This study will look at the efficacy and safety of trastuzumab deruxtecan (T-DXd) in a neoadjuvant setting, in high-risk, HER2-positive early non-metastatic breast cancer.

The target population of interest in this study is participants with high-risk HER2-positive early-stage breast cancer. The purpose of this study is to determine the efficacy and safety of T-DXd neoadjuvant therapy.

Participants will be randomised to one of 3 arms: T-DXd monotherapy (Arm A), T-DXd followed by THP (Arm B), or ddAC-THP (Arm C).

Key Inclusion Criteria:

• Patients must be at least 18 years of age.
• Histologically documented HER2-positive early breast cancer (EBC) participants, including clinical stage at presentation (based on mammogram or breast MRI assessment): T0-4 (inclusive of inflammatory breast cancer), N1-3, M0 or ≥ T3, N0, M0 as determined by the AJCC staging system, 8th edition
• ECOG performance status of 0 or 1 at randomization
• Adequate organ and bone marrow function
• LVEF ≥ 50% within 28 days before randomization
• FFPE tissue block (2 cores) or 20 freshly-cut, serial tumor slides for HER2 assessment by central lab. If blocks are incomplete or fewer than 20 slides are available, participants may be eligible following discussion with the AstraZeneca Study Physician

Exclusion Criteria:

• prior history of invasive breast cancer
• stage IV breast cancer (determined by AJCC staging system)
• any primary malignancy within 3 years (except resected non-melanoma skin cancer, curatively treated in situ disease) Note: This includes a second current breast primary malignancy (ie, bilateral breast cancer)
• history of DCIS (except those treated with mastectomy >5 years prior to current diagnosis)
• History of, or current, ILD/pneumonitis
• Prior systemic therapy for the treatment of breast cancer
• Previous treatment with anthracyclines, cyclophosphamide or taxanes for any malignancy

Qualified researchers can request access to anonymized individual patient data from AstraZeneca Group of Companies, sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ Disclosure Commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure

When a request has been approved, AstraZeneca will provide access to the de-identified patient level data in an approved sponsor tool. Signed Data Sharing Agreements (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure