Study Assessing the Efficacy and Safety of Alpelisib Plus Fulvestrant or Letrozole, Based on Prior Endocrine Therapy, in Patients With PIK3CA Mutant, HR+, HER2- Advanced Breast Cancer Who Have Progressed on or After Prior Treatments

Key Inclusion Criteria: Subjects eligible for inclusion in the Core Phase of the study fulfilled the following key inclusion criteria:

• Subject was an adult male or female ≥ 18 years of age.
• Subjects with histologically and/or cytologically confirmed diagnosis of estrogen receptor (ER)-positive and/or progesterone receptor (PgR)-positive breast cancer by local laboratory.
• Subjects with a confirmed human epidermal growth factor receptor-2 (HER2)-negative aBC.
• Subjects with gene encoding the p110alpha catalytic subunit of PI3K (phosphatidylinositol-3-kinase) (PIK3CA) mutation.
• In case of women, both premenopausal and postmenopausal subjects were allowed to be included in this study.
• Subjects with documented evidence of tumor progression on or after:

i. Cyclin-Dependent Kinase 4 and 6 inhibitor (CDK4/6i) treatment as last treatment regimen in Cohorts A and B.

ii. aromatase inhibitor (AI) treatment (either in adjuvant or metastatic setting) and received systemic chemotherapy or ET (monotherapy or combination except CDK4/6i + AI) as last treatment regimen in Cohort C. Upon completion of enrollment of Cohort B, subjects who received CDK4/6i + fulvestrant as immediate prior therapy were eligible for Cohort C.

iii. No more than 2 prior anticancer therapies for aBC. iv. Received no more than 1 prior regimen of chemotherapy for the treatment of advanced/metastatic disease was permitted.

v. Recovered to grade 1 or better from any adverse events (AEs) related to previous anticancer therapy prior to study entry (except alopecia or other toxicities not considered a safety risk for the subject at the investigator's discretion).

• Subjects with:

i. Measurable disease, i.e., at least 1 measurable lesion as per RECIST v1.1 criteria; or ii. If no measurable disease was present, at least 1 predominantly lytic bone lesion had to be present.

• Subjects with adequate bone marrow and coagulation function, liver function and renal function as shown by laboratory values.
• Subjects with Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 2.

Key exclusion criteria were:

• Subjects with a known hypersensitivity to alpelisib, fulvestrant, letrozole, goserelin, or leuprolide or to any of their excipients.
• Subjects with prior treatment with any PI3K inhibitor (PI3Ki).
• Subjects with central nervous system (CNS) involvement unless they met all of the following criteria:

i. At least 4 weeks from prior therapy completion (including radiation and/or surgery) to starting the study treatment, ii. Clinically stable CNS tumor at the time of screening untreated or without evidence of progressions for at least 4 weeks after treatment as determined by clinical examination and brain imaging (magnetic resonance imaging (MRI) or computed tomography (CT) during screening period and stable low dose of steroids for 2 weeks prior to initiating study treatment.

• Subjects with an established diagnosis of diabetes mellitus type I or uncontrolled type II.
• Any concurrent severe and/or uncontrolled medical conditions that would, in the investigator's judgment, contraindicate subject participation in the study (e.g., chronic active hepatitis, severe hepatic impairment, etc.).
• Subjects with a history of noncompliance to medical regimens.
• Subjects with impairment of gastrointestinal (GI) function or GI disease that could significantly alter the absorption of the study drugs based on investigator discretion.
• Subjects with documented pneumonitis/interstitial lung disease which was active and requiring treatment.
• Subjects concurrently using other anticancer therapy. All anticancer therapy had to be discontinued prior to Day 1 of study treatment.
• Subjects who had major surgery within 14 days prior to starting treatment with alpelisib, or did not recover from major side effects.
• Subjects with significant cardiac abnormalities.
• History of acute pancreatitis within 1 year of screening or past medical history of chronic pancreatiti