1. Is at least 18 years of age or of the legal adult age per local standard at the time of signing the informed consent.

2. Has Stage II or III (according to AJCC cancer staging manual anatomic staging table, edition 8) histologically confirmed invasive breast carcinoma. A minimum tumor size of 2 cm determined by imaging is required (for participants whose tumors are node negative or node positive). Participants with inflammatory breast cancer (T4d) are eligible.

3. Has histologically confirmed HER2-positive breast cancer according to ASCO/CAP Guidelines (Wolff, 2018).

a. Participants with local/site assessed IHC3+ defined as circumferential membrane staining that is complete, intense, and in > 10% of tumor cells per ASCO/CAP Clinical Practice Guidelines (Wolff, 2018) performed on tumor tissue taken during diagnostic biopsy utilizing an FDA approved or CE-marked HER2 in vitro diagnostic in accordance with the instructions for use are randomized directly.

   − The most recently available tissue blocks or freshly cut slides will be submitted to a sponsor-designated central laboratory to retrospectively confirm HER2 positivity.

b. Participants with local/site assessed IHC2+ (and ISH+) defined as weak to moderate membrane staining observed in > 10% of tumor cells per ASCO/CAP Clinical Practice Guidelines (Wolff, 2018) performed on tumor tissue taken during diagnostic biopsy utilizing an FDA approved or CE-marked HER2 in vitro diagnostic in accordance with the instructions for use require central confirmation prior to randomization.

   − The most recently available tissue blocks or freshly cut slides will be submitted to a sponsor-designated central laboratory to confirm HER2 positivity prior to randomization.

   − Note: The proportion of participants with tumors expressing IHC2+/ISH+ will be monitored such that up to approximately 20% will be included to reflect the proportion observed across historical studies (Earl, 2019; Krop, 2022; Pérez-García, 2021; de Haas, 2023; Tarantino, 2024). Based on ongoing review of IHC2+ incidence observed on study, enrollment may be capped in this subpopulation.

c. Is able to provide the most recently available tissue block(s) or freshly cut slides for HER2 positivity confirmation and biomarker analysis.

   − This biopsy may have been the participant’s diagnostic biopsy that was obtained prior to consideration of study enrollment (if sufficient tissue is available) or the participant’s pretreatment biopsy obtained during screening (if sufficient tissue is not available). Details regarding tissue amounts will be provided in the laboratory manual.

4. Has a known HR status of the primary tumor performed by local immunohistochemical methods according to the institution standard protocol. Participants may have HR-positive or HR-negative disease, as defined by ASCO-CAP guidelines.

5. Participants with multifocal or multicentric disease are eligible if the largest tumor (which must be larger than or equal to 2 cm in diameter) is HER2-positive, and the treating physician has determined the participant should be treated as HER2-positive.

6. Agrees to undergo a mastectomy or BCS after neoadjuvant therapy.

7. Has an ECOG performance status of 0 or 1.

8. The participant meets the following baseline laboratory criteria:

• Total serum bilirubin < 1.5 × ULN (total serum bilirubin < 3 × ULN in participants with Gilbert’s disease)

• ALT, AST, and alkaline phosphatase ≤ 1.5 × ULN

• Creatinine clearance > 30 mL/min (calculated per Cockcroft, 1976). Additional methods in calculating creatinine clearance are acceptable per investigator discretion and/or institution guidelines for determining eligibility.

• Absolute neutrophil count ≥ 1.5 × 109 /L

• Platelet count ≥ 100 × 109 /L • Hemoglobin ≥ 9 g/dL; participants with chronic anemia (other than autoimmune hemolytic anemia) that is supported by intermittent red blood cell transfusions are eligible.

• INR and (activated) partial thromboplastin time/partial thromboplastin time ≤ 1.5 × ULN unless participant is receiving anticoagulation therapy, as long as prothrombin time and (activated) partial thromboplastin time are within therapeutic range of intended use of anticoagulation. If receiving a direct oral anticoagulant, all general monitoring parameters (signs and symptoms of bleeding, complete blood count, and comprehensive metabolic panel to include liver function tests, albumin, bilirubin, and serum creatinine) must be within the range of intended use and consistent with all eligibility criteria per protocol, as determined by the investigator.

9. The participant has LVEF ≥ 50% as determined by either ECHO or MUGA obtained within 4 weeks prior to first dose of study intervention.

10. Participant agrees to the following based on sex assigned at birth.

   a. Male participants: Male participants are eligible to participate if they agree to the following during the intervention period and for at least 7 months after the last dose of all study interventions or the contraception period for the chemotherapy per local guidance/standard practice, whichever is longer: (This requirement aligns with the contraception period recommended for trastuzumab and is longer than the recommended contraception period for zanidatamab, which is 4 months, and for all other allowed chemotherapy options.)

• Refrain from donating fresh unwashed semen.

• Use contraception as follows:

o Use a male condom and should also be advised of the benefit of a female partner using a highly effective method of contraception (as defined in Table 17 of Appendix 5 Contraceptive and Barrier Guidance), as a condom may break or leak, when having sexual intercourse with a WOCBP who is not currently pregnant.

o Agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person.

   b. Female participants:

• A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:

o Is a WONCBP as defined in Appendix 5 Contraceptive and Barrier Guidance. 

OR

− Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of < 1% per year), with low user dependency or a highly effective method that is user dependent OR 2 effective nonhormonal contraceptive methods that are user dependent, as described in Table 16 of Appendix 5 Contraceptive and Barrier Guidance, during the study intervention period and for at least 7 months after the last dose of all study interventions. The investigator should evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of study intervention. This requirement aligns with the contraception period recommended for trastuzumab and is longer than the recommended contraception period for zanidatamab, which is 4 months, and for all other allowed chemotherapy options. Therefore, 7 months is considered sufficient to collect details of all pregnancies.

• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 3 days before the first dose of study intervention (Section 8.3.7 Pregnancy Testing).

   − If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.

• Additional requirements for pregnancy testing during and after study intervention are provided in Section 8.3.7 Pregnancy Testing.

• The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.

11. Is capable of giving signed informed consent as described in Section 10.1.3, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

1. Has Stage IV (metastatic) breast cancer.

2. Has bilateral breast cancer.

3. Has a history (≤ 6 months before the start of treatment) of any severe and/or uncontrolled medical conditions or other conditions that, in the opinion of the investigator, could affect the participant’s involvement in the study.

4. Has uncontrolled hypertension (systolic > 180 mm Hg and/or diastolic > 100 mm Hg) or clinically significant (ie, active) cardiovascular disease: cerebrovascular accident/stroke or myocardial infarction within 6 months prior to the first dose of study intervention, ventricular arrhythmia requiring therapy, or congestive heart failure of New York Heart Association (NYHA) Class II or higher.

5. Has significant symptoms (Grade ≥ 2) from peripheral neuropathy.

6. Has an active uncontrolled (febrile within the last 48 hours; no evidence of hypotension; no ongoing systemic sequela) infection (≥ Grade 2).

7. Has a history of life-threatening hypersensitivity to monoclonal antibodies or to recombinant proteins or excipients in the drug formulation of zanidatamab or other study interventions.

8. Known active hepatitis B or C infection.

• Participants who are hepatitis B surface antigen positive are eligible if they have hepatitis B virus DNA less than 500 IU/mL.

• Participants positive for hepatitis C virus antibody are eligible only if polymerase chain reaction is negative for hepatitis C virus RNA.

9. Has another malignancy diagnosed within the last 5 years. Exceptions include previously treated nonmelanomatous skin cancers, carcinoma in-situ, and melanoma in-situ.

10. Was treated with chemotherapy, anti-HER2 therapy, radiation therapy, endocrine therapy, or experimental therapy for invasive breast cancer (or DCIS if ipsilateral as the invasive breast cancer).

11. Is planning to receive concurrent therapy with any other investigational agent or anticancer therapy not specified in the protocol prior to the EOT Visit, including chemotherapy; radiotherapy (except for adjuvant radiotherapy for breast cancer after completion of chemotherapy); immunotherapy; or biological, hormonal or targeted anticancer therapy. Estrogen replacement therapy is not permitted in participants with HR-positive tumors.

12. Receipt of a live vaccine within 4 weeks prior to enrollment.

13. Female participants who are breastfeeding or pregnant and female and male participants planning a pregnancy.

14. Has a known hypersensitivity to any components of the study interventions, including chemotherapy.