Key Inclusion Criteria (applicable to all participants and all parts unless otherwise specified):

• Have pathologically documented BC that:

  • Is locally advanced, unresectable or metastatic.
  • Has a confirmed HER2 status as determined by the local laboratory (Part 1, Part 2 Cohorts 2 and 4) or the central laboratory (Part 2, Cohorts 1 and 3) from the most recently collected pre-randomization tumor sample.
  • Has a documented history of HER2 expression consistent with the subgroup definitions (i.e., HER2-low, HER2-ultralow, HER2-null, HER2-positive, or TNBC) as per current American Society of Clinical Oncology/College of American Pathologists guidelines.

• Have measurable disease defined by RECIST v1.1.

• Has left ventricular ejection fraction ≥55% by either echocardiography or multi-gated acquisition (scanning) within 28 days before randomization/enrollment.

Key Exclusion Criteria:

• Have history of small bowel obstruction requiring hospitalization within the past 3 months prior to the first dose of IMP.

• Have an uncontrolled intercurrent illness that would limit compliance with study requirement or substantially increase risk of incurring adverse events.

• Have clinically uncontrolled pleural effusion, ascites or pericardial effusion requiring drainage, peritoneal shunt, or cell-free concentrated ascites reinfusion therapy within 2 weeks prior to randomization/enrollment.

• Have a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, have current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.

• Had prior treatment with topoisomerase I inhibitors, including ADCs with topoisomerase I inhibitor payloads such as trastuzumab deruxtecan.

• Have received any of the following therapies or drugs prior to the initiation of the study:

  • Participants who have previously been randomized to or received treatment in a previous study with BNT323, regardless of treatment assignment.
  • Participants who received prior treatment with a PD-L1/VEGF bispecific antibody. Note: Prior treatment with PD-1/VEGF bispecific antibodies, PD-1/PD-L1 inhibitors or anti-VEGF therapies are permitted.
  • Have received other systemic immunostimulatory agents or immunosuppressive therapies (such as interferon-α, interleukin-2, or methotrexate) within 4 weeks prior to the initiation of study treatment or are within five half-lives of the treatment drug (whichever is longer). Exception: excluding local, intranasal, intraocular, intra-articular or inhaled corticosteroids, short term use (≤7 days) of corticosteroids for prophylaxis (e.g., prevention of contrast agent allergy) or treatment of non-autoimmune conditions (e.g., delayed hypersensitivity reactions caused by exposure to allergens).
  • Have received systemic corticosteroids (at a dosage greater than 10 mg/day of prednisone or an equivalent dose of other corticosteroids) within 3 weeks prior to the initiation of study treatment.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.