A Study Evaluating the Efficacy and Safety of Inavolisib Plus CDK4/6 Inhibitor and Letrozole vs Placebo + CDK4/6i and Letrozole in Participants With Endocrine-Sensitive PIK3CA-Mutated, Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer

Inclusion Criteria:

• Women or men with histologically or cytologically confirmed carcinoma of the breast

• Documented ER-positive and/or progesterone receptor-positive tumor according toAmerican Society of Clinical Oncology/College of American Pathologists (ASCO/CAP)guidelines

• Documented HER2-negative tumor according to ASCO/CAP guidelines

• De-novo HR+ , HER2- ABC, or, alternatively, relapsed HR+ , HER2- ABC after at least 2 years of standard neoadjuvant/adjuvant endocrine therapy without diseaseprogression during that treatment and disease-free interval of at least 1 year sincethe completion of that treatment

• Participants who have bilateral breast cancers which are both HR-positive andHER2-negative

• Confirmation of biomarker eligibility

• Consent to provide fresh or archival tumor tissue specimen

• Measurable disease per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1)

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

• Adequate hematologic and organ function within 14 days prior to initiation of studytreatment

Exclusion Criteria:

• Pregnant or breastfeeding, or intention of becoming pregnant during the study orwithin the time frame in which contraception is required

• Metaplastic breast cancer

• Any prior systemic therapy for locally advanced unresectable or metastatic breastcancer

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

• Any history of leptomeningeal disease or carcinomatous meningitis

• Known and untreated, or active CNS metastases. Participants with a history oftreated CNS metastases are eligible

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

• Symptomatic active lung disease

• History of or active inflammatory bowel disease

• Any active bowel inflammation

• Prior hematopoietic stem cell or bone marrow transplantation

• Treatment with strong cytochrome P450 (CYP) 3A4 inhibitors or strong CYP3A4 inducerswithin 4 weeks or 5 drug-elimination half-lives, prior to initiation of studytreatment