A Study Comparing the Efficacy and Safety of Zanidatamab to Trastuzumab, Each in Combination With Physician's Choice Chemotherapy, for the Treatment of Participants With Metastatic HER2-positive Breast Cancer

You may be eligible if

• 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.