Inclusion Criteria:  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- BC characterized by the absence of HER2 expression and the presence of ER and/or PR expression.  Female patients must be post-menopausal. Female patients who are pre- or peri-menopausal must have ovarian suppression therapy with LHRH while on study.  Menopause is defined by NCCN Guidelines Breast Cancer, version 1.2021 as the following:  Prior bilateral oophorectomy Age ≥ 60 y Age < 60 y and amenorrheic for 12 or more months in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression and FSH and estradiol in the postmenopausal range If taking tamoxifen or toremifene, and age < 60 y, then FSH and plasma estradiol level in postmenopausal ranges Before randomization, 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 (adjuvant therapy included), including:  i. Endocrine therapies including AIs and/or SERMs (1 or 2 lines); OR ii. A CDK4/6 inhibitor in combination with endocrine therapy (1 line), with or without additional line of endocrine therapy (1 line); OR Afuresertib Plus Fulvestrant Versus Placebo Plus Fulvestrant As Treatment for HR+/HER2- Breast Cancer Protocol Number: LAE205INT3101 Document Version: 0.9 NCT Identifier Number: March 15, 2021 44 iii. A chemotherapy (monotherapy or combination therapy, 1 line only), with or without additional line of endocrine therapy.  Notes:  A combination chemotherapy (two chemotherapy drugs or one chemotherapy drug plus one non-chemotherapy drug) is considered as 1 line of chemotherapy. A combination therapy of a CDK4/6 inhibitor with a non-chemotherapy drug is considered as 1 line of CDK4/6 inhibitor treatment. In the Phase Ib part, patients must provide informed consent for the procedures and the tests for PIK3CA/AKT/PTEN alterations. The biomarkers will be tested retrospectively by gene sequencing and/or immunohistochemistry tests using archival tumor sample within 18 months (78 weeks) or from blood or from a tumor biopsy sample. Formalin-fixed, paraffin embedded (FFPE) tissue blocks sectioned on the slides are preferred. The biomarker test results will be correlated to the anti-cancer efficacy and safety results in Phase Ib to decide the patient population in the Phase III pivotal study. Patients with an Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 or 1.  Patients who have adequate organ function as defined below. Specimens must be collected within 10 days prior to the start of study enrollment.  Hematological:  Absolute neutrophil count (ANC) ≥ 1500/μl Platelets count ≥ 100,000/μl Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L Criteria must be met without erythropoietin dependency and without packed red blood cell (PRBC) transfusion within 10 days prior to the screening lab tests.  Renal  Creatinine ≤ 1.5 × ULN OR Measured or calculated per institutional standard creatinine clearance (GFR can also be used in place of creatinine or creatinine clearance) ≥ 30 mL/min for participant with creatinine levels > 1.5 × institutional ULN.  Hepatic  Total bilirubin ≤ 1.5 ×ULN OR direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 × ULN. AST (SGOT) and ALT (SGPT) ≤ 2.5 × ULN (≤ 5 × ULN for participants with liver metastases). Coagulation • International normalized ratio (INR) OR prothrombin time (PT)/Activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN. If the participant is receiving anticoagulant therapy, PT or aPTT should be within therapeutic range of intended use of anticoagulants.  Afuresertib Plus Fulvestrant Versus Placebo Plus Fulvestrant As Treatment for HR+/HER2- Breast Cancer Protocol Number: LAE205INT3101 Document Version: 0.9 NCT Identifier Number: March 15, 2021 45  Patients with type 1 diabetes who do not require insulin and 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); or glycosylated hemoglobin (HbA1c) ≤ 8%. Patients with a life expectancy of 24 weeks or more based on investigator's assessment. Patients who have recovered from adverse events associated with medical treatment, radiation and surgical operation as pre-treatment to ≤ CTCAE v5.0 Grade 1, excluding stable symptoms (e.g., alopecia, peripheral sensory neuropathy, skin hyperpigmentation, dysgeusia, etc.).  Female patients must agree to use effective contraception during the study and for at least 16 weeks after discontinuation from the study, defined as the following:  Total abstinence (if it is their preferred and usual lifestyle) An intrauterine device (IUD) or hormone-releasing system (IUS) A contraceptive implant An oral contraceptive (with additional barrier method) Have a vasectomized partner with confirmed azoospermia Male patients must agree to use an adequate method of contraception from enrollment through 90 days after the last dose of 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.  Exclusion Criteria:  A woman of child-bearing potential (WOCBP) who has a positive urine pregnancy test (e.g., within 72 hours) prior to study treatment. If a urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Patients who had a recent major surgery that required hospitalization (<6 months/26 weeks) from scheduled treatment starting date) or have used IV antibiotics for systemic infection (< 2 months/8 weeks) from scheduled treatment starting date). Patients who have additional known malignancies that are progressing or have required active treatments within 3 years of scheduled treatment starting date. (Note: Patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, that have undergone potentially curative therapy are not excluded). Patients who have a history of seizure or conditions that may predispose them to seizure and require anti-epileptic medications, or patients who have brain arteriovenous malformation, or intracranial masses (e.g., schwannomas and meningiomas) that are causing edema or mass effect.  Patients who have known active CNS metastases and/or carcinomatous meningitis. (Note: Patients with previously treated brain metastases may participate provided that they are radiologically stable (i.e., without evidence of progression for at least 4 weeks by repeated imaging performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to schedule treatment starting date.  Afuresertib Plus Fulvestrant Versus Placebo Plus Fulvestrant As Treatment for HR+/HER2- Breast Cancer Protocol Number: LAE205INT3101 Document Version: 0.9 NCT Identifier Number: March 15, 2021 46  Patients who had prior treatment with fulvestrant or other selective estrogen receptor degraders (SERDs), or any PI3K/AKT/mTOR inhibitors. Patients who had New York Heart Association congestive heart failure of grade II or above, unstable angina, myocardial infarction, arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or serious cardiac arrhythmia associated with significant cardiovascular impairment within 6 months (26 weeks) of scheduled treatment starting date. Patients with prolongation of corrected QTc interval, as corrected by the Frederica's correction formula to > 450 msec for males and > 470 msec for females; unless prolonged QTc interval is due to right bundle branch block or left bundle branch block with a pacemaker. Patients who have uncontrolled hypertension (systolic blood pressure > 160 mmHg or diastolic BP > 100 mmHg under anti-hypertensive treatment). Note: Patients with a history of hypertension are allowed, provided that BP is controlled to within these limits by anti-hypertensive treatment.  Patients who have a Hepatitis B active infection (defined as HBsAg (+), Anti-HBs (-), Anti-HBc total or IgM (+)) or known active Hepatitis C virus (defined as HCV RNA [qualitative] test positive). Patients who have tested positive for HIV infection with 1 or more of the following:  Not receiving highly active antiretroviral therapy Receiving antiretroviral therapy that may interfere with the study drug (consult the Sponsor for review of medication prior to enrollment) CD4 count < 350 based on a test within 3 months of the screening visit An acquired immunodeficiency syndrome-defining opportunistic infection within 6 months (26 weeks) of the start of study screening Patients who have a history or current evidence of any condition, therapy, or laboratory abnormality that in the opinion of the investigator, might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate. Patients who have a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study. Patients who are receiving a strong CYP3CA, OATP, BRCP substrate or inducer. Please see related section for a list of these prohibited medications. Patients who are currently pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 16 weeks after the last dose of study treatment. Patients who have Child-Pugh status of B and C.