Activity and safety of enobosarm, a novel, oral, selective androgen receptor modulator, in androgen receptorpositive, oestrogen receptor-positive, and HER2-negative advanced breast cancer (Study G200802): a randomised, open-label, multicentre, multinational, parallel design, phase 2 trial

Background The androgen receptor is a tumour suppressor in oestrogen receptor -positive breast cancer. The activity and safety of enobosarm, an oral selective androgen receptor modulator, was evaluated in women with oestrogen receptor (ER) -positive, HER2-negative, and androgen receptor (AR) -positive disease. Methods Women who were postmenopausal (aged >= 18 years) with previously treated ER -positive, HER2-negative, locally advanced or metastatic breast cancer with an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled in a randomised, open-label, multicentre, multinational, parallel design, phase 2 trial done at 35 cancer treatment centres in nine countries. Participants were stratified on the setting of immediately preceding endocrine therapy and the presence of bone-only metastasis and randomly assigned (1:1) to 9 mg or 18 mg oral enobosarm daily using an interactive web response system. The primary endpoint was clinical benefit rate at 24 weeks in those with centrally confirmed AR -positive disease (ie, the evaluable population). This trial is registered with ClinicalTrials.gov (NCT02463032). Findings Between Sept 10, 2015, and Nov 28, 2017, 136 (79%) of 172 patients deemed eligible were randomly assigned to 9 mg (n=72) or 18 mg (n=64) oral enobosarm daily. Of these 136 patients, 102 (75%) patients formed the evaluable population (9 mg, n=50; 18 mg, n=52). The median age was 60 center dot 5 years (IQR 52 center dot 3-69 center dot 3) in the 9 mg group and 62 center dot 5 years (54 center dot 0-69 center dot 3) in the 18 mg group. The median follow-up was 7 center dot 5 months (IQR 2 center dot 9-14 center dot 1). At 24 weeks, 16 (32%, 95% CI 20-47) of 50 in the 9 mg group and 15 (29%, 17-43) of 52 in the 18 mg group had clinical benefit. Six (8%) of 75 patients who received 9 mg and ten (16%) of 61 patients who received 18 mg had grade 3 or grade 4 drugrelated adverse events, most frequently increased hepatic transaminases (three [4%] of 75 in the 9 mg group and two [3%] of 61 in the 18 mg group), hypercalcaemia (two [3%] and two [3%]), and fatigue (one [1%] and two [3%]). Four deaths (one in the 9 mg group and three in the 18 mg group) were deemed unrelated to the study drug. Interpretation Enobosarm has anti-tumour activity in patients with ER -positive, HER2-negative advanced breast cancer, showing that AR activation can result in clinical benefit, supporting further clinical investigation of selective AR activation strategies for the treatment of AR -positive, ER -positive, HER2-negative advanced breast cancer.