The landmark TRUST trial has demonstrated that primary cytoreductive surgery significantly extends progression-free survival compared to interval surgery in patients with advanced ovarian cancer, though the study failed to achieve its primary endpoint of improved overall survival. The findings, presented at the 2025 ASCO Annual Meeting, represent the first phase III randomized study to show a progression-free survival benefit for upfront radical surgery in this patient population.
Study Design and Patient Population
The TRUST trial enrolled 796 patients with FIGO stage IIIB/C or IVA/B ovarian cancer (epithelial, fallopian tube, or peritoneal) considered to be resectable. The majority of patients had stage IIIC disease, and more than 90% had high-grade serous histology. Patients were randomly assigned to primary cytoreductive surgery or neoadjuvant chemotherapy followed by interval cytoreductive surgery.
A key strength of the study was its rigorous quality assurance requirements. Participating centers were required to perform at least 36 primary cytoreductive surgeries per year with complete resection rates of at least 50% for upfront surgery in patients with FIGO stage IIIB to IVB disease. Centers also underwent on-site quality assurance reviews that included evaluation of cytoreductive surgery in the operating room and assessment of surgical proficiency and infrastructure.
Surgical Outcomes and Quality Metrics
The trial demonstrated that maximal surgical effort was exerted in both treatment arms. In the primary surgery versus interval surgery groups respectively, median duration of surgery was 5.5 versus 4.7 hours, upper abdominal procedures were performed in 79% versus 67% of cases, intestinal resection occurred in 68% versus 38%, and lymph node dissection was performed in 60% versus 48%.
Complete resection was documented in 70% of patients in the primary surgery group compared to 85% in the interval surgery group. Despite the extensive surgical procedures, morbidity rates remained low at 18% in the primary surgical group and 12% after interval surgery. The 30-day postoperative mortality rate was 0.9% versus 0.7%, respectively.
Primary and Secondary Endpoints
With a median follow-up of 75 months for overall survival and 47 months for progression-free survival, the study's primary endpoint of overall survival showed numerical improvement in the primary surgery arm but did not reach statistical significance. Median overall survival was 54.3 months with upfront surgery and 48.3 months with interval cytoreductive surgery (hazard ratio [HR] = 0.89; P = .24).
However, the study demonstrated a statistically significant improvement in progression-free survival. Median progression-free survival was 22.1 months for the upfront surgery arm and 19.7 months for the interval surgery arm (HR = 0.80; P = .018). In a restricted means analysis, median progression-free survival was 31.7 months and 26.6 months, respectively (P = .007), with the difference between the two arms maintained over time.
Subgroup Analysis Reveals Key Benefits
The benefit in progression-free survival was most striking in specific patient subgroups. For patients with FIGO stage III disease, median progression-free survival was 26.3 months with primary surgery versus 21.4 months with interval surgery (HR = 0.73; P = .005), with 5-year progression-free survival rates of 23% versus 11%.
Among patients achieving complete gross tumor resection across all FIGO stages, median progression-free survival was 27.9 months with primary surgery versus 21.8 months with interval surgery (HR = 0.69; P = .0009), with 5-year progression-free survival rates of 26% versus 11%.
Quality of Life and Safety Profile
The study found no significant differences in overall quality of life at any time point between the two treatment groups. This finding is particularly important given the more extensive nature of primary cytoreductive surgery and its associated immediate morbidity.
Clinical Implications and Expert Commentary
According to study lead Sven Mahner, MD, Chair and Director of the Department of Obstetrics and Gynecology at Ludwig Maximilian University in Munich, "The high rate of complete cytoreduction together with low morbidity and mortality, along with the very encouraging survival outcomes, emphasize the importance of surgical quality assurance programs and the treatment of our patients in such centers."
Invited discussant Emma L. Barber, MD, MS, from Northwestern University, noted that while the study did not meet its primary endpoint, it demonstrated differential beneficial effects for primary debulking surgery in some subgroups. She observed that there appeared to be no benefit to primary debulking in patients with stage IV disease, whereas patients with stage III disease seemed to derive benefit.
Dr. Barber concluded that "selection for primary debulking surgery instead of neoadjuvant chemotherapy should be considered carefully and performed for selected populations of patients with ovarian cancer, such as those with lower-volume (< 5 cm) stage III disease."
Susana M. Campos, MD, MPH, clinical director of the division of gynecologic oncology at Dana-Farber Cancer Institute, emphasized that "both of these groups of individuals — those who went to surgery first vs. those who had chemotherapy followed by surgery — actually did quite well. The complete resection rates were quite high, and the morbidity and the mortality were low."
