The efficacy and safety of zanidatamab in combination with physician's choice of chemotherapy compared with trastuzumab in combination with physician's choice of chemotherapy will be evaluated for the treatment of participants with metastatic HER2-positive breast cancer who have progressed on, or are intolerant to, previous T-DXd treatment.

Zanidatamab, as a monotherapy or in combination with other antineoplastic agents, has shown clinically meaningful efficacy against multiple HER2-positive advanced/metastatic tumors, including in patients with metastatic breast cancer (mBC). Zanidatamab may offer a viable treatment option for patients with metastatic HER2-positive breast cancer.

The primary objective of the study is to compare the efficacy of zanidatamab plus chemotherapy versus trastuzumab plus chemotherapy. The secondary objectives of the study will include further comparing the efficacy, safety and tolerability, patient-reported tolerability, and patient-reported physical functioning of zanidatamab plus chemotherapy versus trastuzumab plus chemotherapy. The pharmacokinetics and immunogenicity of zanidatamab in combination with chemotherapy will also be evaluated.

Participants are eligible to be included in the study only if all of the following criteria apply:

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

2. Has histologically confirmed HER2-positive breast cancer according to ASCO-CAP Guidelines as evaluated by a sponsor-designated central laboratory

3. Participants with unresectable or metastatic HER2 positive breast cancer who have progressed on, or are intolerant to, previous T-DXd treatment.

4. Must have received at least 2 lines of HER2-directed therapy for their metastatic disease.

   1. Prior HER2-targeted neo-adjuvant or adjuvant therapy that resulted in relapse within 6 months of the completion of therapy will be considered a line of treatment for metastatic disease.
   2. Based on the physician's choice, participants' eligibility, and institutional and local guidelines, participants may also have received post-T-DXd therapy, for example, a tucatinib-based regimen and/or T-DM1.
   3. Participants must not have received more than 4 lines of HER2-directed therapy in the metastatic setting.

5. Has measurable disease per RECIST version 1.1.

6. Is eligible to receive one of the chemotherapy options listed in the physician's choice of chemotherapy (eribulin, gemcitabine, vinorelbine, or capecitabine).

7. Participants with history of treated or clinically inactive CNS metastases are eligible as specified in the protocol.

8. Has a life expectancy of at least 6 months, in the opinion of the investigator.

9. Has adequate hematologic parameters as defined in the protocol.

10. Has adequate hepatic function as specified in the protocol.

11. Has creatinine clearance ≥ 50 mL/minute as calculated per local institutional guidelines.

12. Has LVEF ≥ 50% as determined by either echocardiogram or MUGA obtained within 4 weeks before the first dose of study intervention.

13. Has ECOG performance status of 0 or 1.

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

    1. Male participants:

       Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 7 months after the last dose of study intervention or the contraception period for the combination chemotherapy of choice per local guidance/standard practice:

       • Refrain from donating fresh unwashed semen.
       • Use contraception as follows as specified in the protocol

    2. Female participants:

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

         • Is a women of nonchildbearing potential OR
         • Is a woman of childbearing potential (WOCBP) and using a contraceptive method that is highly effective (with a failure rate of < 1% per year), with low user dependency during the study intervention period and for at least 7 months after the last dose of study intervention.

       • 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.

       • Additional requirements for pregnancy testing during and after study intervention are provided in the protocol.

       • 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.

15. Is capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form and in the protocol.

Participants are excluded from the study if any of the following criteria apply:

Medical Conditions

1. Has clinically confirmed leptomeningeal disease, in the opinion of the investigator.

2. Has uncontrolled or significant cardiovascular disease.

3. Has toxicity related to prior cancer therapy that has not resolved to ≤ Grade 1, with exceptions as stated in the protocol.

4. Has uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.

5. Has an infection with HIV-1 or HIV-2, with the exception of participants with well-controlled HIV.

6. Has active hepatitis B or C infection.

7. Has an active SARS-CoV-2 infection. Participants with prior infection that has resolved per local institutions' requirements and screening guidance are eligible.

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

9. Is unable to receive trastuzumab treatment due to medical contraindications.

10. Has any serious underlying medical or psychiatric condition that would impair the ability of the participant to receive or tolerate the planned treatment at the investigational site.

11. Has any condition that would prevent treatment with the physician's choice of chemotherapy.

12. Has any issue or condition that in the opinion of the investigator would contraindicate the participant's participation in the study or confound the results of the study.

    Prior/Concomitant Therapy

13. Has a history of prior allogeneic bone marrow, stem cell, or solid organ transplantation.

14. The washout periods for prior anticancer therapies before randomization as specified in the protocol.

15. Has a history of trauma or major surgery within 4 weeks prior to randomization.

    Other Exclusions

16. Has a known hypersensitivity to any components of the study drugs, including chemotherapy.

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