⁃ 1 Participant must be \>18 years of age inclusive, at the time of signing the informed consent.

⁃ 2 Patients who are willing and capable of giving signed informed consent as described in Appendix A, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

⁃ 3 Participants with pathologically documented breast cancer that:

• is unresectable or metastatic

• HER2-positive expression (IHC 3+ or IHC 2+ with ISH positive) as confirmed by laboratory assessment within last 1 year of study enrolment.

• was previously treated with an anti HER-2 based regimen 4 Adequate bone marrow function, within 14 d before enrolment, defined as:

• a. Absolute neutrophil count ≥ 1.5 × 109/L (granulocyte colony-stimulating factor administration is not allowed within 1 wk prior to Screening assessment); b. Platelet count ≥ 100 × 109/L (Platelet transfusion is not allowed within 1 wk prior to Screening assessment); c. Hemoglobin level ≥ 9.0 g/dL (Red blood cell transfusion is not allowed within 1 wk prior to Screening assessment).

• 5 Adequate renal function within 14 d before enrolment, defined as:

• Creatinine clearance ≥ 30 mL/min, as calculated using the Cockcroft-Gault equation (CLcr (mL/min) = \[140 - age (years)\] × weight (kg) {× 0.85 for females}; 72 × serum creatinine (mg/dL) 6 Adequate hepatic function within 14 d before enrolment, defined as:

• Total bilirubin ≤ 1.5 × upper limit of normal (ULN) if no liver metastases or \< 3

• × ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline, and

• Aspartate transaminase (AST)/alanine transaminase (ALT) ≤ 3 × ULN

• 7 Adequate blood clotting function within 14 d before enrolment, defined as:

• International normalized ratio/prothrombin time ≤ 1.5 × ULN and either partial thromboplastin or activated partial thromboplastin time ≤ 1.5 × ULN 8 Female subjects of reproductive/childbearing potential must agree to use a highly effective form of contraception or avoid intercourse during and upon completion of the study and for at least 7 mo after the last dose of trastuzumab deruxtecan. Male subjects must agree to inform all potential female partners that they are participating in a clinical trial of a drug that may cause birth defects. Male subjects must also agree to either avoid intercourse or that they and/or any female partners of reproductive/childbearing potential will use a highly effective form of contraception during and upon completion of the study and for at least 4.5 mo after the last dose of trastuzumab deruxtecan. Methods considered as highly effective methods of contraception include:

• Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:

• o Oral

• o Intravaginal

• o Transdermal

• Progestogen-only hormonal contraception associated with inhibition of ovulation:

• o Oral

• o Injectable

• o Implantable

• Intrauterine device

• Intrauterine hormone-releasing system

• Bilateral tubal occlusion

• Vasectomized partner

• Complete sexual abstinence defined as refraining from heterosexual intercourse during and upon completion of the study and for at least 7 mo for female subjects (4.5 mo for male subjects) after the last dose of trastuzumab deruxtecan. True abstinence must be in line with the preferred and usual lifestyle of the subject. Periodic abstinence (calendar, symptothermal, postovulation methods) is not an acceptable method of contraception.

⁃ Non-childbearing potential is defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 mo of spontaneous amenorrhea (in questionable cases, a blood sample with simultaneous follicle-stimulating hormone \> 40 mIU/mL and estradiol \< 40 pg/mL \[\< 147 pmol/L\] is confirmatory). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use 1 of the contraception methods outlined for women of childbearing potential if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status prior to study enrollment. For most forms of HRT, at least 2 to 4 wk will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their postmenopausal status, they can resume use of HRT during the study without use of a contraceptive method.

⁃ 9 Male subjects must not freeze or donate sperm throughout the study period beginning at Cycle 1 Day 1 and for at least 4.5 mo after the last dose of trastuzumab deruxtecan or Preservation of sperm should be considered prior to enrollment in this study.

⁃ 10 Female subjects must not donate ova or retrieve them for their own use from the time of Screening and throughout the study treatment period, and for at least 7 mo after the last dose of trastuzumab deruxtecan