TBCRC 058: A randomized phase II study of enzalutamide, enzalutamide with mifepristone, and treatment of physician’s choice in patients with androgen receptor-positive metastatic triple-negative or estrogen receptor-low breast cancer (NCT06099769).

Abstract

TPS1162 Background: Triple-negative breast cancer (TNBC) refers to a heterogenous group of breast cancers that lack expression of ER, PR, and HER2. Despite recent advances with immunotherapy (IO) and antibody-drug conjugates (ADCs), TNBC remains the most aggressive subtype, with short overall survival in the metastatic setting. Breast tumors with low levels of ER and PR expression (1-10%) clinically behave like TNBC, and clinical management follows the TNBC treatment (tx) paradigm. We and others have identified a subset of ER/PR/HER2-negative breast cancers (BCs) that express the androgen receptor (AR). Enzalutamide (enza), an AR-antagonist, has demonstrated activity in AR-positive metastatic TNBC (Traina et al, JCO 2018). Activation of the glucocorticoid receptor (GR) has been implicated as a mechanism of resistance to AR inhibition in prostate and BCs (Kach et al, Sci Transl Med 2015). Effective therapies for advanced TNBC remain an unmet need, particularly in patients who are ineligible for or progress following a checkpoint inhibitor. This randomized study evaluates the efficacy of enzalutamide or enzalutamide plus the GR antagonist mifepristone (mif) as compared to physician’s choice chemotherapy (TPC). Methods: This is a randomized phase II trial; 201 patients (pts) will be randomized in a 1:1:1 fashion to enza, enza with mif, or TPC (carboplatin, paclitaxel, eribulin, or capecitabine). The primary endpoint (endpt) is progression-free survival (PFS), and the trial is designed to test the hypothesis that PFS in the pooled enza arms is superior to TPC; there is 80% power to detect a hazard ratio (HR) of 0.70, corresponding to an increase in median PFS from 3.5 months (mos) with TPC to 5.0 mos with enza-based tx. Secondary endpts include comparisons of PFS among the 3 arms and evaluation of response rate, clinical benefit rate, duration of response, overall survival, safety, and patient-reported outcomes by arm. Exploratory endpts include correlation of tumor and circulating markers (constitutively active AR variants in circulating tumor cells and cfDNA) with tx response. Eligible pts must have: ECOG 0-2, metastatic measurable or evaluable disease (dz), normal organ function, no history of brain mets, < prior lines of chemotx, any # of prior endocrine txs, no prior anti-AR tx, no prior mif, no concurrent CYP17 inhibitor use. Tumors must test ER/PR low or negative, HER2 negative, AR >10%. Pts with PD-L1+ BC must have received prior IO if not contraindicated. As of December 28, 2025, 32 of 201 pts have been enrolled on study. Clinical trial information: NCT06099769 .