Abstract P3-08-17: TBCRC 058: A Randomized Phase II Study of Enzalutamide, Enzalutamide with Mifepristone, & Treatment of Physician’s Choice in Patients with Androgen Receptor-Positive Metastatic Triple-Negative or Estrogen Receptor-Low Breast Ca

Abstract 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, 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, had demonstrated activity in AR+ 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 breast cancers (Kach et al, Sci Transl Med 2015). Advanced TNBC remains an area of high unmet need, particularly in patients who are ineligible for or progress following a checkpoint inhibitor. This randomized study will evaluate 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 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 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 low or negative, HER2 negative breast cancer (BC), measurable or evaluable disease (dz), < 2 prior lines of chemotx, any # prior endocrine txs, no prior anti-AR tx, no prior mif, concurrent CYP17 inhibitors prohibited. Pts with PD-L1+ BC must have received prior IO if not contraindicated. Tumors must have AR >/= 10%, normal organ function, no history of brain mets. As of 7/1/2024, 7 of 201 pts have begun protocol-specified tx. This trial is supported by the TBCRC, BCRF, The TaTa Sisterhood Foundation, Pfizer/Astellas, and Corcept Therapeutics. Citation Format: Rita Nanda, Yuan Chen, Katia Khoury, Hope S. Rugo, Erica L. Mayer, Lisa A. Carey, Michelle Melisko, Angemael Syldor, Chaya Friedman, Jennifer Savoie, Fresia Pareja, Britta Weigelt, Sarat Chandarlapaty, Nicholas Turner, Joshua Lang, Marina Sharifi, Suzanne Conzen, Tiffany Traina. TBCRC 058: A Randomized Phase II Study of Enzalutamide, Enzalutamide with Mifepristone, & 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 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-08-17.