The TRUST trial is the first phase III randomized study to show improved progression-free survival for primary cytoreductive surgery compared with interval surgery without compromising short-term or long-term quality of life, although the study failed to meet its primary endpoint of overall survival, according to Sven Mahner, MD, Chair and Director of the Department of Obstetrics and Gynecology at Ludwig Maximilian University in Munich. Dr. Mahner reported the long-awaited findings at the 2025 ASCO Annual Meeting.¹

“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.”

— SVEN MAHNER, MD

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“Patients with advanced ovarian cancer in TRUST had very encouraging progression-free and overall survival after maximal-effort cytoreductive surgery,” Dr. Mahner said. “The observed benefits were linked to high complete resection rates, reinforcing the value of radical upfront surgery in patients with resectable advanced ovarian cancer. The high rate of complete cytoreduction together with low morbidity and mortality, along with the encouraging survival outcomes, emphasize the importance of surgical quality assurance programs and the treatment of our patients in such centers.”

Centers participating in the study were required to perform at least 36 primary cytoreductive surgeries per year in which complete resection rates were at least 50% for upfront surgery in patients with FIGO (International Federation of Gynecology and Obstetrics) stage IIIB to IVB disease. They also had to undergo on-site quality assurance reviews that included evaluation of cytoreductive surgery in the operating room and assessment of surgical proficiency and infrastructure, he said.

Continuing Controversy

Primary cytoreductive surgery followed by chemotherapy was long considered the standard of care, but neoadjuvant chemotherapy followed by interval cytoreductive surgery in selected patients has emerged as an option. The two approaches have been compared in two previous randomized trials, but these studies have suffered from many limitations; therefore, the optimal timing has remained controversial. The TRUST trial was designed to evaluate the optimal timing of “maximal-effort” cytoreductive surgery in patients with advanced ovarian cancer.

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 and interval cytoreductive surgery followed by systemic treatment.

Surgical Outcomes

Maximal surgical effort was exerted in both groups, as these figures attest for the primary surgery vs interval surgical groups, respectively:

• Median duration of surgery: 5.5 vs 4.7 hours
• Upper abdominal procedures: 79% vs 67%
• Intestinal resection: 68% vs 38%
• Lymph node dissection: 60% vs 48%
• Documented complete resection in operated patients: 70% vs 85%.

Trial Results

Median follow-up was 75 months for overall survival and 47 months for progression-free survival. The study’s primary endpoint, overall survival, was numerically improved in the primary surgery arm, but this did not meet statistical significance. A statistically significant improvement was shown, on the other hand, for progression-free survival.

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). Deaths occurred in 54.3% and 48.3% of the arms, respectively.

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, Dr. Mahner added. According to Dr. Mahner, the benefit in progression-free survival was most striking in the two largest subgroups of patients: those with FIGO stage III disease and those achieving complete gross tumor resection across all FIGO stages (Table 1).

TABLE 1: Subsets in the TRUST Trial With Notable Benefit From Primary Cytoreductive Surgery

FIGO = International Federation of Gynecology and Obstetrics; HR = hazard ratio; OS = overall survival; PFS = progression-free survival.

Surgical morbidity rates were low in both arms, 18% in the primary surgical group and 12% after interval surgery. The 30-day postoperative mortality rate was 0.9% vs 0.7%, respectively. “When we analyzed overall quality of life, we found no significant differences at any time point between the two treatment groups,” he stated.

DISCLOSURE: Dr. Mahner reported personal financial relationships with AstraZeneca, Clovis Oncology, GlaxoSmithKline, Janssen-Cilag, Jenapharm, Medac, Novartis/Pfizer, PharmaMar, Regeneron, Roche/Genentech, Teva Pharmaceuticals, ImmunoGen, Merck Sharp & Dohme, Roche, Sensor-Kinesis, and Tesaro.

REFERENCE

1. Mahner S, Heitz F, Salehi S, et al: TRUST: Trial of radical upfront surgical therapy in advanced ovarian cancer (ENGOT ov33/AGO-OVAR OP7). 2025 ASCO Annual Meeting. Abstract LBA5500. Presented June 2, 2025.

EXPERT POINT OF VIEW

The invited discussant of the TRUST trial was Emma L. Barber, MD, MS, Assistant Professor of Obstetrics and Gynecology at Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago. Although the study did not meet its primary endpoint of improved overall survival, she noted, it did demonstrate differential beneficial effects for primary debulking surgery in some subgroups. “There is no observed benefit in overall survival in all-comers with stage III to IV resectable ovarian cancer. However, some of the forest plots and potentially future analyses of the data may suggest populations that are more or less likely to benefit,” she said.

Why a Fifth Study?

“Our traditional approach to stage III to IV ovarian cancer has been primary debulking surgery,” Dr. Barber continued. “However, given the morbidity of upfront surgery, neoadjuvant chemotherapy has been explored in previous randomized trials that span 10 years in publication time. They have different study designs and a wide range of surgical effort…. However, in all of them, there was no difference in overall survival between neoadjuvant chemotherapy and primary debulking surgery. So why was this fifth study undertaken?” she questioned.

For one thing, there were limitations and criticisms of past studies, and they have largely been overcome by the TRUST trial, noted Dr. Barber. The result was “very high–quality surgery was performed by high-volume surgeons and centers.” She acknowledged, however, that even in these high-quality centers, upfront surgery still carried a higher rate of complications. “Primary debulking surgery has higher immediate morbidity than neoadjuvant chemotherapy, but we perform it because we think this upfront morbidity pays off with long-term survival,” she pointed out. Unfortunately, this approach did not significantly improve overall survival in this study.

“There are, however, some interesting results on the forest plots,” Dr. Barber said. In particular, 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, which she called “an interesting trend observed in TRUST and previous studies.”

Additional Considerations

Dr. Barber said additional data from the study will be important, including the following:

• Preoperative information on the patients: baseline CA-125, presence of ascites, frailty scores, albumin, and objective preoperative disease burden scores;
• Molecular alterations that could affect survival: BRCA mutation status and homologous recombination repair status;
• Additional outcomes: time to chemotherapy, chemotherapy dosing, length of hospital stay, late complications, and treatment-related mortality.

“Given the results of the TRUST trial and the four previous randomized trials on this topic, 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,” Dr. Barber concluded.

DISCLOSURE: Dr. Barber reported no conflicts of interes