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

Inclusion Criteria:

• If pre/perimenopausal women and men treatment with luteinizing hormone-releasinghormone (LHRH) agonist therapy beginning at least 2 weeks prior to Day 1 of Cycle 1

• Histologically or cytologically confirmed adenocarcinoma of the breast that islocally advanced or metastatic and is not amenable to surgical or radiation therapywith curative intent

• Documented HR +/ HER2- tumor according to American Society of ClinicalOncology/College of American Pathologists (ASCO/CAP) guidelines

• Confirmation of biomarker eligibility: detection of specified mutation(s) of PIK3CAvia specified test

• Disease progression after or during treatment with a combination of CDK4/6i andendocrine therapy: <= 2 prior lines of systemic therapy in mBC setting; CDK4/6ibased therapy does not need to be the last one received prior study entry; one lineof chemotherapy in mBC setting allowed

• Measurable or evaluable disease per Response Evaluation Criteria in Solid Tumorsversion 1.1 (RECIST v1.1)

• Participants for whom endocrine-based therapy is recommended and treatment withcytotoxic chemotherapy is not indicated at time of entry into the study, as pernational or local treatment guidelines

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2

• Life expectancy of > 6 months

• Adequate hematologic and organ function prior to initiation of study treatment

Exclusion Criteria:

• Metaplastic breast cancer

• Prior treatment in locally advanced or metastatic setting with any PI3K, AKT, ormTOR inhibitor or any agent whose mechanism of action is to inhibit thePI3K/-AKT/-mTOR pathway

• Participant who relapsed with documented evidence of progression > 12 months fromcompletion of adjuvant CDK4/6i based therapy with no treatment for metastaticdisease

• Pregnant, lactating, or breastfeeding, or intending to become pregnant during thestudy or at least 60 days after the final dose of study treatment

• Type 2 diabetes requiring ongoing systemic treatment at the time of study entry; orany history of Type 1 diabetes

• Inability or unwillingness to swallow pills

• Malabsorption syndrome or other condition that would interfere with enteralabsorption

• Any history of leptomeningeal disease or carcinomatous meningitis

• Known and untreated, or active central nervous system (CNS) metastases. Participantswith a history of treated CNS metastases are eligible if they meet specific certaincriteria

• Known active, systemic infection at study enrollment, or any major episode ofinfection requiring treatment with intravenous antibiotics or hospitalization within 7 days prior to Day 1 of Cycle 1

• Any concurrent ocular or intraocular condition that, in the opinion of theinvestigator, would require medical or surgical intervention during the study periodto prevent or treat vision loss that might result from that condition

• Active inflammatory or infectious conditions in either eye or history of idiopathicor autoimmune-associated uveitis in either eye

• Requirement for daily supplemental oxygen

• Symptomatic active lung disease, including pneumonitis

• History of or active inflammatory bowel disease

• Any active bowel inflammation

• Clinically significant and active liver disease, including severe liver impairment,viral or other hepatitis, current alcohol abuse, or cirrhosis

• Participants with known human immunodeficiency virus infection that meet specificcriteria

• Investigational drug(s) within 4 weeks before randomization or within 5 half-livesof the investigational drug(s), whichever is longer

• History of other malignancy within 5 years prior to screening, except for cancerswith very low risk of recurrence

• Chronic therapy of >= 10 mg of prednisone per day or an equivalent dose of otheranti-inflammatory corticosteroids or immunosuppressants for a chronic disease

• Allergy or hypersensitivity to components or excipients of the inavolisib,fulvestrant, or alpelisib formulations

• History of severe cutaneous reactions like Stevens-Johnson Syndrome, ErythemaMultiforme, Toxic Epidermal Necrolysis, or Drug Reaction with Eosinphilia andSystemic Symptoms

• Active ongoing osteonecrosis of the jaw