The combination of immunotherapy, targeted therapy, and chemotherapy could be the new standard first-line treatment of patients with high-grade, advanced ovarian cancer with BRCA wild-type, homologous recombination deficiency (HRD)-positive tumors, according to data presented during the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer.1
The DUO-O/ENGOT-ov46/GOG-3025 study included patients with newly diagnosed Federation of Gynecology and Obstetrics (FIGO) stage III or IV high-grade ovarian cancer who had BRCA wild-type disease. Patients were randomly assigned to one of three treatment arms: arm 1 (standard chemotherapy with carboplatin, paclitaxel, and bevacizumab, followed by bevacizumab maintenance); arm 2 (carboplatin, paclitaxel, bevacizumab, and durvalumab, followed by bevacizumab and durvalumab maintenance); or arm 3 (carboplatin, paclitaxel, bevacizumab, and durvalumab, followed by bevacizumab, durvalumab, and olaparib maintenance).
The primary endpoint of the trial was progression-free survival in arm 3 vs arm 1, first in the HRD-positive population, followed by the intention-to-treat population. The study also included a separate cohort of patients with BRCA-positive disease, with results to be reported later.
“The median progression-free survival of 45.1 months observed in arm 3 for the HRD-positive population is the longest ever reported in this setting.”— Philipp Harter, MD, PhD
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At the meeting, Dr. Harter presented the final planned progression-free survival analysis and the first interim overall survival analysis was presented by lead study author Philipp Harter, MD, PhD, of the Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen, Germany. The study had previously met its primary endpoint at the planned interim analysis, demonstrating a statistically significant and clinically meaningful improvement in progression-free survival for arm 3 compared with arm 1, with hazard ratios of 0.49 in the nontumor BRCA-mutated HRD-positive population and 0.63 in the intention-to-treat population.
Key Updated Findings
The final progression-free survival analysis of the DUO-O study demonstrated a clinically meaningful progression-free survival benefit with first-line durvalumab plus paclitaxel/carboplatin and bevacizumab followed by durvalumab, bevacizumab, and olaparib maintenance (arm 3) vs a control regimen of paclitaxel/carboplatin (arm 1)—25.1 months vs 19.3 months (hazard ratio [HR] = 0.61). Of note, the triplet regimen was particularly effective in the subpopulation of patients with HRD-positive disease, with a median progression-free survival of 45.1 months in arm 3. Although the interim overall survival analysis was not statistically significant in the intention-to-treat population, a favorable trend in overall survival was also observed in the BRCA wild-type, HRD-positive population.
“The median progression-free survival of 45.1 months observed in arm 3 for the HRD-positive population is the longest ever reported in this setting,” emphasized Dr. Harter.
After a median follow-up of 33 months, the final progression-free survival analysis confirmed the benefit of adding durvalumab and olaparib to standard chemotherapy. In the HRD-positive population, arm 3 showed a hazard ratio of 0.46 compared with arm 1, with median progression-free survival increasing from 23.3 months to 45.1 months. Arm 2 also demonstrated a numerical benefit with the addition of durvalumab. In the intention-to-treat population, arm 3 showed a hazard ratio of 0.61 compared with arm 1, with arm 2 again showing a numerical benefit.
The first interim overall survival analysis in the HRD-positive cohort showed a numerical difference favoring arm 3 compared with arm 1, although the data were immature (maturity of approximately 21%). In the intention-to-treat population, no significant differences were detected between the three treatment arms at this interim analysis.
Of note, in the HRD-negative population, which has the highest unmet medical need, arm 3 demonstrated an improvement in median progression-free survival with a hazard ratio of 0.68 compared with arm 1. However, the interim overall survival analysis did not show a significant difference between the treatment arms in this subgroup.
KEY POINTS
- The DUO-O study demonstrated a clinically meaningful progression-free survival benefit with the addition of durvalumab and olaparib to standard chemotherapy and bevacizumab in the first-line treatment of BRCA wild-type, advanced ovarian cancer.
- The median progression-free survival of 45.1 months observed in arm 3 for the HRD-positive subpopulation is the longest ever reported in this setting.
Although the interim overall survival analysis has not yet shown statistical significance in the intention-to-treat population with BRCA wild-type disease, Dr. Harter noted a favorable trend in the HRD-positive subgroup.
Safety findings were consistent with the primary analysis, with the most common grade 3 adverse events in arm 3 being neutropenia (31%) and anemia (25%). Three patients in arm 3 experienced pure red cell aplasia and autoimmune hemolytic anemia during the maintenance phase, but all events resolved. The safety profile of the combination therapy remains consistent with earlier analyses and the known profiles of each agent, Dr. Harter reported.
“The DUO-O study is ongoing, and further insights into the long-term benefits of this novel combination will be provided with additional follow-up,” Dr. Harter concluded.
DISCLOSURE: Dr. Harter has received honoraria from Amgen, AstraZeneca, GSK, Roche, Immunogen, Sotio, Stryker, Zai Lab, MSD, Clovis, Miltenyi, Eisai, Mersana, Exscientia, and Daiichi Sankyo; has served on advisory boards for AstraZeneca, Roche, GSK, Clovis, Immunogen, MSD, Miltenyi, Novartis, and Eisai; and has received research funding from AstraZeneca, Roche, GSK, Genmab, DFG, European Union, DKH, Immunogen, Seagen, Clovis, and Novartis.
REFERENCE
EXPERT POINT OF VIEW
Abstract discussant Jonathan Ledermann, MD, Professor of Medical Oncology and Clinical Director at UCL Cancer Institute, University College London, and Consultant Medical Oncologist at UCL Hospitals, London, addressed the results of the DUO-O trial in the context of other PARP inhibitor studies and analyzed the potential impact of durvalumab vs olaparib.1
Jonathan Ledermann, MD
As Dr. Ledermann explained, among patients with homologous recombination deficiency (HRD)-positive disease, the results showed a progression-free survival of 23.3 months in the control group receiving paclitaxel/carboplatin plus bevacizumab and a “slight improvement” with the addition of the immunotherapy durvalumab (25.1 months; hazard ratio [HR] = 0.89). However, the addition of olaparib to durvalumab and standard chemotherapy led to a “striking” progression-free survival of 45.1 months (HR = 0.46).
“The big question is, to what extent is this [attributable to] olaparib and to what extent is it durvalumab?” said Dr. Ledermann, who underscored the importance of mature overall survival data. “The final overall survival analysis will be critically important if we are going to dissect out whether there is a benefit of adding these two drugs together.”
Dr. Ledermann also noted a similar magnitude of benefit with respect to hazard ratio in this non–BRCA-mutated, HRD-positive population across other PARP inhibitor studies, including PAOLA-1,2 although he cautioned against cross-trial comparison.
“Does the inclusion of durvalumab influence median progression-free survival and the shape of the curve?” Dr. Ledermann asked. He added that neither the median value nor the tail of the curve in arm 2 (durvalumab alone) differs from the control curve.
“If there is going to be a benefit from adding olaparib to durvalumab or the other way around, then we would need to see synergy,” Dr. Ledermann concluded. “For that, we’re going to have to wait until the overall survival data are available.”
DISCLOSURE: Dr. Ledermann reported financial relationships with AstraZeneca, Clovis Oncology, GSK, Artios Pharma, Merck/MSD, VBL Therapeutics, Bristol Myers Squibb, Nuvation Bio, Ellipses, Immagene, Independent Data Monitoring Committee Mersana, and Sutro Bio Clinical.
REFERENCES
2. Lorusso D, Mouret-Reynier MA, Harter P, et al: Updated progression-free survival and final overall survival with maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial. Int J Gynecol Cancer 34:550-558, 2024.
