Background: The PI3K pathway is frequently altered in hormone receptor positive (HR+) breast cancer (BC) and 40% of patients have PIK3CA mutations. The PI3Kα-specific inihibitor, Alpelisib, is FDA-approved in combination with fulvestrant for treatment of patients with HR+ HER2 negative (HER2-) PIK3CA mutated, advanced BC following progression on or after a non-fulvestrant endocrine therapy (ET) based regimen. We hypothesized that the benefit seen in the seminal SOLAR-1 study that compared alpelisib plus fulvestrant to placebo with fulvestrant, was due to the addition of alpelisib, rather than the change to fulvestrant, such that addition of alpelisib to ongoing ET at time of progression could lead to similar outcomes. Unlike SOLAR-1, our study continues prior ET at time of progression and requires prior CDK4/6 inhibitor therapy. Methods: We designed a phase II single arm study that tests the efficacy of adding alpelisib to ongoing ET at time of progression on ET. The primary objective is to estimate the progression–free survival (PFS) of alpelisib with continued ET (aromatase inhibitor or fulvestrant) following progression in patients with HR+ HER2-, PIK3CA mutant advanced BC. Secondary objectives are to estimate overall response rate, clinical benefit rate, duration of response, overall survival and safety/tolerability. Correlative studies include evaluation of PIK3CA activity in circulating tumor cell liquid biopsy at baseline, C1D15, C2D1, C4D1 and at progression and correlation with primary and secondary objectives. Eligibility: Men and postmenopausal female patients with histologically confirmed ER and/or PR ≥1%, HER2- metastatic or unresectable BC with PIK3CA mutation and either measurable disease or at least one predominantly lytic bone lesion. No more than two lines of ET and no chemotherapy in the metastatic setting is allowed and patients must have received treatment with a CDK4/6 inhibitor and have progressed on ET as last line of therapy. Exclusions include prior PIK3CA, mTOR or AKT inhibitors in the metastatic setting, symptomatic active CNS metastases or CNS metastases that require therapeutic interventions. Statistical Analysis. The sample size calculation is based on testing the null hypothesis that the median PFS is at most 5 months against the alternative that the PFS is greater than 5 months (based on data from SOLAR-1). An increase of at least 3 months in the median PFS will be considered a sufficient efficacy signal. A sample size of 44 subjects is required to detect an anticipated increase in the median PFS from 5 to 8 months at the one-sided 0.10 significance level with 90% power, assuming a uniform accrual period of 24 months. Clinical trial information: NCT04762979.