Background: Targeting the androgen receptor (AR) may be the next important endocrine therapy for advanced breast cancer. The AR has been demonstrated to be a tumor suppressor when activated. Enobosarm is an oral selective AR targeting agonist that activates the AR in breast cancer. Preclinical studies in CDK4/6 inhibitor resistant PDX models demonstrated combinatorial synergistic activity of enobosarm plus CDK 4/6 inhibitors. An open-label, Phase 2 study, was conducted in 136 women with heavily pretreated ER+ HER2- metastatic breast cancer that were randomized to oral daily enobosarm at a dose of 9 or 18 mg. The efficacy evaluable (EE) group were patients that were AR positive (> 10% AR nuclear staining). In the EE population with measurable disease at baseline, 10 patients had received prior endocrine therapy + a CDK 4/6 inhibitor. Subsequent treatment with enobosarm resulted in a clinical benefit rate of 50% and the best overall response rate (ORR) was 30% (2CRs and 1 PR). Of the 10 patients, 7 had AR nuclear staining ≥40%. None of the patients with AR nuclear staining < 40% responded to enobosarm. Although a small subset of the study, it appears that enobosarm has activity in patients who had ≥40% AR staining and who had progressed on standard endocrine therapy with a CDK 4/6 inhibitor. Overall, treatment with enobosarm was well tolerated with significant positive effects on quality-of-life measurements. Methods: The ENABLAR-2 trial is an ongoing Phase 3, randomized, open-label, efficacy and safety study in patients with AR+ ER+ HER2- MBC with AR nuclear staining of ≥40%, who have progressed after one line of systemic therapy comprising estrogen blocking agent and palbociclib. The planned sample size is 186 patients randomized 1:1 to enobosarm + abemaciclib OR fulvestrant if the first line of therapy for MBC was a non-steroidal AI plus palbociclib, until disease progression, toxicity, or loss of clinical benefit. If first line therapy for metastatic breast cancer was fulvestrant plus palbociclib, then the patient will be randomized 1:1 to either enobosarm + abemaciclib OR an AI. Randomization will be stratified by AR% nuclear staining, ≥60% versus < 60%, as well as by estrogen blocking agent such that each cohort will have the same number of subjects previously receiving fulvestrant + palbociclib in first line therapy. The key objectives are to determine the safety and efficacy of enobosarm and abemaciclib combination versus an alternative estrogen blocking agent with the primary endpoint of PFS. Secondary endpoints include ORR, duration of response, overall survival, change from baseline in Short Physical Performance Battery (SPPB), change in EORTC Quality of Life Questionnaire (EORTC-QLQ) and change in body composition as measured by DEXA. Clinical trial information: NCT05065411.