Study to Assess the Efficacy and Safety of Alpelisib Plus Fulvestrant in Participants With HR-postitive (HR+), HER2-negative, Advanced Breast Cancer After Treatment With a CDK4/6 Inhibitor and an Aromatase Inhibitor.

The purpose of this study is to complement Study CBYL719C2301 (SOLAR-1) and obtain more comprehensive data on the efficacy and safety of alpelisib (BYL719) in combination with fulvestrant compared with placebo plus fulvestrant in men or postmenopausal women with HR-positive, HER2-negative advanced breast cancer with a PIK3CA mutation who progressed or relapsed on or after treatment with an AI plus a CDK4/6 inhibitor.

This is a Phase III, randomized, double-blind, placebo-controlled, international, multi-center trial. Approximately 234 men and postmenopausal women will be randomized to either alpelisib plus fulvestrant or alpelisib-matching placebo plus fulvestrant. Randomization will follow a 1:1 randomization ratio and be stratified by presence of lung and/or liver metastases (yes vs. no) and setting at last prior CDK4/6 inhibitor therapy (adjuvant vs metastatic).

Study treatment with alpelisib plus fulvestrant or alpelisib-matching placebo plus fulvestrant will be initiated on Cycle 1 Day 1, and will continue until disease progression per RECIST v1.1 as per BIRC assessment, start of new antineoplastic therapy, death, lost to follow-up, or withdrawal of consent. A cycle is defined as 28 days.

Participants randomized to the alpelisib-matching placebo plus fulvestrant arm who have disease progression per RECIST v1.1 as assessed by BIRC will have the option to crossover to be treated with alpelisib plus fulvestrant.

Unblinding a single participant at a site will be permitted after disease progression confirmed by BIRC after discussion with the Novartis team to determine eligibility for cross-over to treatment with alpelisib plus fulvestrant.

Eligibility Criteria:
Inclusion Criteria:

* Participant is an adult ≥ 18 years old at the time of informed consent and has signed informed consent before any trial related activities and according to local guidelines.
* If female, then the participant must be in postmenopausal status. Postmenopausal status is defined either by: prior bilateral oophorectomy, age ≥60 or age \<60 and amenorrheic for 12 or more months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression and follicle-stimulating hormone (FSH) and estradiol in the postmenopausal range per local normal range.
* Participant has a histologically and/or cytologically confirmed diagnosis of ER+ and/or PgR+ breast cancer by local laboratory.
* Participant has HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (Fluorescent in situ hybridization (FISH), Chromogenic in situ hybridization (CISH), or Silver-enhanced in situ hybridization (SISH)) test is required by local laboratory testing.
* Participant has at least one measurable lesion as per RECIST v1.1 criteria as assessed by Investigator (a lesion at a previously irradiated site may only be counted as a target lesion if there is clear sign of progression since the irradiation).
* Participant has recurrence or progression of disease during or after combined AI (i.e. letrozole, anastrozole, exemestane) and CDK4/6 inhibitor therapy. The combined AI and CDK4/6 inhibitor therapy does not need to be the latest treatment regimen (including adjuvant setting).
* Participant has received ≤2 prior lines of systemic therapies overall in the metastatic setting, of which a maximum of 1 line of prior treatment with chemotherapy (except for neoadjuvant/ adjuvant chemotherapy).
* Participant must show the presence of a PIK3CA mutation(s) determined in tumor tissue prior ro enrollment either by a Novartis designated laboratory or in tumor tissue or plasma ctDNA by a local laboratory using a Food and Drug Administration (FDA)-approved PIK3CA Companion Diagnostics (CDx) test for alpelisib or the CE-IVD QIAGEN Therascreen® PIK3CA RGQ PCR test.

Exclusion Criteria:

* Participant with symptomatic visceral disease that makes the participant ineligible for endocrine therapy (ET) per the investigator's best judgment.
* Participant who relapsed with documented evidence of progression more than 12 months from completion of (neo)adjuvant endocrine/endocrine-based therapy with no treatment for metastatic disease
* Participant has received prior treatment with fulvestrant, any oral selective estrogen receptor degrader (SERDs), any Phosphatidylinositol-3-Kinase (PI3K), mammalian Target of Rapamycin (mTOR) or Protein Kinase B (AKT) inhibitor

Other Inclusion and Exclusion Criteria do apply