A Study of Tersolisib (LY4064809/STX-478) With Other Anti-Cancer Treatments in Participants With Advanced Breast Cancer With a Genetic Change (PIK3CA)

Inclusion Criteria:

• Are willing to follow contraception requirements. Contraceptive use by participantsshould be consistent with local regulations regarding the methods of contraceptionfor those participating in clinical studies.

• If assigned female at birth, pre-/peri- and postmenopausal status is allowed. Thosewith pre- or peri-menopausal status at study entry must agree to use ovarianfunction suppression with any locally approved gonadotropin-releasing hormone (GnRH)agonist.

• If assigned male at birth with an estrogen receptor positive (ER+) breast cancerdiagnosis, they must agree to use hormone suppression with a GnRH agonist.

• Have histologically or cytologically confirmed breast cancer, defined as individualswith

• locally advanced breast cancer not amenable to curative therapy (for example,surgery) or metastatic disease, and

• hormone receptors (HR)+/human epidermal growth factor receptor 2 (HER2)- orHR+/HER low defined by American Society of Clinical Oncology (ASCO)/College ofAmerican Pathologists (CAP) Guidelines

• HR status: Documented ER+ and/or progesterone receptor-positive (PR+)tumor according to ASCO/CAP Guidelines, defined as greater than or equalto (≥)1 percent (%) of tumor cells stained positive based on the mostrecent tumor biopsy and assessed locally

• HER status: immunohistochemistry score of 1+ or score of 2+ with anegative Fluorescence In Situ Hybridization (FISH) based on local resultsas defined in the ASCO/CAP Guidelines

• Have evidence of an activating PIK3CA mutation, detected in tumor or blood samplesusing an appropriate assay.

• Have measurable disease or non-measurable, evaluable bone disease

• Part 1:

• Received 0-2 prior systemic treatments for advanced breast cancer not amenableto curative therapy (for example, surgery) or metastatic disease.

• Up to 1 of these prior systemic treatments may contain chemotherapy

• Part 2:

• Received 0 prior systemic treatment for advanced breast cancer not amenable tocurative therapy (for example, surgery) or metastatic disease.

• Individuals who are eligible are either

• Population 1 (P1): Endocrine sensitive

• newly diagnosed with advanced breast cancer (de novo)

• relapsed with documented evidence of progression greater than (>)12months from completion of (neo)adjuvant ET ± cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor, or

• Population 2 (P2): Endocrine resistant

• relapsed with documented evidence of progression less than or equalto (≤)12 months of completing (neo)adjuvant ET ± CDK4/6 inhibitor.

• if a CDK4/6 inhibitor was included as part of neoadjuvant or adjuvanttherapy, progression event must be >12 months since completion ofCDK4/6 inhibitor portion of neoadjuvant or adjuvant therapy.

Exclusion Criteria:

• Have an established diagnosis of Type 1 diabetes mellitus or Type 2 diabetesmellitus with hemoglobin A1c (HbA1c) ≥8%, fasting blood glucose (FBG) ≥140milligrams per deciliter (mg/dL) (7.7 millimoles per liter [mmol/L]), or requiringinsulin.

• Have inflammatory or metaplastic breast cancer.

• History of leptomeningeal disease or carcinomatous meningitis.

• Have known and untreated or active central nervous system (CNS) metastases.Exception: Asymptomatic brain or spinal metastases if treated by surgery, surgeryplus radiotherapy, or radiotherapy alone with no evidence of radiographicprogression or hemorrhage within at least 28 days before randomization and norequirement for anticonvulsants or systemic corticosteroids for at least 28 daysbefore randomization.

• Have received treatment with any local or systemic antineoplastic therapy orinvestigational anticancer agent within 14 days or 4 half-lives, whichever islonger, prior to randomization up to a maximum washout period of 28 days.

• Have a diagnosis of immunodeficiency or is receiving chronic systemic steroidtherapy (dose more than 10 milligrams [mg] daily of prednisone equivalent) or anyother form of immunosuppressive therapy within 7 days prior to randomization.

• Are pregnant, breastfeeding, or intend to become pregnant during the study or within 6 months of the last dose of study intervention and at least 2 years after the lastdose of fulvestrant and/or CDK4/6 inhibitor after the final administration of studytreatment.