Fam-T-Dxd Demonstrates Superior Outcomes in Early HER2-Positive Breast Cancer Across Phase 3 DESTINY Trials

Recent results from 2 phase 3 DESTINY trials (DESTINY-Breast05, NCT04622319; and DESTINY-Breast11, NCT05113251)^1,2 highlight the growing role of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu; AstraZeneca/Daiichi Sankyo) as a potential practice-changing therapy for patients with high-risk early-stage breast cancer.

Breast cancer remains the most commonly diagnosed cancer among women worldwide, with HER2-positive disease representing approximately 15% to 20% of all cases. Although advances in HER2-directed therapies have significantly improved outcomes, patients with high-risk early-stage breast cancer continue to face recurrence challenges despite standard-of-care treatment. These 2 recent trials show promising results for patients and could represent a new standard of care for some patients with breast cancer.

DESTINY-Breast05: T-DXd vs T-DM1 in the Adjuvant Setting

The DESTINY-Breast05 trial compared T-DXd vs ado-trastuzumab emtansine (T-DM1) in patients with high-risk, HER2-positive early breast cancer who had residual invasive disease after neoadjuvant therapy. The results showed a statistically significant and clinically very important prolongation of invasive disease-free survival (iDFS) with T-DXd. This finding led to the first antibody-drug conjugate (ADC) to show superiority in this head-to-head setting.^1,3

DESTINY-Breast11: T-DXd in the Neoadjuvant Setting

The DESTINY-Breast11 trial was simultaneously conducted to compare T-DXd followed by a trastuzumab/pertuzumab-based chemotherapy regimen (THP) with standard-of-care therapies in the neoadjuvant setting for patients with high-risk, HER2-positive early-stage disease. The outcomes showed that improvement in pathologic complete response (pCR) rates with the T-DXd–based regimen was statistically significant and clinically meaningful.^2,4

Neoadjuvant therapy leading to pCR has been correlated with reduced disease recurrence and survival extension. By significantly improving pCR rates, T-DXd could reshape the treatment paradigm for patients with HER2-positive breast cancer at risk of recurrence after surgery.

Clinical Context and Mechanism of Action

T-DXd is a HER2-targeted ADC that connects trastuzumab to a topoisomerase I inhibitor payload through a cleavable linker. The treatment has shown strong activity in several cancers, notably heavily pretreated HER2-positive metastatic breast cancer, HER2-low breast cancer, gastric cancer, and non–small cell lung cancer.⁵

The structure of the ADC allows for the bystander effect, which means that the toxic payload can still reach the surrounding cancer cells that are not dependent on the heterogeneity of HER2 expression. Such a process is especially important in the early stage of the disease when small metastatic or leftover cells with different HER2 expression might be present.

Implications for Pharmacists and Patient Care

One of pharmacists' central roles in integrating T-DXd into practice is to explain to patients the advantages and risks of ADC therapy vs previously used treatments. They will also be safety supervisors, especially for the occurrence of interstitial lung disease, an adverse effect that may develop due to the use of T-DXd and requires prevention through immediate diagnosis and treatment. In addition, pharmacists can help optimize adherence and coordinate multidisciplinary care to ensure patients receive guideline-directed treatment sequencing and the best possible outcomes.

What Does This Mean for Patients and Pharmacists?

The phase 3 DESTINY-Breast05 and DESTINY-Breast11 trials have verified that T-DXd offers notable clinical benefits beyond the currently available standards in both the adjuvant and neoadjuvant settings for high-risk HER2-positive early breast cancer. The findings deepen the indications of the drug in advanced breast cancer and have the potential to change the way early-stage breast cancer is treated.

Pharmacists are an essential part of the process, as they are responsible for the integration of T-DXd into practice, patient counseling, safety monitoring, thus facilitating the achievement of long-term positive outcomes.

REFERENCES

1. A Study of Trastuzumab Deruxtecan (T-DXd) Versus Trastuzumab Emtansine (T-DM1) in High-risk HER2-positive Participants With Residual Invasive Breast Cancer Following Neoadjuvant Therapy (DESTINY-Breast05). Clinicaltrials.gov. Updated May 9, 2025. Accessed September 20, 2025. https://clinicaltrials.gov/study/NCT04622319

2. Trastuzumab Deruxtecan (T-DXd) Alone or in Sequence With THP, Versus Standard Treatment (ddAC-THP), in HER2-positive Early Breast Cancer. Clinicaltrials.gov. Updated August 8, 2025. Accessed September 30, 2025. https://clinicaltrials.gov/study/NCT05113251

3. Enhertu (fam-trastuzumab deruxtecan-nxki) demonstrated highly statistically significant and clinically meaningful improvement in invasive disease-free survival vs. T-DM1 in DESTINY-Breast05 phase III trial in patients with high-risk early breast cancer following neoadjuvant therapy. September 29, 2025. Accessed September 30, 2025. https://www.astrazeneca-us.com/media/press-releases/2025/ENHERTU-fam-trastuzumab-deruxtecan-nxki-demonstrated-highly-statistically-significant-and-clinically-meaningful-improvement-in-invasive-disease-free-survival-vs-T-DM1-in-DESTINY-Breast05-Phase-III-trial-in-patients-with-high-risk-early-breast-cancer-following-neoadjuvant-therapy.html

4. Enhertu (fam-trastuzumab deruxtecan-nxki) followed by THP before surgery showed statistically significant and clinically meaningful improvement in pathologic complete response in patients with high-risk HER2-positive early-stage breast cancer in DESTINY-Breast11 phase III trial. May 7, 2025. Accessed September 30, 2025. https://www.astrazeneca-us.com/media/press-releases/2025/ENHERTU-fam-trastuzumab-deruxtecan-nxki-followed-by-THP-before-surgery-showed-statistically-significant-and-clinically-meaningful-improvement-in-pathologic-complete-response-in-patients-with-high-risk-HER2-positive-early-stage-breast-cancer-in-DESTINY-Breast11-Phase-III-trial.html

5. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1)9-20. doi:10.1056/nejmoa2203690