• Female or male patients must be ≥ 18 years of age on the day of signing the informed consent and be able to provide written informed consent for the study.

• Patients with histologically or cytologically confirmed HR+/HER2- Breast Cancer characterized by the absence of HER2 expression and the presence of ER with/without PR expression.

• Female patients may be post-menopausal, pre-menopausal or peri-menopausal. Male and Pre- and peri-menopausal females may be enrolled if continuously treated with ovarian suppression therapy (use LHRHa at least starting from C1D1) for the duration of study participation.

• Before enrollment, patients who have undergone anti-cancer treatment must have a washout period of 4 weeks or 5 half-lives, whichever comes earlier.

• HR+/HER2- BC patients must meet all the following criteria to join this study:

∙ Relapsed locally advanced (LABC) or metastatic (mBC) disease; AND

‣ Have received 1 to 2 prior lines of systemic treatments for LABC or mBC(at least one line was ET). If disease relapse during adjuvant therapy or relapse within 12 months from completion of adjuvant endocrine therapy, the adjuvant therapy will be counted as 1 line), including:

• i. Endocrine therapies including AIs and/or SERMs (1 or 2 lines) with or without a CDK4/6 inhibitor (up to 1 therapy); OR ii. A chemotherapy (monotherapy or combination therapy, at most 1 line only), with 1 additional line of endocrine therapy .

• For phase Ib part, patients must have at least one lesion that meets the definition of measurable disease by RECIST 1.1 criteria; for phase III, have measurable disease and/or at least 1 lytic or mixed (lytic + sclerotic) bone lesion that can be assessed by RECIST 1.1 criteria; patients with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible (Appendix 2).

• In the Phase Ib part, Patients must provide informed consent for the procedures and the tests for PIK3CA/AKT/PTEN alterations and ESR1 mutations. The biomarkers will be tested retrospectively by gene sequencing tests using archival tumor sample (preferably within 18 months/78 weeks) or from peripheral blood or from a tumor biopsy sample. Formalin-fixed, paraffin embedded (FFPE) tissue blocksare preferred. In phase III, blood sample is mandatory for this test.

• In Phase III, subjects need to provide blood sample during the screening period for PIK3CA/AKT1/PTEN test, which will be conducted in the central laboratory. Only patients with PIK3CA/AKT1/PTEN alterations could include.

• Patients with an Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 or 1.

⁃ Patients who have adequate organ function as defined.

⁃ Patients without a pre-existing diagnosis of diabetes mellitus (DM) who have a fasting glucose ≤ 126 mg/dL (or ≤ 7.0 mmol/L); or patients with type 2 diabetes who have a fasting glucose ≤ 167 mg/dL (or ≤ 9.3 mmol/L) AND glycosylated hemoglobin (HbA1c) ≤ 8%. Patients with DM type 1 or patients with DM type 2 requiring insulin or ≥21 anti-abetic medications for glycemic control are excluded.

⁃ Patients with a life expectancy of 24 weeks or more based on investigator's assessment.

⁃ Patients who have recovered from adverse events associated with pre-study medical, radiation and surgical treatments to ≤ Grade 1, excluding stable symptoms (e.g., alopecia, peripheral sensory neuropathy, skin hyperpigmentation, dysgeusia, etc.).

⁃ Female patients of childbearing potential must have a negative pretreatment serum pregnancy test.

⁃ Female patients of childbearing potential must agree to use effective contraception from enrollment to 1 year after discontinuation from the last dose of this study treatment.

⁃ Patients who are able to swallow and retain oral medication and without gastrointestinal diseases to interfere with drug absorption.

⁃ Patients must have no contraindications to fulvestrant.