The primary purpose of the study is to assess the safety, tolerability, and anti-tumor activity of HER3-DXd and T-DXd in the combination dosing regimens in participants with hormone receptor positive, HER2-low or HER2-ultralow, unresectable, or metastatic breast cancer.

Key Inclusion Criteria:

1. Pathologically documented breast cancer that meets the following:

   1. Unresectable or metastatic.

   2. HR+ based on testing performed locally. HR+ (estrogen receptor [ER] and/or progesterone receptor [PgR] positive [ER or PgR greater than equal to (≥)1 percent (%)] per American Society of Clinical Oncology [ASCO]/College of American Pathologists [CAP] 2020 guidelines) in the unresectable or metastatic setting.

   3. Assessed as HER2-low (defined as Immunohistochemistry (IHC)2+/In-situ hybridization (ISH)- or IHC1+) or HER2-ultralow (defined as IHC 0 with any membrane staining in greater than (>) 0 and lesser than equal to (≤)10% of the cancer cells) locally for Part 1 and centrally for Part 2. The HER2 result must be from a tumor sample obtained in the unresectable or metastatic setting.

      • For Dose Regimen Determination (Part 1), HER2 status used for eligibility assessment must be determined locally (according to applicable regulations) using the PATHWAY anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody (Ventana Medical Systems, Inc.). Additional HER2 testing will be performed locally and according to applicable regulations using the prescribed test during Screening only if prior results obtained with this test are not available for eligibility assessment.
      • For Dose Expansion (Part 2), HER2 testing will be performed prospectively at a central laboratory using the pretreatment tumor tissue sample.

2. Provides a pretreatment tumor tissue sample that meets one of the following collection requirements:

   1. Tissue biopsy collected from ≥1 lesion not previously irradiated and performed since progression with the most recent systemic cancer therapy regimen and prior to signature of the Tissue Screening informed consent form (ICF) (ARCHIVAL PRETREATMENT sample).

      OR

   2. Newly obtained pretreatment tumor biopsy from ≥1 lesion not previously irradiated and amenable to sampling, after signature of the Tissue Screening ICF (FRESH PRETREATMENT sample).

3. Documented radiologic disease progression as per investigator assessment per RECIST v1.1 criteria (during or after most recent treatment).

4. Documented refractoriness to endocrine therapy, defined as disease progression on one or more line of endocrine therapy in the unresectable or metastatic setting and determined by the investigator that participant would no longer benefit from further treatment with endocrine therapy.

5. Prior treatment with a Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor in any setting. Subsequent endocrine therapies administered after progression on CDK4/6 inhibitor are allowed.

6. Participants with genomic alterations/mutations (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA), phosphatase and tensin homolog (PTEN), AKT, or Breast Cancer gene (BRCA)1/2) who are eligible for approved targeted therapies in combination with endocrine therapy or as monotherapy (according to local label and availability) must have received the corresponding therapy prior to enrollment, unless contraindicated or not accessible in their country/region.

7. No prior chemotherapy for unresectable or metastatic breast cancer. Participants who have received chemotherapy in the neoadjuvant or adjuvant setting are eligible.

8. ECOG performance status 0 or 1 at the time of Screening.

9. Has ≥1 measurable lesion on CT or MRI per RECIST v1.1 by investigator assessment.

10. Has adequate bone marrow reserve and organ function based on local laboratory data within 7 days prior to the first dose as specified in the protocol.

Key Exclusion Criteria:

1. Prior treatment with an anti-HER3 antibody and/or antibody-drug conjugate (ADC) that consists of a topoisomerase I inhibitor (e.g., T-DXd) or any other topoisomerase I inhibitor therapy.

2. Has any history of interstitial lung disease (ILD)/pneumonitis irrespective of steroid use, or current ILD, or suspected ILD, or ILD that cannot be ruled out by imaging at Screening. Examples of suspected ILD/pneumonitis by imaging include the presence of lung parenchymal fibrosis, such as CPFE, and any radiographic features consistent with ILA, including but not limited to, extensive ground glass opacities, reticular opacities, traction bronchiectasis, and honeycombing. Participants may be eligible if they had history of radiation pneumonitis that did not require steroids.

3. Is receiving chronic systemic corticosteroids dosed at >10 mg prednisone daily or equivalent anti-inflammatory activity or any form of immunosuppressive therapy prior to randomization. Participants who require use of bronchodilators, inhaled or topical steroids, or local steroid injections may be included in the trial.

4. Evidence of spinal cord compression or brain metastases, defined as being clinically active and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Participants with clinically inactive or treated brain metastases who are asymptomatic (i.e., without neurologic signs or symptoms and do not require treatment with corticosteroids or anticonvulsants) may be included in the trial but must have a stable neurologic status for ≥4 weeks prior to Cycle 1 Day 1. Participants with asymptomatic brain metastases and treated with anticonvulsants as prophylaxis can enroll.

5. Inadequate washout period of prior treatment before randomization:

   1. Whole brain radiation therapy less than (<)28 days.
   2. Monoclonal antibodies other than immune checkpoint inhibitors, such as anti-vascular endothelial growth factor (VEGF) (e.g., bevacizumab) and anti-epidermal growth factor receptor (EGFR) (e.g., cetuximab) < 28 days.
   3. Immune checkpoint inhibitor therapy <21 days.
   4. Major surgery (excluding placement of vascular access) <28 days.
   5. Radiotherapy treatment to more than 30% of the bone marrow or wide field radiation or palliative stereotactic radiation to chest <28 days or palliative stereotactic radiation therapy to other anatomic areas <14 days.
   6. Chloroquine or hydroxychloroquine ≤14 days.
   7. Hormonal therapy <21 days prior to first dose of HER3-DXd.
   8. Live or live attenuated virus vaccination <30 days.

6. Uncontrolled or significant cardiovascular disease, including any of the following:

   1. QTcF prolongation interval >450 milliseconds (ms) (average of triplicate determinations at screening).
   2. Left ventricular ejection fraction (LVEF) ≤50%.
   3. Resting systolic blood pressure >160 millimeters of mercury (mmHg) or diastolic blood pressure >100 mmHg.
   4. Myocardial infarction within 6 months.
   5. New York Heart Association (NYHA) Classes 3 or 4 congestive heart failure.
   6. Uncontrolled angina pectoris within 6 months.
   7. Cardiac arrhythmia requiring ongoing antiarrhythmic treatment.
   8. Diagnosed or suspected long QT syndrome or known family history of long QT syndrome.
   9. History of clinically relevant ventricular arrhythmias, such as ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes.
   10. Bradycardia of <50 beats per minute (bpm) unless the participant has a pacemaker.
   11. History of second- or third-degree heart block. Participants with a history of heart block may be eligible if they currently have pacemakers and have no history of fainting or clinically relevant arrhythmia with pacemakers.
   12. Coronary/peripheral artery bypass graft within 6 months.
   13. Complete left bundle branch block.

7. Has history of other active malignancy within 3 years prior to randomization, except the following:

   1. Adequately resected nonmelanoma skin cancer.
   2. Adequately treated intraepithelial carcinoma of the cervix.
   3. Any other curatively treated in situ disease.
   4. Prostate carcinoma with a prostate-specific antigen value <0.2 nanograms per milliliter (ng/mL).

8. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute-Common Terminology Criteria for Adverse Events version 5.0 (NCI-CTCAE v5.0) Grade ≤1 or baseline.

9. Any known contraindication to treatment, including hypersensitivity to either the drug substances or inactive ingredients in the drug products.

Note: Other protocol specified inclusion/exclusion criteria may apply.

De-identified individual participant data (IPD) on completed studies and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/

Completed studies that has reached a global end or completion with all data set collected and analyzed, and for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.

Formal request from qualified scientific and medical researchers on IPD and clinical study documents on completed clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.