Trastuzumab Deruxtecan vs Endocrine Therapy in Low-HER2 HR+ Advanced Breast Cancer

Inclusion Criteria: 1. Histologically or cytologically confirmed hormone receptor-positive advanced breast cancer patients 1. Have recurrent, metastatic, or unresectable disease 2. Have HER2-low expression status, defined as IHC 2+/ISH- or IHC 1+,with a validated assay by ASCO/CAP guidelines 3. Have no previous history of HER2-positive breast cancer (IHC 3+ or ISH+) by ASCO/CAP guidelines 4. The hormone receptor (HR) status is defined by ER/PR IHC nuclear staining, and ER or PgR ≥1% is defined as hormone receptor-positive status 2. Patients who progressed on 1st line endocrine + CDK4/6 inhibitor therapy for advanced breast cancer and received no other systemic therapy for advanced breast cancer. The all FDA-approved CDK4/6 inhibitors (palbociclib, ribociclib, and Abemaciclib) are allowed, and combination with aromatase inhibitors or fulvestrant are both allowed. 3. Patients who have received chemotherapy or adjuvant endocrine therapy in the neo-adjuvant or adjuvant setting are eligible. 4. Female patients with ≥19 years of age 5. Radiologic or objective evidence of disease progression on or after the last systemic therapy prior to starting study treatment 6. Patients must have at least one measurable lesion by RECIST 1.1 criteria, which was not previously irradiated or showed objective progression after irradiation to that lesion 7. Patients must have an adequate tumor tissue sample available for assessment of HER2 by central laboratory and other exploratory biomarker analyses 8. Patients with ECOG performance status 0 or 1 9. Both pre- and post-menopausal patients are eligible, and pre-menopausal patients should receive ovarian function suppression treatment (GnRH agonist injection or surgical bilateral oophorectomy) while receiving fulvestrant or aromatase inhibitor treatment in the control arm. 10. Adequate organ function for treatment Adequate organ and bone marrow function within 14 days before randomization/enrolment as described below:" a) Haemoglobin: ≥ 9.0 g/dL NOTE: Participants requiring ongoing transfusions or growth factor support to maintain haemoglobin ≥9.0 g/dL are not eligible. (Red blood cell transfusion is not allowed within 1 week prior to C1D1) b) Serum albumin: ≥ 2.5 g/dL c) International normalised ratio or Prothrombin time and either partial thromboplastin or activated partial thromboplastin time: ≤ 1.5 × ULN d) Absolute neutrophil count (ANC) ≥1500 cells/mm3 * granulocyte-colony stimulating factor administration is not allowed within 1 week prior to C1D1 ) e) Platelets ≥100,000 cells/mm3 * Platelet transfusion is not allowed within 1 week prior to C1D1) f) Estimated creatinine clearance ≥50 mL/min, or serum creatinine \<1.5x institution upper limit of normal (ULN) g) Bilirubin≤1.5 x ULN * if no liver metastases or \< 3×ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline h) AST (SGOT) ≤2.5 x ULN (5.0 x ULN if hepatic metastases) i) ALT (SGPT) ≤2.5 x ULN (5.0 x ULN if hepatic metastases) 11. 12-Lead electrocardiogram (ECG) with normal tracing or non-clinically significant changes that do not require medical intervention 12. QTc interval ≤470 msec and without history of Torsades de pointes based on average of the screening triplicate 12-lead ECG 13. Pointes or other symptomatic QTc abnormality 14. LVEF (by MUGA or echocardiogram) of ≥50% within 28 days before randomization/enrollment 15. No history of pneumonitis other than radiation pneumonitis 16. The patient has provided signed informed consent 17. Neither pregnant or breastfeeding female patients 18. Fertile women who are not in pregnancy or breastfeeding should use effective contraception for a period from two weeks before the start of research treatment, during treatment and up to seven months after last dose of study treatment 19. No other concurrent severe and/or uncontrolled medical disease which could compromise study participation, including any of the following: 20. Adequate treatment washout period before enrollment are below -Major surgery ≥ 4 weeks -Radiation Therapy including palliative stereotactic radiation therapy to chest ≥ 4 weeks -Palliative stereotactic radiation therapy to other anatomic areas including whole brain radiation ≥ 2 weeks -Anti-Cancer chemotherapy \[Immunotherapy (non-antibody based therapy)\], retinoid therapy, hormonal therapy ≥ 3 weeks -Antibody based anti-cancer therapy ≥ 4 weeks -Targeted agents and small molecules ≥ 2 weeks or 5 half-lives, whichever is longer -Nitrosoureas or mitomycin C ≥ 6 weeks -Chloroquine/Hydroxychloroquine ≥ 14 days -Cell-free and CART, peritoneal shunt or drainage of pleural effusion, ascites or pericardial effusion ≥ 2 weeks prior to screening assessment Exclusion Criteria: 1. Previous history of T-DXd or Dato-Dxd treatment for advanced breast cancer 2. Severe Cardiac disease (e.g., uncontrolled hypertension, congestive cardiac failure, ventricular arrhythmias, active ischemic heart disease, myocardial infarction within the past year, Left Ventricular Ejection Fraction (LVEF) \> grade 2) 3. Patients with a medical history of myocardial infarction (MI) within 6 months before randomization/enrolment, symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV), Subjects with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial related symptoms, should have a cardiologic consultation before enrollment to rule out MI. 4. Current active hepatic or biliary disease (except for Gilbert syndrome, asymptomatic gallstones, liver metastasis or stable chronic liver disease per investigator assessment) 5. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals 6. Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of T-DXd. 7. Has unresolved toxicities fr