A Study of DB-1303/BNT323 vs Investigator's Choice Chemotherapy in HER2-Low, Hormone Receptor Positive Metastatic Breast Cancer (DYNASTY-Breast02)

Inclusion Criteria:

1. Male or female adults (defined as ≥ 18 years of age or acceptable age according tolocal regulations at the time of voluntarily signing of informed consent).

2. Pathologically documented breast cancer that:

3. Is advanced or metastatic

4. Has HER2-low expression (IHC 1+ or IHC 2+/ISH-) as determined by the centrallaboratory result.

5. Was never previously reported as HER2-positive (IHC 3+ or ISH+) as per AmericanSociety of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines.

6. Is documented as HR+ (either estrogen receptor [ER] and/or progesterone receptor [PgR] positive [ER or PgR ≥1%]) per ASCO/CAP guidelines (Allison et al 2020).

7. Must have an adequate tumor tissue sample available for assessment of HER2 bycentral laboratory, in formalin fixation and paraffin embedding (FFPE) blocks basedon a mandatory FFPE tumor sample preferably obtained at the time of metastaticdisease or later;

8. Eastern Cooperative Oncology Group performance status of 0 or 1.

9. Must have had either:

10. Disease progression on endocrine therapy + CDK4/6 inhibitor within 6 months ofstarting first line treatment for metastatic disease and considered appropriate forchemotherapy as the next treatment by the investigator, OR

11. Disease progression on at least 2 previous lines of ET with or without a targetedtherapy (such as CDK4/6, mammalian target of rapamycin [mTOR] or phosphoinositide 3-kinase [PI3-K] inhibitors) administered for the treatment of metastatic disease.

12. No prior chemotherapy for advanced or metastatic breast cancer. Subjects who havereceived chemotherapy in the neo-adjuvant or adjuvant setting are eligible, as longas they have had a disease-free interval (defined as completion of systemicchemotherapy to diagnosis of advanced or metastatic disease) of >12 months.

13. Life expectancy ≥12 weeks at screening.

14. Subjects must have at least one measurable lesion as defined per RECIST v1.1 (Forbone only disease, subjects with lytic or mixed lytic bone lesions that can bemeasured by CT or MRI are eligible; subjects with sclerotic/osteoblastic bonelesions are not eligible).

15. Has LVEF ≥ 50% by either echocardiography (ECHO) or multiple-gated acquisition (MUGA) within 28 days before randomization.

16. Adequate organ and bone marrow function within 14 days before randomization.

17. Has adequate treatment washout period before randomization.

18. Evidence of post-menopausal status or negative serum pregnancy test for females ofchildbearing potential who are sexually active with a non-sterilized male partner.For women of childbearing potential, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be available at thescreening visit and urine beta-human chorionic gonadotropin (β-HCG) pregnancy testprior to each administration of study treatment.

Women of childbearing potential are defined as those who are not surgically sterile (i.e., underwent bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal.

13. Female subjects of childbearing potential who are sexually active with anon-sterilized male partner must use at least one highly effective method ofcontraception from the time of screening and must agree to continue using suchprecautions for 7 months after the last dose of study treatment. Not all methods ofcontraception are highly effective. Abstinence is acceptable only as true abstinencewhen this is in line with the preferred and usual lifestyle of the subject for theduration of the study treatment and the drug washout period (7 months). Periodicabstinence (e.g., calendar ovulation, symptothermal, post ovulation methods), therhythm method, and the withdrawal method are not acceptable methods ofcontraception. Female subjects must not donate ova, or retrieve for their own use,from the time of screening and throughout the study treatment period, and for atleast 7 months after the last dose of study treatment. They should refrain frombreastfeeding throughout this time. Preservation of ova may be considered prior torandomization in this study.

14. Non-sterilized male subjects who are sexually active with a female partner ofchildbearing potential must use a condom with spermicide from screening andthroughout the duration of the study treatment and the washout period (4 monthsafter the last dose of DB-1303, 6 months after the last dose of paclitaxel ornab-paclitaxel, and 3 months after the last dose of capecitabine). Abstinence isacceptable only as true abstinence when this is in line with the preferred and usuallifestyle of the subject for the duration of the study treatment and the drugwashout period. Periodic abstinence (e.g., calendar ovulation, symptothermal, postovulation methods), the rhythm method, and the withdrawal method are not acceptablemethods of contraception. It is strongly recommended for the female partners of amale subject also use at least one highly effective method of contraceptionthroughout this period. In addition, male subjects should refrain from fathering achild or donating sperm throughout the duration of the study and the washout period (4 months after the last dose of DB-1303, 6 months after the last dose of paclitaxelor nab paclitaxel, and 3 months after the last dose of capecitabine). Preservationof sperm should be considered prior to randomization in this study.

15. Must be able and willing to comply with the protocol requirements and must sign anddate the informed consent form prior to any screening evaluations.

Exclusion Criteria:

1. Ineligible for all options in the investigator's choice chemotherapy arm.

2. Uncontrolled intercurrent illness, including but not limited to, ongoing or activeinfection, uncontrolled or significant cardiovascular disease, serious chronicgastrointestinal conditions associated with diarrhea, or psychiatric illness/socialsituations that would limit compliance with study requirement, substantiallyincrease risk of incurring adverse events or compromise the ability of the subjectto give written informed consent.

3. Clinically uncontrolled pleural effusion, ascites or pericardial effusion requiringrepeated drainage, peritoneal shunt or cell-free concentrated ascites reinfusiontherapy within 2 weeks prior to the randomization.

4. Uncontrolled or significant cardiovascular disease

5. Has a medical history of interstitial lung diseases (e.g., non-infectiousinterstitial pneumonia, pneumonitis, pulmonary fibrosis, and radiation pneumonitiswhich needs glucocorticoids and antibiotics) or current interstitial lung diseasesor who are suspected to have these diseases by imaging at screening.

6. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline or Grade ≤ 2 anemia.

7. Previous treatment with anti-HER2 therapy.

8. Prior treatment with antibody-drug conjugate that comprised an exatecan derivativethat is a topoisomerase I inhibitor.

9. Prior randomization or treatment in a previous DB-1303/BNT323 study regardless oftreatment assignment.

10. Has substance abuse or any other medical conditions such as psychologicalconditions, that may, in the opinion of the Investigator, interfere with thesubject's participation in the clinical study or evaluation of the clinical studyresults.

11. Individuals who are dependent on the Sponsor, clinical site, or Investigator (e.g.,is an employee of the Sponsor or the clinical trial site, a dependent of theInvestigator, or any site staff member otherwise supervised by the Investigator).

12. Individuals who are committed to an institution by virtue of an order issued eitherby the judicial or the administrative authorities, in accordance with localregulations.

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