Abstract PS5-09-04: Tbcrc 058: a randomized phase 2 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)

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, characterized by a high risk of recurrence and a 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 breast tumors which are ER/PR/HER2 negative and express the androgen receptor (AR). Enzalutamide (enza), an AR-antagonist, has demonstrated activity in AR+ metastatic TNBC (Traina et al, JCO 2018). Activation of glucocorticoid receptor (GR) activity has been implicated as a mechanism of resistance to AR inhibition in prostate and breast cancers (Kach et al, Sci Transl Med 2015). Advanced TNBC remains an area of high unmet need, particularly in chemotherapy and checkpoint inhibitor resistant. This randomized study will evaluate the efficacy of AR antagonism alone (enza monotherapy) or enza plus the GR antagonist mifepristone (mif) as compared to physician’s choice chemotherapy (TPC). This is a randomized phase II trial; 201 patients (pts) will be randomized in a 1:1:1 fashion to enza, enza plus 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 enzalutamide arms is superior to TPC; there is 80% power to detect a hazard ratio (HR) of 0.70, corresponding to increase in 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/toxicity, and patient-reported outcomes by arm. Exploratory endpts include correlation of tumor and circulating markers (AR-V7 in circulating tumor cells and circulating tumor cell DNA) with tx response. Eligible pts must have: ECOG 0-2, metastatic ER/PR/HER2 negative or low breast cancer (BC), tumor AR expression >/= 10% by central testing, measurable or evaluable disease, up to 2 prior lines of chemotx, any # prior endocrine txs, no prior anti-AR tx, no prior mif tx, and concurrent CYP17 inhibitor use prohibited. Pts with PD-L1+ BC must have received prior IO if not contraindicated. Pts must have normal organ function and no history of brain mets. As of 7/9/2025, 19 of 201 pts have begun protocol-specified tx. This trial is supported by the Translational Breast Cancer Research Consortium, The Breast Cancer Research Foundation, The TaTa Sisterhood Foundation, Pfizer/Astellas, and Corcept Therapeutics. R. Nanda, Y. Chen, Y. Abdou, N. Jahan, E. L. Mayer, M. Melisko, A. Syldor, C. Friedman, J. Savoie, F. Pareja, B. Weigelt, S. Chandarlapaty, N. Turner, M. Sharifi, S. Conzen, T. Traina. Tbcrc 058: a randomized phase 2 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]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-09-04.