Background: Endocrine therapy (ET) is the standard of care for postmenopausal women with hormone receptor positive (HR⁺; typically, estrogen receptor [ER] positive) advanced breast cancer (ABC). However, women with HR⁺ ABC can progress while on ET. Crosstalk between ER signaling and the mammalian target of rapamycin (mTOR) pathway enhances tumor progression. Co-targeting these signaling pathways with the combination of everolimus (EVE), an orally bioavailable mTOR inhibitor, and ET (letrozole [LET] or tamoxifen) has been shown to significantly improve clinical outcomes in the neoadjuvant setting and in patients with HR⁺ ABC progressing on/after nonsteroidal aromatase inhibitors. In a pivotal phase 3 trial in women with HR⁺ ABC progressing on ET, EVE + exemestane (EXE) prolonged progression-free survival (PFS; local/central assessment: 7.8/11.0 mo [P < .0001]) compared with EXE alone (3.2/4.1 mo [P < .0001]). This study (BOLERO-4) will extend previous investigations to evaluate the safety and effectiveness of EVE+LET as first-line therapy in ER⁺ HER2^– metastatic BC (mBC), and the potential benefits of continuing EVE+ET beyond initial progression. Methods: In this multicenter, open-label, international, single-arm, phase 2 study, 200 postmenopausal women age ≥18 y with ER⁺ HER2^– mBC or locally ABC without prior therapy for advanced disease will receive EVE (10 mg/d) + LET (2.5 mg/d) until first disease progression. Upon disease progression, patients continuing in the trial will receive EVE+EXE (25 mg/d) until further disease progression. Patients who discontinue therapy in the first-line metastatic setting because of unacceptable toxicity will not be offered second-line therapy. The primary endpoint is PFS with EVE+LET in the first-line setting. Secondary endpoints include PFS in the second-line setting, overall survival, objective response rate, clinical benefit rate, safety, and the efficacy of oral dexamethasone solution to reduce the severity and/or duration of stomatitis using Oral Stomatitis Daily Questionnaire (OSDQ). Accrual across Europe, Asia, and the Americas begins Q1 2013. Estimated study completion is Q4 2015. Clinical trial information: NCT01698918.