Sein

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

• Is 18 years of age or of the legal adult age per local standard at the time of signing the informed consent.
• Has histologically confirmed HER2-positive breast cancer according to ASCO-CAP Guidelines as evaluated by a central laboratory
• Participants with unresectable or metastatic HER2 positive breast cancer who have progressed on, or are intolerant to, previous T-DXd treatment.
• Has measurable disease per RECIST version 1.1.
• Is eligible to receive one of the chemotherapy options listed in the physician's choice of chemotherapy (eribulin, gemcitabine, vinorelbine, or capecitabine).
• Participants with history of treated or clinically inactive CNS metastases are eligible as specified in the protocol.
• Has a life expectancy of at least 6 months, in the opinion of the investigator.
• Has adequate hematologic parameters as defined in the protocol.
• Has adequate hepatic function as specified in the protocol.
• Has creatinine clearance ≥ 30 mL/minute as calculated per local institutional guidelines.
• Has LVEF ≥ 50% as determined by either echocardiogram or MUGA obtained within 4 weeks before the first dose of study intervention.
• Has ECOG performance status of 0 or 1.
• 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.

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

Male participants:

• Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 5 months after the last dose of study intervention or the contraception period for the combination chemotherapy of choice per local guidance/standard practice, whichever is longer:

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

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 5 months after the last dose of study intervention or the contraception period for the combination chemotherapy of choice per local guidance/standard practice, whichever is longer.
• 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.

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

Medical Conditions

• Has known or suspected leptomeningeal disease.
• Has uncontrolled or significant cardiovascular disease.
• Has toxicity related to prior cancer therapy that has not resolved to ≤ Grade 1, with exceptions as stated in the protocol.
• Has uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.
• Has known HIV infection.
• Has active hepatitis B or C infection.
• Has an active SARS-CoV-2 infection. Participants with prior infection that has resolved per local institutions' requirements and screening guidance are eligible.
• Has a history of life-threatening hypersensitivity to monoclonal antibodies or to recombinant proteins or excipients in the drug formulation of zanidatamab.
• Is unable to receive trastuzumab treatment due to medical contraindications.
• 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.
• Has any condition that would prevent treatment with the physician's choice of chemotherapy.

• 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

• Has a history of prior allogeneic bone marrow, stem cell, or solid organ transplantation.
• Was treated with any local or systemic antineoplastic therapy (including hormonal therapies for breast cancer) or any investigational therapy within 4 weeks or 5 half-lives (whichever is longer) prior to randomization.

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

  Other Exclusions

• Has a known hypersensitivity to any components of the study drugs, including chemotherapy.
• Female participants who are breastfeeding or pregnant, and female and male participants planning a pregnancy.