Lancet Study: Darolutamide Shows No Clinical Benefit in AR+ Triple-Negative Breast Cancer

Findings from the phase II UCBG 3-06 START trial (Study on Androgen Receptor and Triple Negative Breast Cancer) recently published in The Lancet Oncology revealed that treatment with the anti-androgen darolutamide did not achieve the clinical benefit endpoint in patients with triple-negative, androgen receptor (AR)-positive advanced breast cancer.

Herve Bonnefoi, MD, from the Department of Medical Oncology, Breast Unit, Institute Bergonié, in France, and colleagues wrote, “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.”

The trial sought to evaluate the clinical benefit in patients diagnosed with AR-positive triple-negative breast cancers (TNBCs), as determined by immunohistochemistry and RNA profiling.

In the non-comparative multicenter trial, 90 eligible women with TNBC AR-positive breast cancer were randomly assigned 2:1 to darolutamide (600 mg twice daily, n=58) or capecitabine (1,000 mg/m² twice daily for 2 weeks on and 1 week off, n=32) until disease progression or toxicity, lack of follow-up, or termination of consent.

The researchers categorized tumors into groups with high and low AR activity (MA-^high and MA-^low) employing transcriptomic analysis.

The primary endpoint was the clinical benefit rate at 16 weeks and to demonstrate at least a 40% rate in the darolutamide group.

At 16 weeks, clinical benefit was observed in 29% (darolutamide) and 59% (capecitabine). MA-^high tumors responded better to darolutamide (57%) compared to MA-^low tumors (16%) (P=0.0020).

The most common grade 3 adverse events included headache (5%) in the darolutamide group and palmar-plantar erythrodysesthesia (6%) in the capecitabine group, with no grade 4 or 5 events. Drug-associated serious adverse events were reported as 5% and 9% for the darolutamide and capecitabine groups, respectively.

“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,” concluded the authors.

Reference

Bonnefoi H, et al. Lancet Oncol. 2025 Mar;26(3):355-366. doi: 10.1016/S1470-2045(24)00737-X.