The study is a nationwide, multicenter single-arm phase 2 study. The current phase 2 study investigates the efficacy of the combination of fulvestrant and alpelisib directly after progression on fulvestrant (either in first or second line, with or without previous use of CDK4/6-inhibitor) in patients with HR+ HER2- advanced breast cancer with PIK3CA mutated tumors.

All eligible patients must have progressive disease on fulvestrant as latest treatment line.

Previous treatment with a CDK4/6 inhibitor in first or second line is obligatory. After progressive disease is confirmed, it is important to continue fulvestrant (without CDK4/6 inhibition) during the screening period awaiting study enrollment.

After study enrollment all participants will be treated with alpelisib and fulvestrant beyond progression. Follow-up time will be until progression or death or until a different oncolytic treatment has started (in case no progressive disease during previous fulvestrant and alpelisib treatment has been documented).

Should participants discontinue due to reasons other than progression or death (e.g. toxicity), then they should still be evaluated for disease progression every 8 weeks as per protocol until progression, unless they do not wish to proceed with these screenings, or receive a different oncolytic treatment.

Inclusion Criteria:

• Adult women and men (≥ 18 years of age) with proven diagnosis of adenocarcino-ma of the breast withlocoregional recurrent or metastatic disease not amenable to resection or radiation therapy with curative intent andfor whom chemotherapy is not clinically indicated
• Estrogen receptor (ER) expression >10% and/or progesterone receptor (PR) expression >10% breast cancerbased on local la-boratory results. Tumor must be HER2- as defined by ASCO-CAP guidelines
• Patients must have progressed on fulvestrant as a preceding treatment line (as first or second line therapy)
• Previous treatment with a CDK4/6 inhibitor in the advanced setting
• The presence of an activating PIK3CA mutation
• Evaluable disease* as defined per RECIST v.1.1
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2

Exclusion Criteria:

• Patients with advanced, symptomatic, visceral spread, who are at risk of life-threatening complications in theshort term
• Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningealdisease as indicated by clinical symptoms, cerebral edema, and/or progressive growth
• Prior treatment with a PI3K /AKT/mTOR inhibitor
• Type 1 diabetes or uncontrolled type 2 diabetes (Hba1C > 68 mmol/mol)
• Clinically significant, uncontrolled heart disease and/or recent cardiac events