Background: Everolimus (EVE), an orally bioavailable inhibitor of the mammalian target of rapamycin (mTOR), has shown clinical activity as monotherapy and in combination with endocrine therapy (ET) in hormone-receptor–positive (HR⁺; estrogen and/or progesterone receptors) advanced breast cancer (ABC). In a pivotal phase 3 trial in patients with HR⁺ ABC progressing on ET, EVE + exemestane (EXE) significantly prolonged median progression-free survival (PFS) vs EXE alone per local (7.8 vs 3.2 months; log-rank P<.0001) or central (11.0 months for EVE+EXE vs 4.1 months for EXE alone; log-rank P<.0001) assessment. Capecitabine, an orally administered fluoropyrimidine carbamate indicated as monotherapy in paclitaxel and/or anthracycline-refractory ABC, has shown clinical benefit in patients with HR⁺, human epidermal growth factor receptor 2-negative (HER2^-) ABC. The BOLERO-6 study in patients with HR⁺, HER2^- ABC progressing on prior anastrozole or letrozole will compare PFS following EVE+EXE combination therapy vs EVE or capecitabine monotherapy. Methods: In this multicenter, open-label, randomized, 3-arm, phase 2 study, 300 patients will be randomized to receive either EVE (10 mg/d) + EXE (25 mg/d) combination therapy, or EVE (10 mg/d) alone, or capecitabine (1,250 mg/m²twice daily for 14 d/3-wk cycle) alone, until disease progression. Patients will be stratified based on the presence of visceral disease. Key eligibility criteria include age ≥18 years, postmenopausal status; histologic or cytologic confirmation of estrogen-receptor–positive, HER2^- ABC; radiologic or objective evidence of recurrence or progression on prior aromatase inhibitors; Eastern Cooperative Oncology Group (ECOG) performance status ≤2. The primary endpoint is PFS with EVE+EXE vs EVE, based on local radiologic assessment (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1). The key secondary endpoint is PFS with EVE+EXE vs capecitabine. Other secondary endpoints include overall survival, objective response rate, clinical benefit rate, safety, quality of life, and patient satisfaction with treatment. Enrollment will start in Q1 2013. Estimated study completion in Q1 2015. Clinical trial information: NCT01783444.