Lack of funding

The objective of this trial, DBCG R25, will be to evaluate the effect of trastuzumab-deruxtecan versus standard of care on progression-free survival (PFS) in first-line for patients with non-Luminal A, ER-positive/HER2-negative metastatic breast cancer

Study design and setting We will conduct an international, multicentre, open-label, randomised controlled trial. All oncological departments who treat patients with metastatic breast cancer can participate. The EU Clinical Trial Regulation will be applied.

Interventions Trial participants will be randomised to trastuzumab deruxtecan or standard treatment.

Trastuzumab deruxtecan

Patients randomised to trastuzumab deruxtecan will be treated as:

Trastuzumab deruxtecan until progression or intolerable toxicity, Trastuzumab deruxtecan: 5.4 mg/kg intravenous on day 1 of a 21 days cycle.

Standard

Patients randomised to standard will be treated as:

CDK4/6 inhibitor with an endocrine therapy until progression or intolerable toxicity CDK4/6 inhibitor: Physician's choice of ribociclib (600mg daily for 21 days in a 28 days cycle) or abemaciclib (150mg twice daily).

Endocrine therapy: letrozole (2.5mg daily), anastrozole (1mg daily), exemestane (25mg daily), tamoxifen (20mg daily) or fulvestrant (intramuscular 500mg every 4 weeks)

Other treatment Prophylactic antiemetics are allowed, including corticosteroids. Prophylactic antibiotics are allowed if deemed necessary for the patient. G-CSF is allowed when needed.

All other symptomatic treatment to perform best of care is allowed as long as name, administration and length is documented in the chart. Bone targeted agents are allowed. No other antineoplastic treatment is allowed.

Radiological evaluation Patients will initially be scanned every 9-12 weeks as per investigator's or co-investigator's discretion with minimum a CT of the thorax and abdomen or a FDG-PET/CT. Patients with response can have this interval extended. Upon progression treatment/control is to be done according to department preferences, but subsequent treatment and day of death must be registered.

Inclusion Criteria:

• Women aged 18 or above.
• Radiologically/pathologically verified metastatic breast cancer.
• ER-positive (1% or more) and HER2-low (HER2 1+ or HER2 2+/ISH-neg)10,11.
• PAM50 Luminal B, HER2-enriched or Basal-like.
• Performance status 0-1.
• Evaluable disease

Exclusion Criteria:

• Patients who are incapable of understanding the written material received
• Patients with inaccessible tumour tissue
• Other malignant disease within 5 years (in situ cervix and non-melanoma skin cancer excluded)