A total of 224 subjects of HER2-positive advanced breast cancer with brain metastases are planned to be enrolled. Eligible subjects will be randomly assigned in a 1:1 ratio to the group receiving Trastuzumab Rezetecan combined with radiotherapy or the group receiving Trastuzumab Rezetecan monotherapy until disease progression, intolerable toxicity, withdrawal of informed consent, or the study determines that treatment must be terminated (whichever occurs first).

Inclusion Criteria:

1. Females ≥18 yrs old;
2. Pathologically confirmed HER2-positive advanced breast cancer;
3. At least one measurable intracranial lesion according to RANO-BM criteria, which had not received local treatment;
4. Without prior cranial radiation and had no indication for immediate local treatment or refuse to local treatment;
5. Life expectancy is not less than 6 months.
6. Adequate function of major organs.

Exclusion Criteria:

1. Subjects with leptomeningeal metastasis
2. CNS complications requiring emergency neurosurgical intervention
3. Previous treatment with trastuzumab deruxtecan (DS-8201a) or any other antibody drug conjugate (ADC) which consists of an exatecan derivative that is a topoisomerase 1 inhibitor;
4. Suffering from heart disease that is not well controlled or having clinical symptoms
5. History of clinically significant lung disease；
6. Other malignant tumors, excluding cured cervical carcinoma in situ, skin basal cell carcinoma or skin squamous cell carcinoma, have been diagnosed in the past five years.
7. Female subjects during pregnancy and lactation
8. Any other conditions that researchers believe that patients are unsuitable for this study.

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