Inclusion Criteria:

          1. Patient must have signed a written informed consent form prior to any study specific
             procedures. When the patient is physically unable to give his/her written consent, a
             trusted person of his/her choice, independent from the investigator or the sponsor,
             can confirm in writing the patient's consent.

          2. Female or male subjects aged ≥18 years.

          3. Patient with histologically-confirmed diagnosis of invasive breast cancer. Tumors can
             be either HER2 immunohistochemistry (IHC)3+/in situ hybridization (ISH) positive or
             IHC2+/ISH positive or IHC2+/ISH negative or IHC1+ or IHC0+, of most recent tumor
             tissue sample available.

          4. Patient with a documented radiologic metastatic progression.

          5. Patient considered by the investigator as not amenable to any other validated
             therapeutic option, after at least 1 line of chemotherapy in metastatic setting.
             Patient must have been previously treated with anthracyclines and taxanes (in
             (neo-)adjuvant and/or metastatic setting). Additionally:

               -  Patient with HER2 over-expressing (IHC3+ and IHC2+/ISH+) tumor must have been
                  treated and have progressed on trastuzumab and on TDM-1. Prior treatment with
                  pertuzumab is not required.

               -  Patient with HER2 negative (IHC0, 1+, and 2+/ISH-) and hormone receptor positive
                  (estrogen receptor (ER)+ and/or progesterone receptor (PR)+) tumor must be
                  resistant to endocrine therapy and CDK4/6 inhibitors, and must have been treated
                  with capecitabine.

          6. Non-bone metastatic site easily accessible to biopsy.

          7. Presence of at least one measurable lesion according to Response Evaluation Criteria
             In Solid Tumors (RECIST) v1.1.

          8. Patient with world health organization (WHO) performance status ≤1.

          9. Adequate bone marrow function: absolute neutrophil count (ANC) ≥1.5 × 10⁹/L, platelet
             count ≥100 × 10⁹/L, and hemoglobin ≥9 g/dL (transfusion is not allowed within 1 week
             prior to baseline assessment).

         10. Adequate liver function: total bilirubin level ≤1.5 × the upper limit of normal (ULN)
             range if no liver metastases or <3 x ULN in the presence of documented Gilbert's
             Syndrome or liver metastases. Aspartate aminotransferase (AST) and alanine
             aminotransferase (ALT) levels ≤3 × ULN (AST and ALT≤ 5 ULN when documented liver
             metastasis).

         11. Adequate blood clotting function: International Normalized Ratio (INR)/Prothrombin
             Time (PT) and activated Partial Thromboplastin Time (aPTT) ≤1.5 x ULN.

         12. Adequate renal function: estimated creatinine clearance ≥30 mL/min according to the
             Cockcroft-Gault formula or serum creatinine ≤1.5 x ULN.

         13. Adequate cardiac function: left ventricular ejection fraction (LVEF) ≥ 50% at baseline
             as determined by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan
             within 28 days before inclusion.

         14. Male and female subjects of reproductive/childbearing potential must agree to use of a
             highly effective contraception for subjects throughout the study and for at least 4.5
             months after last study treatment administration if the risk of conception exists.

         15. Women of childbearing potential must have a negative serum pregnancy test within 14
             days of enrolment or urine pregnancy test 72 hours prior to enrolment.

         16. Patient is willing to comply with 2 sequential tumor biopsies (baseline and at first
             progression), and with a series of blood samples throughout the study.

         17. Patients must be affiliated to a Social Security System.

        Exclusion Criteria:

          1. Patient with a breast cancer amenable for resection or radiation therapy with curative
             intent.

          2. Patient has spinal cord compression or clinically active central nervous system
             metastases, defined as untreated and symptomatic, or requiring therapy with
             corticosteroids or anticonvulsants to control associated symptoms. Subjects with
             clinically inactive brain metastases may be included in the study. Subjects with
             treated brain metastases that are no longer symptomatic and who require no treatment
             with corticosteroids or anticonvulsants may be included in the study if they have
             recovered from the acute toxic effect of radiotherapy.

          3. Patient with bone metastatic disease only.

          4. Patient with multiple primary malignancies within 3 years, except adequately resected
             non-melanoma skin cancer, curatively treated in-situ disease, other solid tumors
             curatively treated, or contralateral breast cancer.

          5. Persistent unresolved toxicities with grade ≥2 (except alopecia and renal function).
             Subject with chronic Grade 2 toxicities may be eligible per the discretion of the
             Investigator after consultation with the Sponsor (eg, Grade 2 chemotherapy-induced
             neuropathy).

          6. Patient receiving treatments such as chemotherapy (including antibody drug therapy,
             retinoid therapy, hormonal therapy) within 3 weeks before inclusion (within 2 weeks or
             5 half-lives, whichever is longer, for small-molecule targeted agents, within 6 weeks
             for nitrosureas or mitomycin C), immunotherapy within 4 weeks before inclusion,
             radiotherapy within 4 weeks (if palliative stereotactic radiotherapy: within 2 weeks)
             or major surgery within 4 weeks. Participation in other studies involving
             investigational drug(s) within 4 weeks prior to study entry and/or during study
             participation.

          7. Patient using drugs that could have pharmacokinetics interaction with investigational
             drugs. Concomitant use of strong CYP3A4 inhibitors or OATP 1B inhibitors should be
             avoided. If concomitant use of strong CYP3A4 or OATP 1B inhibitors is unavoidable,
             consider delaying DS-8201a treatment until the inhibitors have cleared from the
             circulation (approximately 3 elimination half-lives of the inhibitors) when possible.
             If a strong CYP3A4 inhibitor or an OATP 1B inhibitor is co-administered and DS-8201a
             treatment cannot be delayed, patients should be closely monitored for adverse
             reactions.

          8. Patients with a concomitant use of chronic systemic (intravenous or oral)
             corticosteroids or other immunosuppressive medications except for managing adverse
             events (inhaled steroids or intra articular steroid injections are permitted in this
             study.) Subjects with bronchopulmonary disorders who require intermittent use of
             bronchodilators (such as albuterol) will not be excluded from this study.

          9. Patient with history of (noninfectious) interstitial lung disease (ILD)/pneumonitis
             that required steroids, has current ILD/pneumonitis, or suspected ILD/pneumonitis that
             cannot be ruled out by imaging at screening.

         10. Patient with clinically significant corneal disease in the opinion of the
             Investigator.

         11. Known prior severe hypersensitivity to investigational product or any component in its
             formulation, including known severe hypersensitivity reactions to study drug (National
             Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 Grade
             ≥3).

         12. Patient has a history of severe hypersensitivity reactions to other monoclonal
             antibodies.

         13. Patients previously treated with topoisomerase 1 inhibitor.

         14. Patient has substance abuse or any other medical conditions that would increase the
             safety risk to the subject or interfere with participation of the subject or
             evaluation of the clinical study in the opinion of the Investigator.

         15. Known history of testing positive for HIV or known acquired immunodeficiency syndrome.

         16. Known active hepatitis B virus or hepatitis C virus infection at screening.

         17. Active infection requiring systemic therapy (as intravenous antibiotics, antivirals,
             antifungals,…).

         18. Other severe acute or chronic medical conditions or psychiatric conditions including
             recent (within the past year) or active suicidal ideation or behavior; or laboratory
             abnormalities that may increase the risk associated with study participation or study
             treatment administration or may interfere with the interpretation of study results
             and, in the judgment of the investigator, would make the patient inappropriate for
             entry into this study.

         19. Patient with a history of symptomatic congestive heart failure (New York Heart
             Association Class II to IV), serious cardiac arrhythmia requiring treatment, history
             of myocardial infarction or troponin levels consistent with myocardial infarction 28
             days prior to inclusion, or unstable angina within 6 months prior to inclusion, or
             current dyspnea at rest due to advanced malignancy.

         20. Patient with a corrected QT interval (QTc) prolongation to >470 ms (females) or >450
             ms (males) based on average of the screening triplicate12-lead electrocardiogram
             (ECG).

         21. Pregnant women, women who are likely to become pregnant or are breastfeeding or women
             who want donate, or retrieve for their own use, ova from the time of screening and
             throughout the study and for at least 4.5 months after last study treatment
             administration.

         22. Patient with any psychological, familial, sociological or geographical condition
             potentially hampering compliance with the study protocol and follow-up schedule; those
             conditions should be discussed with the patient before registration in the trial.

         23. Patient unwilling to participate to the biological investigations.

         24. Individual deprived of liberty or placed under legal protection.