A Study of Dato-DXd Versus Investigator's Choice Chemotherapy in Inoperable or Metastatic Hormone Receptor-positive, HER2-negative Breast Cancer

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• 1. Any evidence of diseases which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol. 2. History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before the first dose of study intervention and of low potential risk for recurrence. Exceptions include basal cell carcinoma of the skin and squamous cell carcinoma of the skin that has undergone potentially curative therapy, adequately resected non-melanoma skin cancer, curatively treated in situ disease, or other solid tumors curatively treated. 3. Persistent toxicities caused by previous anticancer therapy (excluding alopecia), not yet improved to CTCAE Version 5.0 Grade ≤ 1 or baseline. Note: participants may be enrolled with some chronic, stable Grade 2 toxicities (defined as no worsening to > Grade 2 for at least 3 months prior to first dosing and managed with SoC treatment) which the investigator deems related to previous anticancer therapy. 4. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals; suspected infections (eg, prodromal symptoms); or inability to rule out infections. 5. Known active or uncontrolled hepatitis B or C infection; or positive for hepatitis B or C virus based on the evaluation of results of tests for hepatitis B (HBsAg, anti-HBs, anti-HBc, or HBV DNA) or hepatitis C (HCV antibody or HCV RNA) infection at screening. 6. Known HIV infection that is not well controlled. 7. Uncontrolled or significant cardiac disease, including myocardial infarction or uncontrolled/unstable angina within 6 months prior to C1D1, CHF (New York Heart Association Class II to IV), uncontrolled or significant cardiac arrhythmia, or uncontrolled hypertension (resting systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg). 8. Investigator judgment of 1 or more of the following: • Mean resting corrected QTcF interval > 470 ms • History of QT prolongation associated with other medications that required discontinuation of that medication, or any current concomitant medication known to prolong the QT interval and cause Torsades de Pointes. • Congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives. 9. History of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
• 10. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder, or any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement, or prior pneumonectomy. 11. Leptomeningeal carcinomatosis. 12. Clinically significant corneal disease. 13. Known active tuberculosis infection 14. Any of the following prior anticancer therapies: o Any treatment (including ADC) containing a chemotherapeutic agent targeting topoisomerase I - - TROP2-targeted therapy o Prior treatment with same ICC agent 15. Any concurrent anticancer treatment, with the exception of bisphosphonates, denosumab, for the treatment of bone metastases. 16. Concurrent use of systemic hormonal replacement therapy (eg, estrogen). However, concurrent use of hormones for non-cancer related conditions (eg, insulin for diabetes) is acceptable. 17. Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 3 weeks of the first dose of study intervention or an anticipated need for major surgery during the study. 18. Receipt of live, attenuated vaccine within 30 days prior to the first dose of study treatment. 20. Previous treatment in the present study. 21. Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 4 weeks prior to first dosing, randomization into a prior Dato-Dxd or T-DXd (trastuzumab deruxtecan) study regardless of treatment assignment, or concurrent enrolment in another clinical study, unless it is an observational (noninterventional) clinical study or during the follow-up period of an interventional study. 22. Participants with a known hypersensitivity to Dato-DXd, or any of the excipients of the product (including, but not limited to, polysorbate 80). 23. Known history of severe hypersensitivity reactions to other monoclonal antibodies. 24. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). 25. Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions and requirements. 26. For women only, currently pregnant (confirmed with positive pregnancy test) or breastfeeding, or who are planning to become pregnant.