• Patient is an adult male or postmenopausal female ≥18 years old at the time of informed consent(s) and has signed informed consent(s) before any trial related activities and according to local guidelines.

• Patient with histologically and/or cytologically confirmed diagnosis of HR+, HER2- breast cancer, as determined by the local laboratory.

• Patient has identified PI3K pathway alteration, defined as a PIK3CA mutation or PTEN loss or an AKT1 mutation using a Food and Drug Administration (FDA)-approved test, as determined either during Screening or was previously determined to have the alteration as evidenced by written documentation.

• Patient has locally advanced (not amenable to curative therapy or metastatic) breast cancer meeting any of the following categories:

‣ Relapsed disease, not amenable to curative therapy, with documented evidence of progressive disease (PD) following receipt of both (neo) adjuvant endocrine therapy and a CDK 4/6 inhibitor therapy (either alone or in combination with endocrine therapy) in the early stage or metastatic setting.

⁃ Newly diagnosed advanced breast cancer, with relapsed disease (i.e., documented evidence of PD) while receiving or after endocrine therapy plus a CDK 4/6 inhibitor.

• Patient has measurable disease per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

• For bone lesions, lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can be evaluated by cross-sectional imaging techniques such as computed tomography (CT) or magnetic resonance imaging (MRI) can be considered as measurable lesions if the soft tissue component meets the definition of measurability per RECIST 1.1. Blastic bone lesions are non-measurable.

• For bone metastases only (without measurable lesions), patients may be accrued to the safety Cohorts only.

• Patient has an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ≤1

• Patient has a Screening fasting plasma glucose (FPG) level ≤140 mg/dL (7.7 mmol/L) and an HbA1c ≤6.4% (47 mmol/mol) for those taking alpelisib, or an HbA1c \<8% (64 mmol/mol) for those taking capivasertib.

• Patient has a body mass index (BMI) ≥ 20 kg/m2.

• Patient is male or postmenopausal female. Postmenopausal is defined as any of the following:

‣ ≥45 years of age and has not had menses for \>2 years.

⁃ Amenorrheic for \>2 years without a hysterectomy and oophorectomy and a follicle-stimulating hormone value in the postmenopausal range upon pre-study (screening) evaluation.

⁃ Post hysterectomy with oophorectomy. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. In case of oophorectomy alone, hormone level assessment (follicle-stimulating hormone, estradiol) will be done locally at Screening to confirm postmenopausal status. Patients who are on ovarian function suppression also qualify.

⁃ Patient is allowed prior fulvestrant treatment, provided they remain eligible for fulvestrant treatment. Patients whose disease progressed while receiving fulvestrant monotherapy are not allowed.

⁃ Patient is allowed prior mTOR or PI3K inhibitor treatment for patients otherwise eligible for capivasertib treatment. Likewise, patient is allowed prior mTOR or AKT treatment if they are otherwise eligible for alpelisib treatment.

⁃ Patient is allowed up to one (1) prior chemotherapy for their metastatic disease.

⁃ Patient agrees to, and is willing and able to arrive at the hospital/clinic in a fasted state (\>8 hours) on designated fasting days.

⁃ Patient has adequate bone marrow and organ function as defined by the following laboratory values:

∙ Platelet count ≥140×109/L

‣ In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×the upper limit of normal (ULN). If the patient has liver metastases, ALT and AST ≤5×ULN.

‣ Total bilirubin ≤1.5×ULN except for patient with Gilbert's syndrome who may only be included if the total bilirubin is ≤3.0×ULN or direct bilirubin ≤1.5×ULN.

‣ Fasting serum amylase ≤2×ULN.

‣ Fasting serum lipase ≤1.5×ULN.

‣ Hemoglobin ≥ 9 g/dL.

‣ Absolute neutrophil count (ANC) ≥1500/mL.

‣ Creatinine clearance ≥ 50 mL/min using either the Cockcroft-Gault equation or the CKD-EPI formula for calculation of eGFR, or has chronic kidney disease (CKD) grade ≤1 as evidenced by a treating nephrologist. Alternatively, a 24-hour urine test can be performed to confirm renal sufficiency.

‣ Albumin ≥ 3.5 gm/dL.

⁃ Patient is able to take oral medications.