This clinical trial is for adult participants who have triple-negative breast cancer (TNBC) without pathological complete response (pCR), as determined at the time of their surgery following neoadjuvant therapy. The term TNBC refers to the fact that the cancer cells do not have estrogen or progesterone receptors (ER or PR) and also do not make any or much of the protein called HER2 (human epidermal growth factor receptor 2). The term pCR refers to the absence of all signs of cancer in tissue removed during surgery. The term neoadjuvant therapy refers to treatment given as a first step to shrink a tumor before surgery is performed.
   
The purpose of this study is to learn more about whether an investigational drug called datopotamab deruxtecan (also called Dato-DXd), either alone or in combination with another investigational drug called durvalumab, will work and be safe for the treatment of triple-negative breast cancer (TNBC). Dato-DXd is considered investigational because it is not yet approved by the U.S. Food and Drug Administration (FDA), except for use in research studies like this one. Durvalumab is still in the development stage for the treatment of TNBC, and is not approved for treatment of TNBC.
   
The study will be comparing the investigational treatment (Dato-DXd with or without durvalumab) with FDA-approved treatments called capecitabine and pembrolizumab. Capecitabine and pembrolizumab will be given as stand-alone treatment agents or in combination. In this study, capecitabine and pembrolizumab are referred to as “Investigator’s Choice of Therapy” or “ICT”.
   
Participants will be randomly assigned a study treatment. “Randomly assigned” means that whatever treatment a participant gets will be by chance, like drawing names out of a hat. Participants have a 60% chance of being given the investigational treatments (either Dato-DXd with durvalumab or Dato-DXd alone) and a 40% chance of being given ICT (capecitabine and/or pembrolizumab). The timing of receiving treatments will be different depending on the study arm a participant is assigned to.

Dato-DXd is given by an intravenous (IV) infusion once every 3 weeks. Durvalumab is given by an IV infusion once every 3 weeks. Capecitabine is given as an oral tablet, taken twice a day on days 1-14 out of every 21 days (3 weeks). Pembrolizumab is given by IV infusion once every 3 weeks.

Participants will be in the study for approximately 8 years, though the length of participation will vary based on participants’ health and the study events. Participants will continue to receive treatment in this study until completion of planned therapy, or they experience toxicity (side effects that are severe), or they withdraw their consent from the study, or it is decided by the study doctor or AstraZeneca to stop their participation.