In a French phase II trial (UCBG 3-06 START) reported in The Lancet Oncology, Bonnefoi et al found that treatment with the antiandrogen darolutamide did not reach the clinical benefit endpoint in patients with triple-negative, androgen receptor (AR)-positive advanced breast cancer.
Triple-negative breast cancer includes tumors with disparate biology, and appropriate treatment is dependent on an understanding of the distinct biology. The name molecular apocrine was applied to estrogen receptor–negative, androgen receptor (AR)–positive tumors that resemble hormone-sensing cells in 2005. Further research focusing on triple-negative breast cancer confirmed the existence of this rare subtype.
As stated by the investigators: “We proposed…that androgens replace estrogens as the driver steroids in a subgroup of triple-negative breast cancer …with AR expression called molecular apocrine [MA] …. Here, we report the analysis of a clinical trial evaluating the antitumour activity of the antiandrogen darolutamide in MA breast cancer.”
Study Details
In the noncomparative multicenter trial, 90 evaluable women were randomly assigned 2:1 between April 2018 and July 2021 to receive darolutamide at 600 mg twice daily (n = 58) or capecitabine at a minimum of 1,000 mg/m2 twice daily for 2 weeks on and 1 week off (n = 32) until disease progression or unacceptable toxicity. Patients had previously received a maximum of one line of chemotherapy for advanced disease. Transcriptomic analysis was used to classify tumors into groups with high and low AR activity (MA-high and MA-low). The primary endpoint was clinical benefit rate at 16 weeks, with the objective of showing at least a 40% rate in the darolutamide group.
Key Findings
Clinical benefit at 16 weeks was observed in 17 of 58 patients in the darolutamide group (29%, 90% confidence interval [CI] = 19%–39%) and in 19 of 32 patients in the capecitabine group (59%, 90% CI = 45%–74%). In the darolutamide group, clinical benefit at 16 weeks was observed in 12 of 21 patients (57%, 95% CI = 36%–78%) with MA-high tumors and in 5 of 31 patients (16%, 95% CI = 3%–29%) with MA-low tumors (P = .0020).
The most common grade 3 adverse events were headache in the darolutamide group (5% vs 0%) and palmar-plantar erythrodysesthesia syndrome in the capecitabine group (6% vs 0%); no grade 4 or 5 adverse events were observed. Drug-related serious adverse events occurred in 5% of the darolutamide group and 9% of the capecitabine group.
The investigators concluded: “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 tumors sensitive to antiandrogens.”
Hérve Bonnefoi, MD, of the Department of Medical Oncology, Breast Unit, Institut Bergonié, Bordeaux, is the corresponding author of The Lancet Oncology article.
Disclosure: The study was funded by Bayer and Fondation Bergonié. For full disclosures of all study authors, visit The Lancet Oncology.
