• Histological diagnosis of metastatic or inoperable locally advanced ER positive/HER2 negative breast cancer. Assessment of ER and HER2 status as per local assessment. Histologically proven primary ER+ (Allred score 3/8 or greater, or stain in \>1% of cancer cells) and HER2- (immunohistochemistry 0/1+ or negative by in situ hybridization) breast cancer as determined by local laboratory.

• Be willing to consent for an archival tumour tissue sample (of advanced disease) to be requested for transfer to the Royal Marsden for future review during study screening. Patients without a metastatic biopsy may be eligible if archival tumour from the breast primary tumour is available, but only after discussion with the Chief Investigator.

• Previously treated with no more than one prior line of chemotherapy for advanced disease.

• Patients eligible according to standard of care for fulvestrant in combination with a CDK4/6 inhibitor (abemaciclib, palbociclib, or ribociclib).

• Patients must have received at least one prior line of hormone therapy for advanced disease and progressed on or within 1 month from stopping prior endocrine therapy for advanced disease, or relapsed on or within 12 months of completing adjuvant endocrine therapy.

• Measurable disease (RECIST 1.1) or assessable bone disease (lytic or mixed lytic sclerotic).

• Eastern Cooperative Oncology Group (ECOG) performance status 0,1 or 2.

• Estimated life expectancy of at least 3 months.

• Adequate bone marrow, renal, and liver function within 14 days before the first study treatment on Day 1 of Cycle 1, defined by the following:

∙ Neutrophils (ANC ≥ 1500/μL), Haemoglobin ≥9 g/dL, Platelet count ≥100,000/μL

‣ Serum albumin ≥3 g/dL

‣ Total bilirubin ≤1.5 x the upper limit of normal (ULN), with the following exception: patients with known Gilbert syndrome who have serum bilirubin ≤3 x ULN may be enrolled

‣ AST and ALT ≤2.5 x ULN, with the following exception: patients with documented liver or bone metastases may have AST and ALT ≤5 x ULN.

‣ ALP ≤2 x ULN, with the following exceptions: patients with known liver involvement may have ALP ≤5 x ULN, patients with known bone involvement may have ALP ≤7 x ULN

‣ Serum creatinine ≤1.5 x ULN or creatinine clearance ≥50 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation.

‣ INR \<1.5 x ULN and aPTT \<1.5 x ULN. Patients requiring formal anticoagulation should receive either low-molecular weight heparin or a direct oral anticoagulant.

⁃ Fasting glucose ≤150mg/dL and HbA1c ≤7.5%.

⁃ Negative serum pregnancy test at screening (females of childbearing potential).

⁃ Patients able to have children must agree to use two highly effective methods of contraception throughout the study and for 2 years after last dose of fulvestrant and at least two years after last dose. Patients must additionally agree to refrain from donating eggs during this period.

⁃ Signed and dated informed consent.

⁃ Patients willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other procedures.

⁃ Pre/peri-menopausal patients must be treated with GnRH agonist beginning at least 7 days prior to Day 1 of Cycle 1 and continuing every 28 days for the duration of study treatment.