Premedication With Dexamethasone for Preventing Interstitial Lung Disease in Patients With Breast Cancer Treated With Trastuzumab Deruxtecan (MARGARET)

Inclusion Criteria:

1. Provision of signed, written and dated study informed consent, data protection informed consent and any locally required
2. Women or men aged ≥18 years (or the minimum age of consent in accordance with the local law), at the time of informed consent signature.
3. Histologically or cytologically confirmed metastatic breast cancer for which T-DXd treatment is approved and available at the participating center.

4. Diagnosis of metastatic breast cancer candidate to start a treatment with T-DXd in the subsequent settings:

   1. HR-positive with expression of HER2 (low or ultralow) ≤ 2 lines of chemotherapy in advanced disease
   2. HR-negative with expression of HER2-low ≤ 2 lines of chemotherapy in advanced disease
   3. HER2-positive independently from HR-positivity ≤ 3 lines of treatment in advanced disease
5. ECOG performance status of 0 or 1.

6. Adequate bone marrow as defined by the following laboratory values:

   1. ANC ≥1.5 × 109 /L
   2. Platelets ≥100 × 109 /L
   3. Hemoglobin ≥9.0 g/dL
7. Adequate hepatic function: Serum albumin ≥ 2.5 g/dL; total bilirubin ≤ 1.5 times upper limit of normal (ULN) (≤ 3 in patients with liver metastases or know history of Gilbert's disease); alkaline phosphatase (ALP) ≤ 2.5 times ULN; aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 times ULN (≤ 5 in patients with liver metastases); international normalized ratio (INR) < 1.5.
8. Adequate washout before randomization, including ≥4 weeks from major surgery or chest radiotherapy (≥2 weeks for non-chest stereotactic radiotherapy)
9. Patient willing and able to comply with the protocol procedures for the duration of the study including undergoing treatment and scheduled visits and examinations including follow-up.

Exclusion Criteria:

1. Patients with uncontrolled diabetes mellitus both type 1 and type 2 (HbA1c > 8.5%).
2. Patients with contraindications to dexamethasone, as determined by the investigator in consultation with medical monitoring before enrolment.
3. Patients already undergoing chronic steroid treatment (e.g. 10 mg/day of prednisone/prednisolone or equivalent).
4. Patients requiring oxygen therapy at rest.
5. Documented pneumonitis/ILD prior to Cycle 1 Day 1.
6. Uncontrolled or significant cardiovascular disease, including recent myocardial infarction (within 6 months), symptomatic heart failure (NYHA II-IV), elevated troponin without symptoms requiring cardiology evaluation, uncontrolled hypertension or arrhythmias, and QTcF prolongation >470 ms in females or >450 ms in males.
7. Impaired renal function with creatinine clearance <30 mL/min (calculated by Cockcroft-Gault formula).
8. Active or newly diagnosed CNS metastases, including meningeal carcinomatosis.
9. Patients with recent (<28 days) respiratory infections.
10. Inability to take oral medications, refractory or chronic nausea, gastrointestinal conditions (including significant gastric or bowel resection), history of malabsorption syndrome, or any other uncontrolled gastrointestinal condition that impacts the absorption of the study drug.
11. Palliative limited-field radiotherapy: <2 weeks (non-chest) or <4 weeks (chest or >30% bone marrow).
12. 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 trastuzumab deruxtecan. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 390 days after the last dose of IMP.
13. Active and uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
14. Evidence of ongoing alcohol or drug abuse as assessed by the Investigator.
15. Any severe medical or psychiatric condition that, in the Investigator's opinion, would preclude the patient's participation in a clinical study
16. Male and female subjects of reproductive/childbearing potential must agree to use a highly effective form of contraception or avoid intercourse during study participation. Female subjects without childbearing potential are defined as women who are surgically sterile (hysterectomy or documented bilateral tubal ligation) or postmenopausal, defined as at least 12 months of spontaneous amenorrhea.
17. Known allergy or hypersensitivity to study drugs or any excipient.