Destiny-05: This phase III trial will compare the safety and effectiveness of two targeted cancer drugs in patients with HER-2 positive, invasive breast cancer following neoadjuvant therapyA Phase 3, Multicenter, Randomized, Open-Label, Active-Controlled Study of Trastuzumab Deruxtecan (T-DXd) Versus Trastuzumab Emtansine (T-DM1) in Participants With High-Risk HER2-Positive Primary Breast Cancer Who Have Residual Invasive Disease in Breast or Axillary Lymph Nodes Following Neoadjuvant Therapy (DESTINY-Breast05)

Inclusion

• Adults ≥18 years old (local regulatory requirements will apply if the legal age of consent for study participation is >18 years old).

• Pathologically documented HER2-positive breast cancer (BC):

  • HER2-positive expression defined as an immunohistochemistry (IHC) score of 3+ and/or positive by in situ hybridization (ISH) confirmed prior to study randomization.
• Histologically confirmed invasive breast carcinoma.
• Clinical stage at disease presentation: T1-4, N0-3, M0; patients presenting with T1N0 tumors are not eligible.

• Pathologic evidence of residual invasive carcinoma in the breast and/or axillary lymph nodes following completion of neoadjuvant therapy meeting one of the following high-risk criteria:

  • Inoperable breast cancer at presentation (prior to neoadjuvant therapy), defined as clinical stages T4, N0-3, M0 or T1-3, N2-3, M0.
  • Operable at presentation, defined as clinical stages T1-3,N0-1,M0, with axillary node positive disease (ypN1-3) following neoadjuvant therapy.

• Completion of neoadjuvant systemic therapy, including taxane-based chemotherapy and HER2-directed treatment prior to surgery.

  • Systemic therapy must consist of at least 6 cycles of neoadjuvant therapy with a total duration of at least 16 weeks, including at least 9 weeks of trastuzumab (± pertuzumab) and at least 9 weeks of taxane-based chemotherapy to be completed prior to surgery. Patients may have received an anthracycline as part of neoadjuvant therapy in addition to taxane chemotherapy.
• Adequate excision as confirmed per medical records: surgical removal of all clinically evident disease in the breast and axillary lymph nodes.
• An interval of no more than 12 weeks between the date of last surgery and the date of randomization.
• Known hormone receptor (HR) status, per local laboratory assessment, as defined by ASCO-CAP guidelines (≥1%): HR positive status defined by either positive estrogen receptor (ER) and/or positive progesterone receptor (PR).

status. HR-negative status defined by both known negative ER and known negative PR.

• Left ventricular ejection fraction (LVEF) ≥50% within 28 days prior to randomization.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at Screening.
• Has adequate organ function within 14 days before randomization.