DESTINY-Ovarian01 Phase 3 Trial Launches to Test ENHERTU as First-Line Maintenance Therapy for HER2-Expressing Ovarian Cancer
Key Insights
The DESTINY-Ovarian01 phase 3 trial has initiated dosing to evaluate ENHERTU combined with bevacizumab versus bevacizumab alone as first-line maintenance therapy in patients with HER2 (search)-expressing advanced ovarian cancer (search).
The global trial will enroll approximately 580 patients across multiple continents, with progression-free survival as the primary endpoint in the HER2 (search) IHC 3+/2+ population.
HER2 (search) expression is present in up to 55% of ovarian cancers and is associated with advanced disease stages, higher recurrence rates, and poor response to platinum-based chemotherapy.
The first patient has been dosed in the randomization phase of the DESTINY-Ovarian01 phase 3 trial, marking a significant milestone in ovarian cancer (search) treatment research. This global study evaluates ENHERTU (trastuzumab deruxtecan) in combination with bevacizumab versus bevacizumab monotherapy as first-line maintenance therapy in patients with HER2 (search)-expressing advanced high-grade epithelial ovarian cancer (search).
The trial represents a collaborative effort between major international oncology research groups, including the European Network of Gynaecological Oncological Trial Groups (ENGOT), with the Spanish cooperative group (GEICO) as the lead ENGOT group, The GOG Foundation, Inc. (GOG-F), and Asia-Pacific Gynaecologic Oncology Trials Group (APGOT).
Addressing Critical Unmet Medical Need
Ovarian cancer (search) presents a formidable clinical challenge, ranking as the third most common gynecologic cancer and the seventh most common cancer among women worldwide. More than 324,000 women were diagnosed with ovarian cancer worldwide in 2022, with the prognosis remaining poor. The estimated five-year survival rate for those with advanced disease is only 31.8%.
The disease burden is particularly severe for patients with advanced ovarian cancer (search). Approximately 70% to 80% of patients with advanced ovarian cancer (Stage 3 or 4) will experience disease recurrence following standard treatment with surgery and platinum-based chemotherapy regimens. Epithelial ovarian cancer (search) accounts for approximately 90% of ovarian cancer cases, with the majority diagnosed at an advanced stage.
Current maintenance therapy strategies include bevacizumab or PARP inhibitor monotherapy or bevacizumab/PARP inhibitor combination treatment, depending on the biomarker status of the tumor. However, as a majority of patients will experience disease progression on or after these therapies, new treatment strategies are urgently needed.
HER2 as a Therapeutic Target
HER2 (search) represents a promising therapeutic target in ovarian cancer (search). This tyrosine kinase receptor growth-promoting protein is expressed on the surface of many types of tumors, with HER2 expression (IHC 3+/2+/1+) present in up to 55% of ovarian cancers. Importantly, HER2 expression is associated with advanced stages, higher frequency of recurrence, shorter survival time, and lower response to platinum-based chemotherapy.
Despite this significant prevalence, currently there are no HER2 (search)-targeted medicines approved as first-line maintenance therapy for patients with HER2-expressing advanced epithelial ovarian cancer (search), highlighting a critical gap in treatment options.
Trial Design and Objectives
DESTINY-Ovarian01 is designed as a global, multicenter, randomized, open-label, phase 3 trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg) in combination with bevacizumab versus bevacizumab monotherapy. The study targets patients with HER2 (search)-expressing (IHC 3+/2+/1+) advanced high-grade epithelial ovarian cancer (search) following treatment with first-line platinum-based chemotherapy in combination with bevacizumab.
The randomized period of the trial was preceded by a non-randomized safety run-in phase to evaluate the safety of ENHERTU in combination with bevacizumab. The trial will enroll approximately 580 patients across multiple sites in Asia, Europe, North America, and South America.
The primary endpoint is progression-free survival (PFS) as assessed by blinded independent central review (BICR) in the HER2 (search) IHC 3+/2+ population. The key secondary endpoint is overall survival (OS) in the HER2 IHC 3+/2+ population. Additional secondary endpoints include PFS as assessed by BICR and OS in the HER2 IHC 3+/2+/1+ population as well as PFS as assessed by investigator in both the HER2 IHC 3+/2+ and HER2 IHC 3+/2+/1+ populations.
Scientific Rationale
The development of ENHERTU in ovarian cancer (search) builds on encouraging preliminary data. According to Abderrahmane Laadem, MD, Head, Late-2 Stage Oncology Clinical Development at Daiichi Sankyo, "Results from the ovarian cancer cohort of DESTINY-PanTumor02 demonstrated clinically meaningful and durable responses in previously treated patients with HER2 (search) expressing advanced ovarian cancer, supporting the development of Enhertu in earlier lines of therapy."
Dr. Laadem emphasized the potential impact of this research: "Given the important role first-line maintenance therapy can play in disease control, we have initiated this first phase 3 trial in ovarian cancer (search) to evaluate whether Enhertu combined with bevacizumab could become a new maintenance strategy for patients with HER2 (search) expressing advanced high-grade epithelial ovarian cancer (search)."
About ENHERTU
ENHERTU is a specifically engineered HER2 (search)-directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca. Designed using Daiichi Sankyo's proprietary DXd ADC Technology, ENHERTU consists of a HER2 monoclonal antibody attached to a number of topoisomerase I (search) inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.
The drug has already demonstrated significant clinical success across multiple cancer types. ENHERTU (5.4 mg/kg) is approved in more than 90 countries/regions worldwide for various HER2 (search)-positive breast cancer (search) indications, more than 85 countries/regions for HER2-low breast cancer, and more than 60 countries/regions for HER2-mutant non-small cell lung cancer (search), among other approvals.