Background: Exemestane (EXE) is a commonly used aromatase inhibitor (AI) in patients (pts) with advanced ER/PgR+ breast cancer (BC). The androgen receptor (AR), expressed in the majority of ER/PgR+ BC, is believed to play a role in resistance to AI therapy. Enzalutamide (ENZA), a potent inhibitor of AR signaling, induces CYP3A4, an enzyme involved in the metabolism of EXE. We previously reported that the addition of ENZA (160 mg/day) to EXE 25 mg/day resulted in ~40% reduction in EXE exposure. The US product label recommends doubling the dose of EXE when administered in combination with a potent CYP3A4 inducer. This trial investigates daily ENZA 160 mg + EXE 50 mg. Methods: Postmenopausal pts with ER/PgR+ advanced BC received ≥14 days of EXE 50 mg/day prior to initiating ENZA 160 mg/day on Day 1 (NCT01597193). Prior EXE and non-measurable disease was allowed. Blood sampling occurred on Day -1 (no ENZA) and on Day 29 (+ ENZA) to assess PK interactions and effects on circulating estrogens (estradiol and estrone). Available tumor tissue was analyzed centrally for AR expression although AR+ disease was not required. Response assessments (RECIST 1.1) were performed approximately every 3 months. Results: As of 11 Dec 2013, data were available for 18 of the 24 pts enrolled. Median age/ECOG was 66/0; median number of prior hormonal therapies was 2.5. Common (>10%) treatment-related adverse events (AEs) included nausea, vomiting and fatigue. No treatment-related serious AEs or AEs ≥ Grade 3 have been reported. Preliminary data indicate that ENZA + EXE 50 mg achieves similar EXE exposure to EXE 25 mg alone (AUC=127±70 vs. 131±64 ng.h/mL) and maintains estrogen suppression for the majority of pts. Full data on PK, tolerability, estrogen levels and anti-tumor activity will be presented. Conclusions: To date, the combination of daily ENZA 160 mg + EXE 50 mg has been well tolerated. Doubling the dose of EXE appears to restore EXE exposure thereby maintaining the suppression of estrogens. An ongoing randomized double-blind, placebo-controlled phase 2 trial in ER/PgR+ advanced BC will determine if the combination of daily ENZA 160 mg + EXE 50 mg is more active than EXE 25 mg alone. Clinical trial information: NCT01597193.