A Study of Dato-DXd in Inoperable or Metastatic Hormone Receptor-positive, HER2 IHC 0 Breast Cancer

Inclusion Criteria: 1. Participant must be ≥ 18 years (and above legal age) at the time of screening. 2. Inoperable or metastatic HR-positive, HER2 IHC 0 breast cancer (per ASCO/CAP guidelines, on local laboratory results); ie, is documented as HR-positive (either ER and/or PgR positive \[ER or PgR ≥ 1%\]) and HER2 IHC 0 (defined as no staining or incomplete and faint/barely perceptible membrane staining in ≤ 10% of tumour cells). 3. Progressed on and not suitable for further endocrine therapy per investigator assessment. 4. ECOG performance status of 0 or 1, with no deterioration over the previous 2 weeks prior to the first dose of study intervention. 5. Minimum life expectancy of 12 weeks at screening. 6. Provision of acceptable tumour sample (no more than 6 weeks old) prior to the first dose of study intervention or retrospectively as defined in the Laboratory Manual and the Diagnostic Testing Manual 7. Participants must have measurable disease as per RECIST 1.1 or evaluable disease. Lesions that will be subject to mandatory biopsy before, during, and after the dosing cannot be considered as TLs as per RECIST requirements. 8. Adequate bone marrow reserve and organ function within 7 days before the first dose of study intervention. 1. Haemoglobin ≥ 9.0 g/dL (red blood cell/plasma transfusion is not allowed within 1 week prior to screening assessment). 2. Absolute neutrophil count ≥ 1.5×109/L (granulocyte colony stimulating factor administration is not allowed within 1 week prior to screening assessment). 3. Platelet count ≥ 100×109/L (platelet transfusion is not allowed within 1 week prior to screening assessment). 4. Serum albumin ≥ 2.5 g/dL. 5. TBL ≤ 1.5 × ULN or ≤ 3 × ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinaemia). 6. Except in the setting of HBV, ALT and AST ≤ 2.5 × ULN; for participants with hepatic metastases, ALT and AST ≤ 5 × ULN. See Exclusion Criterion 8 for requirements in the setting of HBV. 7. Calculated CrCL ≥ 30 mL/min as determined by Cockcroft Gault (using actual body weight). 9. Male and/or female assigned at birth, inclusive of all gender identities. 10. Contraceptive use by participants or participant partners should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies; (a) Male participants: (i) Use of a condom plus an additional contraceptive method, or avoid intercourse from enrolment and throughout study for at least 4 months after the last dose of Dato-DXd, in addition to the female partner using a highly effective contraceptive method. (ii) Starting at the time of first dose of Dato-DXd, male participants must not freeze or donate sperm at any time during this study and for at least 4 months after the last dose of Dato-DXd. Preservation of sperm should be considered prior to the first dose of study intervention. (b) Female participants:Female participants not of child-bearing potential (ii) Female participants receiving HRT and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for WOCBP if they wish to continue using HRT during the study. Otherwise, HRT must be discontinued to allow confirmation of post-menopausal status prior to study enrolment; (iii) WOCBP must use one highly effective form of contraception or avoid intercourse from enrolment throughout study and for at least 7 months after the last dose of Dato-DXd. All WOCBP must have a negative serum pregnancy test documented during screening. (iv) Starting at the time of first dose of Dato-DXd, female participants must not donate, or retrieve for their own use, ova at any time during this study and for at least 7 months after the last dose of Dato-DXd. Preservation of ova should be considered prior to the first dose of study intervention. 11. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this CSP. 12. All races, genders, and ethnic groups are eligible for this study. Exclusion Criteria: 1. As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including active bleeding diseases and significant cardiac or psychological conditions), history of allogenic organ transplant, and/or substance abuse which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardise 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 adequately resected non melanoma skin cancer (basal cell carcinoma of the skin or squamous cell carcinoma of the skin) and curatively treated in situ disease. 3. Persistent toxicities caused by previous anticancer therapy, excluding alopecia, not yet improved to 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 the first dose of study intervention and managed with SoC treatment) which the investigator deems related to previous anticancer therapy): 1. Chemotherapy-induced neuropathy 2. Fatigue 3. Residual toxicities from prior immunotherapy treatment: Grade 1 or Grade 2 endocrinopathies, which may include but are not limited to hypothyroidism/hyperthyroidism, Type I diabetes, hyperglycaemia, adrenal insufficiency, or adrenalitis; and skin hypopigmentation (vitiligo) Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention in the opinion of the investigator may be included (eg, hearing loss). 4. Spinal cord compression or brain metastases (unless asymptomatic, stable, and not requiring treatment with corticosteroids or anticonvulsants for at least 2 weeks prior to the first dose of study intervention). Participants with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants must have recovered from the acute toxic effect of radiotherapy (eg, dizziness and signs of increased intracranial pressure). A minimum of 2 weeks must have elapsed between the end of brain radiotherapy and the first dose of study intervention. A minimum of 3 days must have elapsed between the end of corticosteroid therapy for CNS metastatic disease and the first dose of study intervention. 5. Leptomeningeal carcinomatosis or metastasis. 6. Has significant third-space fluid retention (eg, ascites or pleural effusion) and is not amenable for required repeated drainage. 7. Clinically significant corneal disease. 8. Has active or uncontrolled hepatitis B or C virus infection. Participants are eligible if they: 1. Have been curatively treated for HCV infection as demonstrated clinically and by viral serologies 2. Have received HBV vaccination with only anti-HBs positivity and no clinical signs of hepatitis 3. Are HBsAg- and anti-HBc+ (ie, those who have cleared HBV after infection) and meet conditions i-iii of criterion 'd' below: 4. Are HBsAg+ with chronic HBV infection (lasting 6 months or longer) and meet conditions i-iii below: (i) HBV DNA viral load \< 2000 IU/mL (ii) Have normal transaminase values or, if liver metastases are present, abnormal transaminases, with a result of AST/ALT \< 3 × ULN, which are not attributable to HBV infection (iii) Start or maintain antiviral treatment if clinically indicated as per the investigator 9. Known HIV infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled: undetectable viral RNA, CD4+ count ≥ 350, no history of AIDS defining opportunistic infection within the past 12 months, and stable for at least 4 weeks on the same anti HIV medications (meaning there are no expected further changes in that time to the number or type of antiretroviral drugs in the regimen). If an HIV infection meets the above criteria, monitoring of viral RNA load and CD4+ count is recommended. Participants must be tested for HIV during the screening period if acceptable by local regulations or an IRB/EC. 10. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals; suspected infections (eg, prodromal symptoms); or inability to rule out infections (participants with localised fungal infections of skin or nails are eligible). 11. Known to have active tuberculosis infection (clinical evaluation that may include clinical history, physical examination, and radiographic findings, or tuberculosis testing in line with local practice). 12. Resting ECG with clinically abnormal findings. 13. Uncontrolled or significant cardiac disease including: 1. Myocardial infarction or uncontrolled/unstable angina within 6 months before the first dose of study intervention. 2. Congestive heart failure (New York Heart Association Class II to IV). 3. Uncontrolled hypertension (resting systolic blood pressure \> 180 mmHg or diastolic blood pressure \> 110 mmHg). 4. Cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (NCI CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted based on the investigator judgement with cardiologist consultation recommended. 14. History of non-infectious ILD/pneumonitis, including radiation pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening. 15. Has severe pulmonary function compromise. 16. Prior exposure to the following anticancer therapies: 1. Any TROP2-targeted therapy. 2. Any treatment (including ADC) containing a chemotherapeutic agent targeting topoisomerase I. 3. Any chemotherapy in the metastatic setting. 17. Prior exposure to chloroquine/hydroxychloroquine without an adequate treatment washout period of \> 14 days before the first dose of study intervention. 18. Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, targeted therapy, biologic therapy, tumour embolisation, or monoclonal antibodies ≤ 3 weeks \[for small molecule targeted agents: ≤ 2 weeks or 5 half-lives, whichever is longer, prior to the first dose of study intervention\]). Herbal or natural products intended as treatment or prophylaxis for any type of cancer that may interfere with the activity of the study intervention are excluded. 19. Any concurrent anticancer treatment with the exception of bisphosphonates, denosumab for the treatment of bone metastases. Concurrent use of hormonal therapy for non cancer related conditions (eg, HRT) is allowed. 20. Received prior radiotherapy to the chest within 4 weeks of the start of study intervention or has ongoing radiation-related toxicities requiring corticosteroids. 21. Palliative radiotherapy with a limited field of radiation within ≤ 2 weeks or with wide field of radiation to chest or to more than 30% of the bone marrow within ≤ 4 weeks prior to the first dose of study intervention. 22. Curative radiotherapy; however, palliative radiotherapy for optimal symptom control or pain management is allowed. 23. Concomitant use of chronic systemic (IV or oral) corticosteroids or other immunosuppressive medications \> 10 mg/day of prednisone or equivalent, except for managing AEs; inhaled steroids, intra-articular steroid injections, and other topical steroid formulations are permitted in this study. 24. 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. 25. Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 4 weeks (unless the safety profile is known prior to the first dose of study intervention), enrolment into a prior Dato-DXd study regardless of treatment assignment, or concurrent enrolment in another clinical study (unless the study is observational \[non-interventional\], or the participant is in the follow-up period of an interventional study). 26. Participants with a known history of severe hypersensitivity reactions to either the drug or inactive excipients (including but not limited to polysorbate 80) of Dato-DXd. 27. Participants with a known history of severe hypersensitivity reactions to other monoclonal antibodies. 28. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). 29. 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. 30. Previous enrolment in the present study. 31. For females only: is pregnant (confirmed with positive serum pregnancy test) or breastfeeding or planning to become pregnant. 32. Female participants should refrain from breastfeeding from enrolment throughout the study and for at least 7 months after last dose of study intervention. 33. Participants for whom the use of steroid-containing mouthwash in contraindicated.