Background: AA plus P treatment in men with metastatic castration-resistant prostate cancer has demonstrated a survival advantage over P alone. Circulating adrenal steroids including DHEA and DHEA-sulfate can stimulate proliferation of breast cancer cell lines in a low-estrogen environment. Thus, it is hypothesized that depletion of adrenal androgens as well as estrogens by AA, a potent CYP17 inhibitor, inhibits tumor growth by disruption of ER-dependent growth signaling. In a previously reported phase I study of AA in patients (pts) with breast cancer (Basu, ASCO 2011), 2/21 pts who were ER+ were on study for ≥ 11 months; 1 had a confirmed PR and continued on treatment > 14 months. Mechanism-based adverse event of grade 3/4 hypokalemia occurred in 4 pts and was managed with potassium supplementation and low dose corticosteroids. Methods: In the current study, 300 postmenopausal women with ER+ Her2- MBC progressing after letrozole or anastrozole are randomized to either AA 1000 mg + P 5 mg daily or AA + P + E 25 mg daily vs E. Disease must have been sensitive to a non-steroidal aromatase inhibitor (AI) prior to study entry. Subjects are stratified by number of prior therapies and by AI use in adjuvant or metastatic setting. Central review of tissue is required prior to randomization. Gene expression profiling (GEP) (AR, ER, PR, Her2, CYP17, Ki-67, CYP 19, and 3-β-HSD) will be performed on FFPE archival tissue. Pre- and post-treatment circulating tumor cells and fresh tumor biopsies will also be obtained for GEP in a subset of pts. Primary endpoint is PFS. Secondary endpoints are OS, ORR, patient reported outcomes, changes in endocrine markers, and PK characterization of AA and E. Subjects randomized to E may crossover to AA + P at time of disease progression. One interim analysis is scheduled after 50% of PFS events have occurred. After review of interim data, the Data Review Committee will make recommendations regarding study continuation. 23pts from 45 active sites have been randomized as of January 24,2012. (ClinicalTrials.gov Identifier: NCT01381874)