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

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.

Keywords: Androgen receptor; Enzalutamide; HER2; Human epidermal growth factor receptor 2; Metastatic breast cancer; Trastuzumab.

Conflict of interest statement

AW reports a role as study investigator with Astellas during the conduct of this study, consulting/advisory roles with, and research funding from, AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pfizer, and Roche outside the submitted work, consulting/advisory roles with Athenex, Coleman Research, Gerson Lehrman, and Guidepoint outside the submitted work, director of Andrew Wardley Limited and the Manchester Cancer Academy, honoraria from AstraZeneca, Athenex, Daiichi Sankyo, Lilly, MSD, Novartis, Pfizer, and Roche, speaker’s bureau fees from AstraZeneca, Lilly, Novartis, Pfizer, and Roche, travel expenses from Daiichi Sankyo, MSD, and Roche, and research funding from Seattle Genetics. JC reports a role as study investigator with Astellas during the conduct of this study and consulting/advisory roles with AstraZeneca, Biothera, Celgene, Cellestia, Eisai, Novartis, Pfizer, and Roche outside the submitted work. LP reports a consulting/advisory role with, and research funding from, Astellas and Medivation during the conduct of this study, a consulting/advisory role with Lilly outside the submitted work, consulting/advisory roles and research funding from Novartis, Pfizer, and Roche outside the submitted work and research funding from GlaxoSmithKline, Merck, and Odonate outside the submitted work. KM, AJC, ICT, MH, RY, RB, LH, SC, PG, PN, and SR report a role as study investigator with Astellas during the conduct of this study. HSR received research funding from Astellas during the conduct of this study. J Steinberg and J Sugg are full-time employees of Astellas. VA reports a role as study investigator with Astellas during the conduct of this study, research funding from Genentech outside the submitted work, and consulting/advisory roles for AbbVie, Daiichi Sankyo, Eisai, and Novartis outside the submitted work. DC reports a role as study investigator with Astellas during the conduct of this study and consulting/advisory roles for Novartis, Pfizer, Roche, and Syntheon outside the submitted work. GSW reports a consulting/advisory role with, and research funding from, Astellas during the conduct of the study and research funding from AbbVie, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, G1 Therapeutics, Genentech, Incyte, Janssen, MacroGenics, Medivation, Merrimack, Novartis, Pfizer, and Tesaro outside the submitted work and stock holdings from Puma and Roche outside the submitted work. M-PG reports a role as study investigator with Astellas during the conduct of this study and consulting/advisory roles with Lilly, Novartis, Pfizer, and Roche outside the submitted work. IEK reports research funding from Pfizer during the conduct of the study, a consulting/advisory role with Astellas during the conduct of this study, a consulting/advisory role with, and research funding from, Genentech/Roche outside the submitted work, and consulting/advisory roles with Context, Daiichi Sankyo, MacroGenics, Novartis, and Taiho outside the submitted work.

Figures

Fig. 1

a Kaplan–Meier curve of progression-free survivala in the full analysis set; b swimmer plot of response to treatment for individual patients aProgression-free survival is defined as the time from the date of first dose of enzalutamide until the date of disease progression per RECIST v1.1 or death from any cause on study (death within 168 days after treatment discontinuation), whichever occurred first CI confidence interval, RECIST Response Evaluation Criteria in Solid Tumors