Background: The androgen receptor (AR) is the most highly expressed steroid receptor in breast cancer (BC) with 75-95% of estrogen receptor positive (ER+) and 50% of ER negative BCs expressing AR. Prior studies have shown that women with metastatic BC (MBC) who are progressing on tamoxifen subsequently respond to non-tissue-selective, synthetic androgens with overall response rates of 20-60%. Unfortunately steroidal androgens have unwanted virilizing effects which limit clinical use. Enobosarm, a nonsteroidal, tissue-selective, AR modulator (SARM), provides a novel targeted approach to exploit the therapeutic benefits of AR activation without virilization or estrogenic effects. Methods: A proof of concept, phase II study is examining efficacy and safety of enobosarm 9mg daily in 22 postmenopausal women with ER+ MBC who previously responded to adjuvant and/or salvage endocrine therapy. Treatment continues until disease progression (PD). Primary endpoint is clinical benefit response (CBR) by 6 months (m) defined as patients (pts) having a complete response (CR), partial response (PR), or stable disease (SD). CBR will be correlated with AR status of metastatic tumor biopsy. Serum prostate specific antigen (PSA) will be evaluated as a biomarker of AR activity. Results: Pt demographics: mean age 63.7 years, mean time from diagnosis 11 years, 68% prior chemo, 94% (15/16) AR+. After a median f/u of 85 days (d) (range 84-209d), preliminary results of 16 pts: 8 SD as best response, median duration 4.5m; 9 PD after a median 84d. Among pts who reached 6m, 3 are AR+ with SD and increased PSA. 7 have yet to reach 6m and no CR or PR has been observed. Enobosarm is well-tolerated, with no drug related serious adverse events. Conclusions: Enobosarm is well tolerated and demonstrates promise as a novel targeted therapy for AR+ MBC. The primary endpoint has been achieved, with 3/15 AR+ pts meeting statistical threshold for success. Serum PSA appears to be a surrogate marker for AR activity and disease response. Final analysis is due in June 2014. Clinical trial information: NCT01616758.