A phase I clinical trial (a type of research study) for people with human epidermal growth factor receptor 2 (HER-2) positive breast cancer with metastasis to the brain. This research study will evaluate how well brain metastases can be controlled using a type of radiation therapy known as stereotactic radiosurgery (SRS) when combined with the therapeutic agent Trastuzumab Deruxtecan (T-DXd). The combined use of SRS with T-DXd is considered investigational.

Inclusion Criteria:

1. Histologically confirmed HER-2-positive breast cancer with newly diagnosed brain metastases.
2. ECOG Performance Status (PS) of 0, 1, 2.
3. Participants with 1-10 brain metastases will be candidates for T-DXd with SRS at the discretion of the treating radiation oncologist. Intra-cranial metastasis must measure 3 cm or less in the greatest dimension.
4. Age ≥ 18 years
5. Signed written informed consent by patient or legally authorized representative. A signed informed consent must be obtained prior to any study-specific procedures.
6. Life expectancy of at least 12 weeks.
7. Any number of prior systemic therapies will be allowed, except T-DXd.
8. Hemoglobin ≥ 9 g/dL, White blood count ≥ 3.0 × 109/L, Absolute Neutrophil count ≥ 1.5 × 109/L and platelet count ≥ 100 × 109/L.
9. Serum bilirubin ≤ 1.5 × upper limit of normal (ULN).
10. AST and/or ALT ≤ 2 × ULN (≤ 5 × ULN when clearly attributable to the presence of liver metastases).
11. Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance > 60 mL/min.
12. Ability to comply with study procedures and monitoring.
13. For individuals of childbearing potential, a negative pregnancy test should be obtained within 7 days prior to the start of therapy.
14. Participants must have left ventricular ejection fraction (LVEF) ≥ 50% by either an echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan within 28 days before enrollment (to be assessed as clinically indicated).
15. Male or female participants of reproductive potential need to employ two highly effective and acceptable forms of contraception throughout their participation in the study and for 7 months after last dose of T-DXd.

Highly effective and acceptable forms of contraception are:

• Male condom plus spermicide
• Cap plus spermicide
• Diaphragm plus spermicide
• Copper T
• Progesterone T
• Levonorgestrel-releasing intrauterine system (e.g., Mirena®)
• Implants
• Hormone shot or injection
• Combined pill
• Mini-pill
• Patch

Postmenopausal individuals on the study (that will not need contraception) is defined as:

• Amenorrhoeic for 1 year or more following cessation of exogenous hormonal treatments.
• LH and FSH levels in the postmenopausal range for individuals < 50 years.
• Radiation-induced oophorectomy with last menses > 1 year ago.
• Chemotherapy-induced menopause with > 1 year interval since last menses.
• Surgical sterilization (bilateral oophorectomy or hysterectomy).

Men and women and members of all races and ethnic groups are eligible for this trial.

Exclusion Criteria:

1. Participants with leptomeningeal metastases documented by MRI or CSF evaluation.
2. Evidence of intra-tumoral or peri-tumoral hemorrhage deemed clinically significant by the treating physician.
3. Brain metastases within 5 mm of the optic chiasm or optic nerve.
4. Significant or recent acute gastrointestinal disorders with diarrhea as a major symptom, e.g., Crohn's disease, malabsorption, or CTCAE grade > 2 diarrhea of any etiology at baseline.
5. History of clinically significant or uncontrolled cardiac disease, including congestive heart failure, angina, myocardial infarction, arrhythmia, New York Heart Association (NYHA) functional classification of 3 or 4.
6. Unable to undergo brain MRI.
7. Screen for human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C. HIV/HBV/HCV testing per institutional practice.
8. All toxicities from prior therapies must have resolved to CTCAE v5.0 grade 1 or better by the time of study enrollment.
9. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., active, or uncontrolled infection, uncontrolled diabetes, second active malignancy) that could cause unacceptable safety risks or compromise compliance with the protocol.
10. Currently receiving other investigational cancer therapy (with the exception of continuing therapy with GnRH analogues) within 4 weeks prior to start of study treatment.
11. Mean QT interval corrected heart rate (QTc) ≥ 470 ms calculated from 3 electrocardiograms using Fredericia's Correction, calculated as: 8.22 ∛(RR interval)
12. LVEF <50%.
13. Ineligible for treatment with T-DXd.
14. Ineligible for treatment with SRS.
15. Active or prior documented ILD/pneumonitis or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
16. History of hypersensitivity to T-DXd.
17. History and/or confirmed corneal ulceration.
18. Pregnant or breast feeding. The patients should not breast feed for 7 months after stopping the drug.
19. Use of anthracyclines will be prohibited while on the protocol.
20. Prior cranial radiation is not allowed.