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 including HER2 null with no staining or incomplete and faint/barely perceptible membrane staining in ≤ 10% of tumour cells) based on a fresh, or recent tissue sample obtained no more than 6 weeks prior to or during the screening period. 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 (newly acquired tumour biopsy at baseline or a tumour biopsy sample collected within 6 weeks prior to screening) as defined in the Laboratory 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 throughout the duration of treatment and 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 throughout the duration of treatment 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 ongoing or active infection), 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