A Phase 3, Multicenter, Randomized, Open-label Trial of Trastuzumab Deruxtecan Versus Standard of Care Chemotherapy With or Without Radiotherapy as Adjuvant Treatment for HER2-Expressing (IHC 3+/2+) Endometrial Cancer (DESTINY-Endometrial02/ GOG-3122/ ENGOT-en30/GINECO)

The primary objective is to compare the efficacy of trastuzumab deruxtecan (T-DXd) versus standard of care (SoC) as measured by disease-free survival (DFS) in patients with HER2-expressing endometrial cancer (IHC 3+/2+). DFS is assessed by blinded independent central review (BICR) or by histopathologic confirmation of disease recurrence per local assessment. This endpoint is clinically relevant as it evaluates the ability of T-DXd to delay or prevent cancer recurrence in the adjuvant setting, which directly impacts long-term patient outcomes in this patient population.

The secondary objectives include:

• To compare the efficacy of T-DXd versus SoC as measured by overall survival (OS) in the HER2 IHC 3+/2+ population

• To compare the efficacy of T-DXd versus SoC with respect to distant metastatic recurrence as assessed radiologically by BICR or by histopathologic confirmation of disease recurrence per local assessment in the HER2 IHC 3+/2+ population

• To compare the efficacy of T-DXd versus SoC with respect to local recurrence as assessed radiographically by BICR or by histopathologic confirmation of disease recurrence per local assessment in the HER2 IHC 3+/2+ population

• To compare the efficacy of T-DXd versus SoC with respect to regional recurrence as assessed radiographically by BICR or by histopathologic confirmation of disease recurrence per local assessment in the HER2 IHC 3+/2+ population

• To evaluate the safety and tolerability of T-DXd versus SoC in the HER2 IHC 3+/2+ population

• To evaluate patient-reported health-related quality of life (HRQoL) in participants treated with T-DXd versus SoC in the HER2 IHC 3+/2+ population

• To evaluate patient-reported symptom burden in participants treated with T-DXd versus SoC in the HER2 IHC 3+/2+ population

• To evaluate the pharmacokinetics (PK) of T-DXd, total anti-HER2 antibody, and DXd in the HER2 IHC 3+/2+ population

• To assess the immunogenicity of T-DXd in the HER2 IHC 3+/2+ population

This clinical trial enrolled a total of **510 participants**, all of whom were **female** adults aged **18 years and older**. The study population consisted of patients with newly diagnosed **FIGO 2023 Stage IIC** (including Stage IICmp53abn) or **Stage III epithelial endometrial carcinoma** with **HER2-expression** (IHC 3+/2+) as confirmed by central laboratory testing using 2016 ASCO-CAP gastric cancer IHC scoring guidelines. All histology types were permitted except for sarcomas, although carcinosarcomas were allowed. Participants were required to be disease-free with no evidence of loco-regional disease or distant metastasis following curative intent surgery that included **hysterectomy** and **bilateral salpingo-oophorectomy**. Key selection criteria included an **ECOG performance status** of 0 or 1, **left ventricular ejection fraction** (LVEF) of at least 50%, and adequate organ and bone marrow function. Participants had not received any prior radiotherapy or systemic therapy for endometrial cancer and were eligible for combination treatment with **carboplatin** and **paclitaxel** as adjuvant therapy. Trial intervention was required to commence within 8 weeks of the endometrial cancer surgery date. Adequate archived tumor tissue samples were necessary for central laboratory assessment of HER2 status, and participants were required to have MMR IHC local test results available.

This is a Phase 3, multicenter, randomized, open-label clinical trial designed to evaluate the efficacy and safety of **trastuzumab deruxtecan** (T-DXd) compared to standard of care chemotherapy with or without radiotherapy as adjuvant treatment in participants with **HER2-expressing endometrial cancer** (IHC 3+/2+). The trial employs a randomized design in which participants are assigned to receive either the investigational medicinal product or comparator regimens. The study is open-label, meaning that both participants and investigators are aware of the treatment assignment. The overall trial duration is estimated from November 2025 to February 2032, spanning approximately six years.

The primary objective is to compare the efficacy of trastuzumab deruxtecan versus standard of care as measured by **disease-free survival** (DFS), assessed by blinded independent central review (BICR) or by histopathologic confirmation of disease recurrence per local assessment in the HER2 IHC 3+/2+ population. Disease-free survival is defined as the time interval from the date of randomization to the first documented **local-regional recurrence**, **distant metastasis**, or death due to any cause, whichever occurs first. Secondary endpoints include **overall survival** (OS), which is defined as the time from randomization to death due to any cause, as well as DFS assessed by investigator, distant metastatic recurrence, local recurrence in the vagina, and regional recurrence in the pelvis or pelvic lymph nodes. Additional secondary endpoints encompass safety assessments, including the incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), adverse events of special interest (AESIs), changes in vital signs, clinical laboratory results, electrocardiograms (ECGs), echocardiography or multigated acquisition scan (ECHO/MUGA), and ophthalmologic assessments. Patient-reported outcomes (PRO) are evaluated using the EORTC QLQ-C30 and EORTC QLQ-EN24 questionnaires to assess quality of life, physical function, and specific symptoms such as back and pelvic pain, tingling or numbness, and muscular pain. Pharmacokinetic assessments include serum concentrations of trastuzumab deruxtecan, total anti-HER2 antibody, and DXd, as well as the incidence of anti-drug antibodies (ADA), titer, and neutralizing antibodies (nAb) when ADA is positive.

Participants eligible for enrollment must be adults aged 18 years or older at the time of informed consent, with histologically confirmed diagnosis of epithelial endometrial carcinoma of any histology except sarcomas (carcinosarcomas are allowed). Participants must have newly diagnosed FIGO 2023 Stage IIC (including Stage IICmp53abn) or Stage III disease and must be disease-free with no evidence of loco-regional disease or distant metastasis post-operatively on imaging as assessed by the investigator and confirmed by BICR. HER2 expression (IHC 3+/2+) must be confirmed by central laboratory testing according to the 2016 ASCO-CAP gastric cancer IHC scoring guidelines. Adequate archived tumor tissue from surgery must be available for central assessment of HER2 status. Participants must have undergone curative intent surgery that included **hysterectomy** and **bilateral salpingo-oophorectomy**, with pelvic and para-aortic lymph node sampling strongly encouraged. Trial intervention must start within 8 weeks of endometrial cancer surgery, and participants must not have received any prior radiotherapy or systemic therapy, including immunotherapy, hormonal therapy, radiosensitizer chemotherapy, or hyperthermic intraperitoneal chemotherapy (HIPEC) for endometrial cancer. Participants must have a **left ventricular ejection fraction** (LVEF) of 50% or greater within 28 days before randomization, an **ECOG performance status** of 0 or 1 assessed no more than 14 days prior to randomization, and adequate organ and bone marrow function as defined in the protocol. Participants must be eligible for combination treatment with **carboplatin** and **paclitaxel** as adjuvant therapy per standard of care and investigator discretion.

The investigational medicinal product, trastuzumab deruxtecan (DS-8201a), is an **antibody drug conjugate** administered as a solution for infusion via **intravenous infusion**. The maximum daily dose is 5.4 mg/kg, with a maximum total dose of 91.8 mg/kg over a maximum treatment period of 51 cycles. Comparator regimens include carboplatin, administered via intravenous infusion at a maximum daily dose of 750 mg and a maximum total dose of 13,500 mg over a maximum treatment period of 18 cycles; paclitaxel, administered via intravenous infusion at a maximum daily dose of 175 mg/m² and a maximum total dose of 1,050 mg/m² over a maximum treatment period of 6 cycles; **cisplatin**, administered via **intravenous injection** at a maximum daily dose of 50 mg/m² and a maximum total dose of 200 mg/m² over a maximum treatment period of 4 cycles; and **docetaxel**, administered via intravenous injection at a maximum daily dose of 75 mg/m² and a maximum total dose of 450 mg/m² over a maximum treatment period of 6 cycles.

The study involves a series of scheduled visits, beginning with a screening visit during which participants provide informed consent for tissue screening and HER2 central testing, followed by the main screening informed consent forms prior to the start of any trial-specific qualification procedures. Participants may also consent to optional pharmacogenomic (PGx) testing prior to any PGx procedures. The screening phase includes assessment of eligibility criteria, confirmation of HER2 status by central laboratory, evaluation of adequate organ and bone marrow function within 14 days prior to randomization, and verification of LVEF and ECOG performance status. Following confirmation of eligibility, participants are randomized to receive either trastuzumab deruxtecan or standard of care chemotherapy regimens. Treatment is initiated within 8 weeks of endometrial cancer surgery. During the treatment phase, participants undergo regular follow-up visits for administration of trial intervention, safety assessments, monitoring of disease status through imaging and clinical evaluation, and collection of blood samples for pharmacokinetic and immunogenicity assessments. Patient-reported outcome questionnaires are completed at specified intervals to assess quality of life and symptom burden. Imaging assessments are performed by both investigator and blinded independent central review to evaluate disease-free survival and detect any local-regional recurrence or distant metastasis. Safety monitoring includes assessment of treatment-emergent adverse events, serious adverse events, adverse events of special interest, vital signs, clinical laboratory tests, electrocardiograms, echocardiography or MUGA scans, and ophthalmologic examinations. The end-of-study visit occurs upon completion of the treatment phase or upon disease recurrence, death, or withdrawal from the study. Long-term follow-up continues for overall survival assessment until the estimated end date of the trial in February 2032.

Participant involvement in the trial extends from the screening phase through the treatment period, which may last up to 51 cycles for trastuzumab deruxtecan or up to 18 cycles for carboplatin-based regimens, depending on the assigned treatment arm and individual tolerance. The total duration of participant involvement includes the treatment phase and subsequent follow-up for disease-free survival and overall survival assessments. Early termination from the study may occur under several conditions, including disease recurrence as assessed radiographically by BICR or by histopathologic confirmation per local assessment, occurrence of unacceptable toxicity or adverse events requiring discontinuation of trial intervention, participant withdrawal of consent, investigator decision based on clinical judgment, loss to follow-up, or death. Participants who discontinue trial intervention prematurely are encouraged to continue follow-up visits for disease assessment and survival monitoring unless consent is withdrawn. The trial protocol includes provisions for dose modifications in response to treatment-emergent adverse events to ensure participant safety while maintaining treatment efficacy.

The experimental treatment in this clinical trial consists of **trastuzumab deruxtecan** (DS-8201a), an **antibody drug conjugate** formulated as a **solution for infusion**. The product is administered via **intravenous infusion** at a maximum daily dose of 5.4 milligrams per kilogram body weight. The maximum total dose is 91.8 milligrams per kilogram over the course of treatment. The maximum treatment period extends to 51 cycles. Trastuzumab deruxtecan contains a protein-based active substance and is designated as the test product in this randomized trial.

The comparator arm includes **docetaxel**, supplied as Docetaxel AqVida 20 milligrams per milliliter concentrate for preparation of solution for infusion. This chemotherapeutic agent is administered via **intravenous injection** at a maximum daily dose of 75 milligrams per square meter body surface area. The maximum total dose is 450 milligrams per square meter, with a maximum treatment period of 6 cycles. Docetaxel is a chemical agent classified as standard-of-care chemotherapy.

**Cisplatin** is utilized as a comparator treatment, provided as Cisplatin Hikma 1 milligram per milliliter concentrate for preparation of solution for infusion. Administration occurs via intravenous injection with a maximum daily dose of 50 milligrams per square meter. The maximum total dose reaches 200 milligrams per square meter over a maximum treatment period of 4 cycles. This platinum-based chemotherapeutic agent represents a chemical compound used in standard chemotherapy regimens.

**Paclitaxel** serves as an additional comparator agent, formulated as Paclitaxel Ribosepharm 6 milligrams per milliliter concentrate for preparation of solution for infusion. The medication is delivered via **intravenous infusion** at a maximum daily dose of 175 milligrams per square meter body surface area. The maximum total dose is 1050 milligrams per square meter, administered over a maximum of 6 treatment cycles. Paclitaxel is a chemical substance employed as standard-of-care chemotherapy.

**Carboplatin** is included as a comparator treatment, available as Carboplatin Hikma 10 milligrams per milliliter concentrate for preparation of solution for infusion. This agent is administered via intravenous infusion at a maximum daily dose of 750 milligrams. The maximum total dose amounts to 13500 milligrams over a maximum treatment period of 18 cycles. Carboplatin represents a platinum-based chemical compound used in standard chemotherapy protocols. The trial design permits the combination of standard-of-care chemotherapy with or without **radiotherapy** as adjuvant treatment.

The primary efficacy endpoint is disease-free survival (DFS), defined as the time interval from the date of randomization to the first documented local-regional recurrence, distant metastasis, or death due to any cause, whichever occurs first. DFS will be assessed radiographically by blinded independent central review (BICR) or by histopathologic confirmation of disease recurrence per local assessment.

Secondary efficacy endpoints include overall survival (OS), defined as the time interval from the date of randomization to the date of death due to any cause. DFS will also be assessed by investigator evaluation, defined as the time from randomization to the first documented local-regional recurrence, distant metastasis, or death due to any cause, whichever occurs first, assessed radiographically by investigator or by histopathologic confirmation of disease recurrence per local assessment. Additional secondary endpoints include distant metastatic recurrence, defined as recurrence outside of vagina, pelvis, or pelvic lymph nodes, local recurrence defined as recurrence in the vagina as assessed radiologically by BICR or by histopathologic confirmation of disease recurrence per local assessment, and regional recurrence defined as recurrence in the pelvis or pelvic lymph nodes as assessed radiologically by BICR or by histopathologic confirmation of disease recurrence per local assessment. Patient-reported outcomes will be evaluated through change from baseline and time to deterioration using the EORTC QLQ-C30 global health status/overall quality of life and physical functioning scales, as well as the EORTC QLQ-EN24 for back and pelvic pain, tingling/numbness, and muscular pain.