Olaparib Combo Enhances PFS Across pMMR Endometrial Cancer Subgroups

“[The analysis] does reinforce the potential for olaparib to be added to durvalumab safely and with efficacy across this biomarker group of [pMMR endometrial cancer],” according to study author Kathleen N. Moore, MD, MS.

The addition of olaparib (Lynparza) maintenance to durvalumab (Imfinzi) plus chemotherapy enhanced the progression-free survival (PFS) benefit across different biomarker and histological subgroups of patients with mismatch repair proficient (pMMR) endometrial cancer, according to exploratory analysis findings from the phase 3 DUO-E trial (NCT04269200) presented at the 2025 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer (SGO).¹

In the pMMR subpopulation of the DUO-E trial, durvalumab plus chemotherapy typically improved PFS vs chemotherapy alone regardless of PD-L1 expression, POLE mutation and TP53 mutation status, homologous recombination repair (HRR)mutation status, BRCA mutation status, histological type at diagnosis, and baseline circulating tumor DNA (ctDNA). For example, the durvalumab combination reduced the risk of progression or death among patients with HRR-mutated disease (HR, 0.45; 95% CI, 0.23-0.87) and those with detectable ctDNA at baseline (HR, 0.61; 95% CI, 0.41-0.88).

Furthermore, adding maintenance olaparib to durvalumab/chemotherapy produced higher PFS benefits across these subgroups.

“The benefit of adding olaparib to durvalumab in this population isn’t driven by 1 particular subset benefiting. It seems to be distributed across the biomarkers, at least as we have tested them,” lead study author Kathleen N. Moore, MD, MS, Virginia Kerley Cade Endowed Chair of Cancer Development, associate director of Clinical Research at the Stephenson Cancer Center, director of the Oklahoma TSET Phase I Program and professor in the Section of Gynecologic Oncology at the University of Oklahoma Health Sciences Center, stated in the presentation.

Of note, the numerically largest reductions in the risk of progression or death with olaparib plus durvalumab/chemotherapy vs chemotherapy alone were reported in patients with detectable ctDNA at baseline (HR, 0.36; 95% CI, 0.23-0.56), positive PD-L1 expression (HR, 0.44; 95% CI, 0.31-0.61), and serous disease histology (HR, 0.46; 95% CI, 0.27-0.76), among others.

“[The analysis] does reinforce the potential for olaparib to be added to durvalumab safely and with efficacy across this biomarker group of [pMMR endometrial cancer],” Moore concluded.

In the double-blind phase 3 DUO-E trial, 718 patients with newly diagnosed stage III or IV recurrent endometrial cancer were randomly assigned 1:1:1 to receive chemotherapy alone followed by placebo maintenance, chemotherapy plus durvalumab followed by durvalumab maintenance, or chemotherapy plus durvalumab followed by maintenance with durvalumab and olaparib.

The trial’s primary end point was PFS per investigator assessment using RECIST criteria in the chemotherapy/durvalumab arm vs chemotherapy arm and the olaparib plus durvalumab/chemotherapy arm vs chemotherapy arm across the intent-to-treat (ITT) population. Secondary end points included overall survival and safety. A prespecified exploratory analysis determined PFS by MMR status across patient subpopulations.

Moore’s presentation featured a recap of findings from the ITT population.² The median PFS was 9.6 months (95% CI, 9.0-9.9) with chemotherapy alone, 10.2 months (95% CI, 9.7-14.7) with durvalumab/chemotherapy, and 15.1 months (95% CI, 12.6-20.7) with olaparib added to durvalumab/chemotherapy. Analysis showed that both experimental arms reached the trial’s primary end point, as PFS improved vs chemotherapy alone in the durvalumab arm (HR, 0.71; 95% CI, 0.57-0.89; P = .003) and the durvalumab/olaparib arm (HR, 0.55; 95% CI, 0.43-0.69; P <.0001).

Of note, the greatest PFS benefit with durvalumab/chemotherapy vs chemotherapy alone occurred in the dMMR subpopulation (HR, 0.42; 95% CI, 0.22-0.80). Additionally, olaparib plus durvalumab/chemotherapy further improved the PFS benefit among patients with pMMR disease (HR, 0.57; 95% CI, 0.44-0.73).

The pMMR biomarker subgroup analysis included 575 evaluable patients with known biomarker status. Furthermore, 100% had known histology at diagnosis, 98% had known PD-L1 status, 86% had known POLE mutation and TP53 mutation status, 86% had known HRR mutation status, and 86% had evaluable BRCA mutation status. Overall, 85% (n = 486) of the pMMR subpopulation had known status for all biomarkers of interest.

The subgroup of patients with pMMR disease and known biomarkers showed high heterogeneity, as Moore noted a frequent overlap of biomarkers. Additionally, 84% of patients had positive expression for 1 or more biomarkers, with PD-L1–positive disease (67%) and TP53 mutations (59%) being the most prevalent.

A total of 291 patients in this pMMR group were not evaluable for ctDNA status. Of the 284 evaluable patients, 79% had detectable ctDNA; the detection rates were higher than 65% across all relevant biomarker subgroups.

Supplementary data showed that across patients with pMMR disease in the chemotherapy, chemotherapy plus durvalumab, and chemotherapy plus durvalumab/olaparib arms, any adverse effects (AEs) occurred in 100%, 98%, and 99% overall, respectively. Additionally, 51%, 53%, and 66% of patients had dose interruptions or study treatment delays due to AEs. Overall, the safety profiles of the study treatments in the pMMR subpopulation were typically comparable with prior reports in the ITT population.

References

1. Moore K, Westin SN, Chon HS, et al. Durvalumab plus carboplatin/paclitaxel followed by durvalumab with/without olaparib in endometrial cancer: biomarkers, histological heterogeneity, baseline circulating tumor DNA, and efficacy in the DUO-E mismatch repair proficient subpopulation. Presented at the 2025 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer (SGO); March 14-17, 2025; Seattle, WA.
2. Westin SN, Moore K, Chon HS, et al. Durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer: the phase III DUO-E trial. J Clin Oncol. 2023;42(3):2024;42(3):283-299. doi:10.1200/JCO.23.02132