The efficacy and safety of enzalutamide with trastuzumab in patients with HER2+ and androgen receptor-positive metastatic or locally advanced breast cancer

Andrew Wardley, Javier Cortes, Louise Provencher, Kathy Miller, A. Jo Chien, Hope S. Rugo, Joyce Steinberg, Jennifer Sugg, Iulia C. Tudor, Manon Huizing, Robyn Young, Vandana Abramson, Ron Bose, Lowell Hart, Stephen Chan, David Cameron, Gail S. Wright, Marie Pascale Graas, Patrick Neven, Andrea RoccaStefania Russo, Ian E. Krop

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Purpose: Androgen receptor (AR) expression occurs in up to 86% of human epidermal growth factor receptor 2-positive (HER2+) breast cancers. In vitro, AR inhibitors enhance antitumor activity of trastuzumab, an anti-HER2 antibody, in trastuzumab-resistant HER2+ cell lines. This open-label, single-arm, phase II study evaluated the efficacy and safety of enzalutamide, an AR-signaling inhibitor, in patients with advanced HER2+ AR+ breast cancer previously treated with trastuzumab. Methods: Eligible patients had measurable or non-measurable evaluable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Eastern Cooperative Oncology Group status ≤ 1, no history of brain metastases, and previously received ≥ 1 anti-HER2 regimen for advanced disease. Patients received 160 mg oral enzalutamide daily and 6 mg/kg intravenous trastuzumab every 21 days until disease progression or unacceptable toxicity. Primary end point was clinical benefit rate at 24 weeks (CBR24); secondary end points included progression-free survival (PFS) and safety. Results: Overall, 103 women were enrolled [median age 60 years (range 34–83)]; 62% had received ≥ 3 lines of prior anti-HER2 therapy. CBR24, comprising patients with confirmed partial responses (5%) and durable stable disease at 24 weeks (19%), was 24% in the efficacy evaluable set (n = 89). CBR24 did not seem related to AR-expression levels or hormone receptor status. Median PFS was 3.4 months (95% confidence interval 2.0–3.8). Overall, 97 (94%) patients experienced treatment-emergent adverse events (TEAEs), with fatigue most common (34%). Dyspnea (4%) and malignant neoplasm progression (3%) were the only TEAEs grade ≥ 3 reported in ≥ 3 patients. 22 patients (21%) reported serious TEAEs. Four patients (4%) experienced fatal, non-drug-related TEAEs. Conclusions: Enzalutamide plus trastuzumab was well tolerated, and a subset of patients in this heavily pretreated population had durable disease control. Determination of biomarkers is needed to identify patients most likely to benefit from this combination.

Original languageEnglish
Pages (from-to)155-165
Number of pages11
JournalBreast Cancer Research and Treatment
Issue number1
StatePublished - May 2021


  • Androgen receptor
  • Enzalutamide
  • HER2
  • Human epidermal growth factor receptor 2
  • Metastatic breast cancer
  • Trastuzumab


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