1. Adults ≥18 years of age at the time of informed consent

2. Histologically or cytologically confirmed diagnosis of advanced breast cancer (ABC; locally advanced not amenable to resection and/or metastatic breast cancer)

3. Progression of disease during or within 12 months of completing (neo)adjuvant ET

4. The following prior therapies are permitted:

   a. Prior (neo)adjuvant treatment with an aromatase inhibitor or tamoxifen

   b. Prior (neo)adjuvant fulvestrant or any selective estrogen-receptor degrader (SERD) only if the treatment duration was <6 months

   c. Prior (neo)adjuvant chemotherapy

   d. Prior (neo)adjuvant therapy with a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor is allowed unless disease progression was on or within 6 months of discontinuation of CDK4/6 inhibitor treatment

5. Confirmed diagnosis of estrogen receptor positive and/or progesterone receptor positive, as per American Society of Clinical Oncology/College of American Pathologists (ASCO-CAP) guidelines (2020), utilizing an assay consistent with local standards

6. Documented HER2 immunohistochemistry (IHC) negative as per ASCO-CAP 2018 guidance (Wolff 2018); if result by IHC is +2 (equivocal), an in-situ hybridization test must be performed.

7. Documentation of radiologically confirmed measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, per local assessment.

   a. For subjects with bone-only disease:

      i. Subjects must have at least one lytic bone lesion or mixed lytic/blastic bone lesion with identifiable soft tissue components that can be evaluated for changes in size.

      ii. Subjects with only blastic bone lesions with no soft tissue component are not eligible for enrollment.

8. Subjects must provide consent for collection of fresh tumor biopsy, archival tumor tissue, or liquid biopsy collection and submit for central assessment of PIK3CA mutations status via specified test. For eligibility in the Phase 3 randomized period of the study:

   a. Subjects with a PIK3CA not detected (ND) result determined by tumor biopsy and subjects who have no archival or fresh tumor sample available with a PIK3CA ND result determined by plasma sample with ctDNA tumor fraction (TF) ≥1% are eligible for enrollment in the study.

   b. Subjects who have no archival or fresh tumor sample available with a PIK3CA ND result determined by plasma sample with ctDNA tumor fraction (TF) <1% are not eligible for enrollment.

9. Eastern Cooperative Oncology Group (ECOG) performance status of 0–2

10. Life expectancy of >6 months, per Investigator judgement

11. Subject dosing may start at least 2 weeks after major surgery and radiation therapy has been completed and subject must have recovered from side effects and complications.

12. Washout period of 2 weeks (or 5 half-lives, whichever is longer) for any prior systemic or hormonal or targeted therapies, and 4 weeks for any antibody-based treatments is required before start of study treatment. Recovery from all acute toxicities must be achieved prior to randomization (adverse events [AEs] from prior anticancer therapies recovered to Grade ≤1 or lower; except alopecia).

13. HbA1c ≤8% and either fasting plasma glucose (FPG) <140 mg/dL or non-fasting glucose <200 mg/dL

14. Adequate bone marrow, hepatic, renal, and coagulation function as defined by the following:

   a. Absolute neutrophil count ≥1.5 × 109 /L (maintained without growth factor support within 7 days of C1D1)

   b. Hemoglobin ≥9.0 g/dL (90 g/L) (maintained without transfusion support within 7 days of C1D1)

   c. Platelets ≥75 × 109 /L

   d. Potassium within normal limits, or corrected with supplements

   e. Calcium (corrected for serum albumin) and magnesium within normal limits or Grade ≤1 if judged not clinically significant by the Investigator

   f. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × upper limit of normal (ULN) (if no hepatic metastases); if hepatic tumor involvement, AST and ALT ≤5 × ULN

   g. Total bilirubin ≤1.5 × ULN (total bilirubin ≤3.0 × ULN in subjects with Gilbert’s Syndrome)

   h. Calculated creatinine clearance (CrCL) >50 mL/min using the Cockcroft and Gault equation (inclusion of subjects with low body weight and clearance 40-50 mL/min can be discussed with medical monitor): 𝐶𝑟𝐶𝐿 = (140 − 𝑎𝑔𝑒) × (𝑤𝑒𝑖𝑔ℎ𝑡 𝑖𝑛 𝑘𝑔) 72 × (𝑠𝑒𝑟𝑢𝑚 𝑐𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 𝑖𝑛 𝑚𝑔/𝑑𝐿) × (0.85 𝑖𝑓 𝑓𝑒𝑚𝑎𝑙𝑒)

15. Must be willing and able to comply with protocol-specified schedules of assessments, treatment plans, laboratory tests, and other study procedures

16. Ability to understand the investigational nature of the study and sign the informed consent prior to any study-specific procedures

17. Must meet one of the following:

   a. Females who are postmenopausal, defined as one of the following:

      i. Females 18–59 years of age (at the time of consent) with cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause, and serum estradiol and folliclestimulating hormone (FSH) level within the laboratory’s reference range for postmenopausal females

      ii. Females ≥60 years of age (at the time of consent) with cessation of menses for at least 12 consecutive months

      iii. Documented bilateral oophorectomy or hysterectomy

      iv. Medically confirmed ovarian failure

   b. Pre/perimenopausal females with medically induced menopause by treatment with the luteinizing hormone-releasing hormone (LHRH) agonist goserelin, the gonadotropin-releasing hormone (GnRH) agonist leuprolide (Lupron Depot), or equivalent agents to induce chemical menopause as described in Section 6.7.1.5

   c. Male subjects should receive LHRH agonist per local standard and must use contraception for up to 2 years after discontinuation of treatment according to Appendix F.

18. Negative pregnancy test for females of childbearing potential; female subjects of childbearing potential must use contraception per local standard and applicable prescribing information for up to 2 years after discontinuation of treatment according to Appendix F.

1. Concurrent malignancies are excluded. The following exceptions apply:

   a. Previous malignancies in remission but curatively treated with no evidence of disease progression and judged by local Investigator to be at low risk of impacting health or survival while on study

   b. Adequately treated nonmelanoma skin cancer or in situ cancer of the cervix are allowed.

2. Prior treatment with a phosphoinositide 3-kinase (PI3K) inhibitor, a protein kinase B (AKT) inhibitor, or a mechanistic target of rapamycin (mTOR) inhibitor

3. Prior treatment with systemic anticancer therapy for ABC

4. Subjects with type 1 diabetes

5. Active human immunodeficiency virus (HIV) infection

   a. Subjects with well-controlled HIV infection may be allowed if CD4+ T-cell (CD4+) counts >350 cells/μL

   b. Subjects without a history of acquired immune deficiency syndrome (AIDS)-defining opportunistic infections may be eligible for enrollment if CD4+ T-cell (CD4+) counts >350 cells/μL and treatment compliance is confirmed.

6. Known seropositive for, or active viral infection with, hepatitis B or C virus unless adequately controlled by medication

   a. Subjects who are HBsAg negative and viral DNA PCR negative for HBV are eligible.

   b. Subjects who are solely HBsAb positive as result of vaccination are eligible.

   c. Subjects with positive hepatitis C virus (HCV) antibodies are eligible with negative PCR test for HCV.

7. Untreated or active brain or leptomeningeal metastases

   a. Subjects with previously treated central nervous system (CNS) metastases may be enrolled in the study if they meet the following criteria:

      i. Do not require supportive therapy with steroids and/or anticonvulsants

      ii. Do not exhibit new seizures and/or active neurological decline in motor function within the last 28 days prior to informed consent

8. Subjects with advanced, symptomatic, visceral spread that are at risk of life-threatening complications in the short-term, including visceral crisis and/or uncontrolled effusions (pleural, pericardial, peritoneal) requiring repeated drainage

9. History of clinically significant cardiovascular abnormalities such as:

   a. Congestive heart failure (New York Heart Association [NYHA] classification III or IV [NYHA 1994])

   b. Myocardial infarction within 12 months of the time of randomization

   c. Uncontrolled (or untreated) clinically significant cardiac arrhythmias, (e.g., ventricular tachycardia), complete left bundle branch block, high grade atrioventricular (AV) block (e.g., bi-fascicular block, Mobitz type II- and third-degree AV block), supraventricular, nodal arrhythmias, or conduction abnormality

   d. Uncontrolled hypertension defined by systolic blood pressure (SBP) ≥160 mmHg and/or diastolic blood pressure (DBP) ≥100 mmHg, with or without antihypertensive medication (initiation or adjustment of antihypertensive medication[s] is allowed prior to randomization)

   e. Diagnosis of pulmonary embolus or deep vein thrombosis diagnosed less than 6 months prior to randomization

   f. Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:

      i. Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, or history of clinically significant/symptomatic bradycardia

      ii. On screening, inability to determine the corrected QT interval using Fridericia’s formula (QTcF) on the electrocardiogram (ECG; i.e., unreadable or not interpretable) or QTcF >470 msec

   g. Cardiac ejection fraction outside institutional range of normal or <50% (whichever is lower)

10. Active inflammatory or infectious conditions in either eye, or any eye conditions expected to require surgery during the study treatment period 11. History of drug-induced symptomatic interstitial lung disease (pneumonitis) or hepatitis

12. Unable to swallow oral medication tablets/capsules, or known malabsorption due to inflammatory or short bowel syndromes

13. Known hypersensitivity to the study drugs or their components

14. Subjects who, in the opinion of the Investigator, are unable to undertake study therapy or comply with study requirements

15. Current uncontrolled medical, psychological, or social conditions that may interfere with the subject’s participation in the study or evaluation of the study results

16. Where applicable per country regulation, the subject must not currently be committed to an institution by virtue of an order issued either by judicial or administrative authorities.

17. Pregnant or breastfeeding females

18. Concurrent participation in another interventional clinical trial