Phase 3 Trial of T-DXd Initiated in HER2+ Endometrial Cancer

AstraZeneca and Daiichi Sankyo have initiated DESTINY-Endometrial02 (NCT07022483), a global phase 3 trial evaluating fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) as an adjuvant treatment for patients with HER2-expressing endometrial cancer.¹

“Following the positive results of DESTINY-PanTumor02 [NCT04482309], which included a cohort of patients with metastatic endometrial cancer, we are now evaluating the use of [T-DXd] in earlier lines of treatment for this disease,” said Abderrahmane Laadem, MD, head of Late-Stage Oncology Clinical Development, Daiichi Sankyo, in a news release. “We recently initiated DESTINY-Endometrial01 [NCT06989112] to evaluate [T-DXd] as a first-line treatment in patients with HER2-expressing primary advanced or recurrent endometrial cancer and are now initiating DESTINY-Endometrial02, the first trial to investigate a HER2-directed therapy in the adjuvant setting for patients with HER2-expressing endometrial cancer, to explore if [T-DXd] can replace current standard of care chemotherapy and improve the long term outcome in this setting.”

Trial Design and Objectives

The DESTINY-Endometrial02 trial is a randomized, open-label, multicenter study designed to assess the efficacy and safety of T-DXd compared with investigator’s choice of chemotherapy (carboplatin and paclitaxel).² The study is enrolling patients with HER2-expressing (immunohistochemistry [IHC] 3+ or IHC 2+) endometrial cancer who have undergone curative-intent surgery but are considered at high risk of disease recurrence.

The primary end point of the trial is disease-free survival as determined by blinded independent central review . Secondary end points include overall survival , time to second progression or death , and safety profiles. The trial aims to determine if the targeted delivery of cytotoxic therapy via the antibody-drug conjugate (ADC) mechanism can improve long-term outcomes over the current standard-of-care systemic chemotherapy.

The Role of HER2 in Endometrial Carcinoma

Endometrial cancer remains the most common gynecologic malignancy in developed nations, with a rising incidence and mortality rate globally. While many patients are diagnosed at an early stage with a favorable prognosis, those with high-risk features or specific molecular profiles face a significantly higher likelihood of recurrence.

HER2 overexpression is a recognized driver in several solid tumors. In endometrial cancer, HER2 expression is observed in approximately 17% to 57% of cases, depending on the histological subtype. It is particularly prevalent in serous endometrial carcinoma, an aggressive variant associated with poor clinical outcomes.³ Historically, HER2-targeted therapy in endometrial cancer was limited to trastuzumab (Herceptin) in combination with chemotherapy for advanced or recurrent disease, based on phase 2 data. The initiation of DESTINY-Endometrial02 reflects a shift toward incorporating potent, next-generation HER2-targeted agents earlier in the treatment continuum.

Mechanism of Action

T-DXd is a HER2-directed ADC consisting of a humanized anti-HER2 IgG1 monoclonal antibody linked to a topoisomerase I inhibitor payload (deruxtecan) via a tetrapeptide-based cleavable linker. The agent is designed to deliver the cytotoxic payload directly to HER2-expressing malignant cells.¹

A distinguishing feature of this ADC is its high drug-to-antibody ratio (approximately 8:1) and its "bystander effect." Once the payload is released within the target cell, its membrane-permeable nature allows it to diffuse into neighboring tumor cells, regardless of their specific HER2 expression levels. This mechanism is hypothesized to be particularly effective in tumors with heterogeneous HER2 expression, which is frequently observed in endometrial pathology.

Clinical Context and Previous Data

The decision to move T-DXd into the adjuvant setting follows robust data from the DESTINY-PanTumor02 phase 2 trial.⁴ In that study, the agent demonstrated clinically meaningful and durable responses across multiple HER2-expressing solid tumors, including a cohort of patients with pretreated endometrial cancer. In the endometrial cohort, the objective response rate was 57.5%, with a median duration of response not reached at the time of initial reporting.

Based on these results, the FDA granted accelerated approval to T-DXd in April 2024 for adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.⁵

REFERENCES

1. DESTINY-Endometrial02 Phase 3 trial of ENHERTU initiated as adjuvant therapy in patients with HER2-expressing endometrial cancer. News release. AstraZeneca. December 22, 2025. https://tinyurl.com/ywdabew5

2. Study of trastuzumab deruxtecan versus standard of care chemotherapy for HER2-expressing (IHC 3+/ 2+) endometrial cancer. ClinicalTrials.gov. Updated December 19, 2025. Accessed December 22, 2025. https://clinicaltrials.gov/study/NCT07022483

3. Buza N. HER2 testing and relevant clinical trials in endometrial carcinoma. Arch Pathol Lab Med. 2021;145(12):1487-1491. doi:10.5858/arpa.2021-0027-RA

4. Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: results from the DESTINY-PanTumor02 Phase 2 trial. J Clin Oncol. 2024;42(1):47-58. doi:10.1200/JCO.23.02005

5. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. News release. FDA. April 5, 2024. Accessed December 22, 2025. https://tinyurl.com/47uuetzn