Abstract PS5-08-08: A phase II neoadjuvant clinical trial of the androgen receptor inhibitor darolutamide in early-stage androgen receptor positive (AR+) triple-negative breast cancer (NCT 07016399)

Abstract Background: Neoadjuvant chemotherapy combined with immunotherapy is the standard of care in the treatment of early-stage triple-negative breast cancer (TNBC) with pathological complete (pCR) rates of approximately 65%. Though TNBC is currently treated as one disease, TNBC is transcriptionally diverse with at least four biological subtypes including basal-like (BL1, BL2), mesenchymal (M) and luminal androgen receptor (LAR) subtypes. The LAR subtype is characterized by androgen receptor (AR)-regulation and luminal gene expression in tumor specimens. Up to 20% of TNBCs are the LAR subtype, and compared to other TNBCs, they are less proliferative, less responsive to chemotherapy, more genomically stable, and are typically diagnosed in older patients. Studies in the metastatic setting have revealed that chemotherapy with/without immunotherapy is not an optimal treatment strategy for LAR tumors. Darolutamide is a potent second-generation AR inhibitor approved for the treatment of prostate cancer. While earlier studies using AR inhibitors in breast cancer showed limited effectiveness, these studies used IHC cut-offs for AR that were below the threshold to capture true LAR tumors and often used less potent AR inhibitors. Ki-67 is a marker of cell proliferation and is validated as a prognostic and predictive marker in estrogen receptor positive breast cancer. Decreases in Ki-67 after two weeks of endocrine therapy correspond with improved outcomes to anti-estrogen therapy. Treatment with the AR inhibitor enzalutamide has been shown to reduce Ki-67 levels in luminal AR tumors. We hypothesize that targeting AR with darolutamide in the neoadjuvant setting and using Ki-67 as a biomarker of response will identify breast cancers responsive to AR inhibitors. Methods: Fifty-one patients with a histologically-confirmed new diagnosis of stage II-IIIa TNBC that is AR positive (>= 80% staining by IHC) will be randomized to receive neoadjuvant standard of care (SOC) chemotherapy and immunotherapy for TNBC. Patients will be randomized 2:1 to receive either the oral androgen inhibitor darolutamide for 14 days followed by darolutamide in combination with SOC treatment for 24 weeks (34 patients) or receive 24 weeks of SOC treatment alone (17 patients). Eligible patients must be appropriate for neoadjuvant treatment, have an ECOG PS of 0-1, and must not have non-resectable or metastatic breast cancer. Biopsies will be taken at baseline, 2 weeks after starting darolutamide or SOC chemotherapy (both arms), 2 weeks after starting darolutamide and SOC chemotherapy (intervention arm only), and at surgery. Blood draws for ctDNA analysis will be taken at the same time points. The primary endpoint is change in Ki-67 level between baseline and post-treatment measurements. This study has 80% power to detect a biologically and clinically significant effect size of 1 with a two-sided type I error of 5%. Secondary endpoints include pCR, EFS, and their correlation to changes in Ki-67 as well as percent nuclear AR positivity. Exploratory objectives include assessing changes in ctDNA levels while undergoing neoadjuvant therapy for TNBC as well as investigating additional AR characteristics and mechanisms of resistance to AR inhibitors. This study is open at Vanderbilt University Medical Center and will be opening at 6 additional sites. Citation Format: L. Duke, J. M. Sharpe, B. Lehmann, C. Brothers, J. Pietenpol, V. G. Abramson. A phase II neoadjuvant clinical trial of the androgen receptor inhibitor darolutamide in early-stage androgen receptor positive (AR+) triple-negative breast cancer (NCT 07016399) [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 PS5-08-08.