Background:Androgen receptor (AR) expression has been observed in up to 77% of human epidermal growth factor receptor 2–positive (HER2+) breast cancer (BC).References:1 Enzalutamide (ENZA) is a potent AR inhibitor approved for patients (pts) with metastatic castration-resistant prostate cancer. In vitro, ENZA enhances antitumor activity of trastuzumab in HER2+ AR+ cell lines and inhibits proliferation in trastuzumab-resistant HER2+ cell lines.2

Methods:Pts with metastatic or locally advanced BC that was HER2+ AR+ by local or central laboratory assessment were enrolled in a single-arm, Simon 2-stage phase 2 study (NCT02091960). Key eligibility criteria included availability of a tissue sample, presence of measurable or evaluable disease per RECIST v1.1, progression on prior trastuzumab and ≥1 prior line of anti-HER2 therapy as the most recent regimen. Brain metastases and history of seizure were exclusionary. Evaluable pts were those with centrally confirmed nuclear AR expression≥10% by immunohistochemistry who received ≥1 dose of ENZA and had ≥1 postbaseline tumor assessment. Pts received ENZA 160 mg daily and trastuzumab 6 mg/kg every 21 days until disease progression. The primary objective was clinical benefit rate at 24 weeks (CBR24), defined as complete or partial response (CR or PR) or stable disease (SD) for ≥24 weeks in evaluable pts. Additional endpoints included safety and progression-free survival (PFS). CBR24 in ≥3 of 21 evaluable pts was required to continue to stage 2 and enrollment of up to 66 evaluable pts total. This design yields a 1-sided type 1 error of 5% and 90% power when the true response is 25%.

Results:Here we present results from stage 1 (data cutoff: Mar 23, 2016), with 22 evaluable pts enrolled (pts 21 and 22 enrolled simultaneously); 18 had received ≥4 prior lines of therapy. Median duration of ENZA exposure was 144 days (range, 22-495), mean number of complete trastuzumab infusions was 6.5. CBR24 was 27.3% (95% confidence interval [CI], 10.7-50.2); 2 confirmed PR and 4 SD ≥24 weeks. Median PFS was 108 days (95% CI, 56-144). All pts experienced ≥1 adverse event (AE) any grade; 5 pts experienced AEs grade ≥3. ENZA-related AEs were reported in 16 pts (72.7%), the most common (in ≥10% of pts) were fatigue (22.7%), nausea (18.2%), diarrhea (13.6%) and arthralgia (13.6%). Serious AEs were reported in 6 pts (27.3%; 2 each of infection and back pain, 1 each of abdominal pain, nausea, vomiting, pyrexia, urinary retention and pulmonary edema). Two pts discontinued due to drug-related AEs: 1 related to both drugs, 1 related to trastuzumab. One on-study death from pulmonary edema was reported, which was not considered related to either drug.

Conclusion:Stage 1 met its primary objective. No new safety signals were identified, and the safety profile in this study was similar to that in men with prostate cancer and women with other BC subtypes treated with ENZA. These results are encouraging for a heavily pretreated population with advanced HER2+ AR+ BC. Enrollment in stage 2 continues with the combination of ENZA and trastuzumab.

1. Micello D et al. Virchows Arch. 2010;457:467-476.

2. Richer J. Presented at AACR Advances in Breast Cancer, San Diego, CA, 2013.

Citation Format: Krop I, Cortes J, Miller K, Huizing MT, Provencher L, Gianni L, Chan S, Trudeau M, Steinberg J, Sugg J, Liosatos M, Paton VE, Peterson A, Wardley A. A single-arm phase 2 study to assess clinical activity, efficacy and safety of enzalutamide with trastuzumab in HER2+ AR+ metastatic or locally advanced breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-08.