Background: Inhibition of the cyclin D–cyclin dependent kinase (CDK)4/6–retinoblastoma pathway may overcome ET resistance and enhance the efficacy of existing ET regimens in HR+, HER2– aBC. Combination of the CDK4/6 inhibitor ribociclib (LEE) with fulvestrant (FUL) has demonstrated potent tumor regressions in preclinical HR+ breast cancer (BC) models (O’Brien et al. Cancer Res 2014;74:Abstr 4756). Methods: In this phase III, double-blind study (NCT02422615), postmenopausal patients with HR+, HER2– aBC (N≈660) will be randomized 2:1 to oral LEE (600 mg QD on Days 1–21 of each 28-day cycle) + FUL (500 mg intramuscularly on Days 1 and 15 of Cycle 1 and Day 1 of each cycle thereafter; Arm A) or placebo + FUL (Arm B). Randomization is stratified by presence of lung or liver metastases and prior ET. Patients may have newly diagnosed aBC that is treatment-naïve, relapsed BC that has progressed at any time during/after (neo)adjuvant ET with no treatment for metastatic disease, relapsed BC that has progressed > 12 months after adjuvant ET and then subsequently progressed after 1 line of ET for metastatic disease, or newly diagnosed aBC that has progressed after 1 line of ET. Patients must have measurable disease or ≥ 1 predominantly lytic bone lesion, and an Eastern Cooperative Oncology Group performance status (ECOG PS) of ≤ 1. Prior chemotherapy (except for [neo]adjuvant chemotherapy), FUL, or any CDK4/6 inhibitor is prohibited. Tumor assessments occur every 8 weeks for the first 18 months and every 12 weeks thereafter until disease progression or study discontinuation. The primary endpoint is progression-free survival (PFS; local, RECIST v1.1). Secondary endpoints include overall survival, PFS (central, RECIST 1.1), overall response rate, clinical benefit rate, time to response, duration of response, safety and tolerability, time to deterioration of ECOG PS, patient-reported outcomes, and pharmacokinetics. Exploratory endpoints include molecular alterations in tumor biopsy and circulating tumor DNA. Clinical trial information: NCT02422615