Background: The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is frequently activated in hormone receptor-positive (HR+) BC and is associated with resistance to endocrine therapy. The combination of the PI3Kα-specific inhibitor alpelisib (BYL719) and fulvestrant showed promising activity in a phase I study of HR+/human epidermal growth factor 2-negative (HER2–) BC, with the strongest treatment benefit in patients (pts) with PIK3CA-mutant tumors (Janku et al. SABCS 2014, Abstract PD5-5). Further data are required to confirm these observations. Methods: In the phase III, randomized, double-blind SOLAR-1 study (NCT02437318), men and postmenopausal women with HR+/HER2– advanced BC are randomized (1:1) to alpelisib or placebo (300 mg once daily) + fulvestrant (500 mg intramuscularly on Days 1 and 15 of Cycle 1 [28 days], and Day 1 of Cycles ≥ 2) until disease progression or discontinuation for other reason. Pts are assigned to 2 cohorts (PIK3CAmutant vs non-mutant status in tumor tissue) prior to randomization, and stratified by presence of liver and/or lung metastases, and prior CDK4/6 inhibitor treatment. Key inclusion criteria include disease progression/recurrence on or after prior aromatase inhibitor therapy, and Eastern Cooperative Oncology Group performance status ≤ 1. Exclusion criteria include symptomatic visceral disease, or disease burden precluding endocrine therapy, and prior therapy with fulvestrant, chemotherapy, ([neo] adjuvant permitted) or PI3K/mTOR/AKT inhibitors. The primary and key secondary endpoints are progression-free survival (PFS; local assessment, RECIST v1.1) and overall survival, respectively. Other secondary endpoints include PFS, as per blinded independent review, PFS based on PIK3CA status in circulating tumor DNA, overall response rate, clinical benefit rate, safety, pharmacokinetics, and global health status/quality of life. Analysis of the primary endpoint will be performed with a stratified log-rank test (95% confidence interval). Global recruitment of the planned 820 pts is ongoing. Clinical trial information: NCT02437318