BACKGROUND: We proposed in 2005 that androgens replace oestrogens as the driver steroids in a subgroup of triple-negative breast cancer (TNBC) with androgen receptor (AR) expression called molecular apocrine (MA) or luminal androgen receptor (LAR). Here, we report the analysis of a clinical trial evaluating the antitumour activity of the anti-androgen darolutamide in MA breast cancer. Our aim was to assess the clinical benefit in patients with AR-positive TNBCs defined by immunohistochemistry and by RNA profiling. METHODS: In this multicentre, non-comparative, randomised, phase 2 trial, women aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1 and with advanced TNBC that was previously treated with a maximum of one line of chemotherapy were recruited from 45 hospitals in France. After central confirmation of TNBC status and AR positivity (≥10%
SP107 antibody), participants were randomly assigned (2:1) to receive darolutamide 600 mg orally twice daily or capecitabine minimum 1000 mg/m FINDINGS: Between April 9, 2018, and July 20, 2021, 254 women were screened and 94 were randomly assigned to darolutamide (n=61) or capecitabine (n=33), of whom 90 were evaluable for efficacy analyses. Median follow-up at the data cutoff on July 20, 2022, was 22·5 months (IQR 16·5-30·5). The clinical benefit rate was 29% (17 of 58
90% CI 19-39) with darolutamide and 59% (19 of 32
90% CI 45-74) with capecitabine. In patients treated with darolutamide, the clinical benefit rate was 57% (12 of 21
95% CI 36-78) in MA INTERPRETATION: This study did not reach its prespecified endpoint for darolutamide activity in patients with triple-negative breast cancer selected on the basis of immunohistochemistry for AR. Further studies selecting patients based on RNA profiling might allow better identification of tumours sensitive to anti-androgens. FUNDING: Bayer and Fondation Bergonié.