: NCT02788981.