Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Oncology, Androgen receptor, Enzalutamide, HER2, Human epidermal growth factor receptor 2, Metastatic breast cancer, Trastuzumab, PHYSICIANS CHOICE, OPEN-LABEL, EMTANSINE, PERTUZUMAB, EXPRESSION, DOCETAXEL, TH3RESA, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Benzamides, Breast Neoplasms, Female, Humans, Middle Aged, Nitriles, Phenylthiohydantoin, Receptor, ErbB-2, Receptors, Androgen, Receptor, erbB-2, 1103 Clinical Sciences, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, 3202 Clinical sciences, 3211 Oncology and carcinogenesis

Abstract:

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. CLINICALTRIALS. GOV NUMBER: NCT02091960.