A Study Evaluating the Efficacy and Safety of Inavolisib Plus Fulvestrant Compared With Alpelisib Plus Fulvestrant in Participants With HR-Positive, HER2-Negative, PIK3CA Mutated, Locally Advanced or Metastatic Breast Cancer Post CDK4/6i and Endocrine Combination Therapy

Exclusion Criteria

• •Metaplastic breast cancer
• •Prior treatment in locally advanced or metastatic setting with any PI3K, AKT, or mTOR inhibitor or any agent whose mechanism of action is to inhibit the PI3K/-AKT/-mTOR pathway
• •Participant who relapsed with documented evidence of progression \> 12 months from completion of adjuvant CDK4/6i based therapy with no treatment for metastatic disease
• •Type 2 diabetes requiring ongoing systemic treatment at the time of study entry; or any history of Type 1 diabetes
• •Inability or unwillingness to swallow pills
• •Malabsorption syndrome or other condition that would interfere with enteral absorption
• •Any history of leptomeningeal disease or carcinomatous meningitis
• •Pregnant, lactating, or breastfeeding, or intending to become pregnant during the study or at least 60 days after the final dose of study treatment
• •Known active, systemic infection at study enrollment, or any major episode of infection requiring treatment with intravenous antibiotics or hospitalization within 7 days prior to Day 1 of Cycle 1
• •Investigational drug(s) within 4 weeks before randomization or within 5 half-lives of the investigational drug(s), whichever is longer
• •Allergy or hypersensitivity to components or excipients of the inavolisib, fulvestrant, or alpelisib formulations
• •History of severe cutaneous reactions like Stevens-Johnson Syndrome, Erythema Multiforme, Toxic Epidermal Necrolysis, or Drug Reaction with Eosinphilia and Systemic Symptoms
• •Pregnant, lactating, or breastfeeding, or intending to become pregnant during the substudy or within 2 weeks after the final dose of inavolisib and within 2 years after the final dose of fulvestrant, whichever is longer
• •Known active, systemic infection at study enrollment, or any major episode of infection requiring treatment with intravenous antibiotics or hospitalization within 7 days prior to Day -4 of Cycle 1
• •Investigational drug(s) within 4 weeks prior to Day -4 or within 5 half-lives of the investigational drug(s), whichever is longer
• •Allergy or hypersensitivity to components or excipients of the inavolisib, fulvestrant formulations
• •Treatment with mild, moderate, or strong inducers of CYP2B6, CYP3A4, and/or CYP2C19 (including St. John's Wort) within 14 days or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study treatment on Day -4 until after the final PK sample has been collected on Day 15 of Cycle 1
• •Treatment with mild, moderate, or strong inhibitors of CYP2B6, CYP3A4, and/or CYP2C19 (including grapefruit juice or supplements) within 14 days or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study treatment on Day -4 until after the final PK sample has been collected on Day 15 of Cycle 1