A French multicenter phase II trial investigating darolutamide in triple-negative, androgen receptor (AR)-positive advanced breast cancer has failed to achieve its primary endpoint, according to findings published in The Lancet Oncology. The study, led by researchers at Institut Bergonié, Bordeaux, provides important insights into the potential role of antiandrogen therapy in this challenging breast cancer subtype.
The UCBG 3-06 START trial enrolled 90 evaluable patients between April 2018 and July 2021, randomizing them in a 2:1 ratio to receive either darolutamide (600 mg twice daily) or capecitabine. All participants had received no more than one previous line of chemotherapy for advanced disease.
Clinical Outcomes and Efficacy Analysis
The primary endpoint analysis revealed a clinical benefit rate of 29% (90% CI = 19%–39%) in the darolutamide group at 16 weeks, falling short of the predetermined 40% threshold. In contrast, the capecitabine group demonstrated a higher clinical benefit rate of 59% (90% CI = 45%–74%).
Notably, a significant difference emerged when analyzing outcomes based on molecular apocrine (MA) status. Patients with MA-high tumors showed markedly better response to darolutamide, achieving a 57% clinical benefit rate (95% CI = 36%–78%), compared to just 16% (95% CI = 3%–29%) in those with MA-low tumors (P = .0020).
Safety and Tolerability Profile
The safety profile of darolutamide proved favorable, with manageable adverse events. The most common grade 3 adverse event in the darolutamide group was headache, affecting 5% of patients. No grade 4 or 5 adverse events were reported. Drug-related serious adverse events occurred in 5% of darolutamide-treated patients, compared to 9% in the capecitabine group.
Molecular Insights and Future Directions
The study's findings highlight the heterogeneous nature of triple-negative breast cancer and the potential importance of molecular profiling in treatment selection. While the overall results did not meet expectations, the marked difference in response between MA-high and MA-low tumors suggests a potential path forward.
Dr. Hérvé Bonnefoi and colleagues propose that future studies should focus on patient selection based on RNA profiling rather than solely on immunohistochemistry for AR expression. This approach could better identify patients most likely to benefit from antiandrogen therapy.
The results underscore the complexity of treating triple-negative breast cancer and the ongoing need for biomarker-driven treatment approaches. While darolutamide showed promise in a specific molecular subgroup, further research is needed to optimize patient selection and treatment strategies in this challenging disease setting.
