Maintenance Durvalumab Plus Olaparib Improves PFS in Advanced or Recurrent Endometrial Cancer

The addition of durvalumab (Imfinzi) to first-line chemotherapy, followed by maintenance therapy with the anti–PD-L1 antibody plus olaparib (Lynparza) significantly improved progression-free survival (PFS) in patients with newly diagnosed advanced or recurrent endometrial cancer, according to data from the phase 3 DUO-E/GOG-3041/ENGOT-EN10 trial (NCT04269200) presented at the 2023 European Society for Medical Oncology Congress.

In particular, PFS benefit with durvalumab was greatest in patients with mismatch repair–deficient (dMMR) disease, whereas adding olaparib to durvalumab maintenance therapy improved PFS in those who were mismatch repair–proficient (pMMR) and those positive for PD-L1.

“DUO-E is the first phase 3 study to demonstrate that durvalumab plus olaparib confers PFS benefit and provides new treatment options for patients with advanced and recurrent endometrial cancer,” Shannon N. Westin, MD, MPH, FACOG, professor, clinical medical director, director of early drug development, and rotation director of the Medical Oncology Fellowship Program, all in the Department of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center, said during a presentation of the data. Westin is also the codirector of the Ovarian Cancer Moonshot Program, cochair of the Scientific Review Committee 1, and cochair of the Executive Scientific Review Committee at MD Anderson Cancer Center.

Primary PFS Analysis Reveals Statistically Significant Data

At the congress, Westin presented the primary analysis of PFS and the first preplanned interim analysis of overall survival (OS). The median duration of follow-up was 16.4 months (range, 0.2-32.9) in the chemotherapy plus placebo followed by placebo maintenance arm (n = 241), 17.1 months (range, 0.2-33.0) in the chemotherapy plus durvalumab followed by durvalumab maintenance arm (n = 238), and 17.5 months (range, 0.2-33.4) in the chemotherapy plus durvalumab followed by durvalumab and olaparib maintenance arm (n = 239).

In the intent-to-treat population, treatment with durvalumab (median PFS, 10.2 months [95% CI, 9.7-14.7]; HR, 0.71; 95% CI, 0.57-0.89; P = .003) and durvalumab plus olaparib (median PFS, 15.1 months [95% CI, 12.6-20.7]; HR, 0.55; 0.43-0.69; P < .0001) resulted in statistically significant improved PFS compared with the control arm (median PFS, 9.6 months; 95% CI, 9.0-9.9). Compared with durvalumab monotherapy, the combination maintenance therapy reduced the risk for disease progression by 22% (HR, 0.78; 95% CI, 0.61-0.99).

Further, Westin highlighted that patients in the control, durvalumab, and durvalumab plus olaparib arms experienced 18-month PFS rates of 21.7%, 37.8%, and 46.3%, respectively. These data demonstrated a more than doubling of the rate between the control and combination maintenance arms.

In the subgroup analysis, all hazard rate–point estimates favored the durvalumab arm over the control arm. “As expected, we see smaller hazard ratios with the mismatch repair–deficient subgroup as opposed to the mismatch repair–proficient subgroup, and in patients with PD-L1–positive as opposed to –negative disease,” Westin said, adding that durvalumab plus olaparib was also favored over placebo. “For the durvalumab/olaparib arm vs the control, all hazard rate–point estimates favored the durvalumab/olaparib arm and we generally see smaller hazard ratios than what we saw for durvalumab vs control, except for the mismatch repair–deficient group. And this was most apparent for patients that had homologous recombination repair mutations [HRRm].”

In a prespecified exploratory analysis of PFS by MMR status, both treatment with durvalumab monotherapy (n = 46) and durvalumab plus olaparib (n = 48) was superior to placebo (n = 49) in the dMMR patient population; the 18-month PFS rates were 67.9% vs 62.7% vs 31.7%, respectively, and the median PFS was NR (95% CI, NR-NR) vs 31.8 months (95% CI, 12.4-NR) vs 7.0 months (95% CI, 6.7-14.8), respectively. In the pMMR patient population, the 18-month PFS rates were 31.3% vs 42.0% vs 20.0% and the median PFS was 9.9 months (95% CI, 9.4-12.5) vs 15.0 months (95% CI, 12.4-18.0) vs 9.7 months (95% CI, 9.2-10.1) in the durvalumab monotherapy (n = 192), durvalumab plus olaparib (n = 191), and placebo (n = 192) arms, respectively.

Similarly, in a prespecified exploratory analysis of PFS by PD-L1 status, both treatment with durvalumab monotherapy (n = 170) and durvalumab plus olaparib (n = 150) was superior to placebo (n = 163) in patients with PD-L1–positive disease; 18-month PFS rates were 40.2% vs 54.9% vs 21.5%, respectively, and the median PFS was 11.3 months vs 20.8 months vs 9.5 months. Patients with PD-L1–negative disease who received durvalumab monotherapy (n = 61) or durvalumab plus olaparib (n = 82) also experienced superior PFS compared with placebo (n = 75); 18-month PFS rates were 31.1% vs 30.4% vs 22.7% and the median PFS was 9.7 months vs 10.1 months vs 9.9 months, respectively.

In an interim analysis of OS, median OS was not reached with durvalumab monotherapy (95% CI, NR-NR) or durvalumab plus olaparib (95% CI, NR-NR), compared with 25.9 months (95% CI, 23.9-NR) with placebo (durvalumab vs control: HR, 0.77 [95% CI, 0.56-1.07]; durvalumab plus olaparib vs control: HR, 0.59 [95% CI, 0.42-0.83]). “Interim OS data showed a positive trend in both experimental arms,” Westin said.

Examining Safety

Grade 3 or higher adverse effects (AEs) were observed in 133 patients (56.4%) in the control arm, 129 patients (54.9%) in the durvalumab arm, and 160 patients (67.2%) in the durvalumab plus olaparib arm. Overall, AEs that led to treatment discontinuation occurred in 18.6%, 20.9%, and 24.4% of patients in the control, durvalumab, and durvalumab plus olaparib arms, respectively, whereas dose interruptions were seen in 50.0%, 54.5%, and 68.9% of patients in the chemotherapy and the maintenance phase, respectively. In the maintenance phase only, discontinuation occurred in 4.1%, 6.0%, and 14.1% of patients, and interruptions were seen in 21.9%, 28.4%, and 58.9%, respectively.

Any grade AEs occurring in 20% or more of patients included anemia, alopecia, fatigue and asthenia, nausea, neutropenia, constipation, diarrhea, thrombocytopenia, and arthralgia. They also included peripheral neuropathy, peripheral sensory neuropathy, vomiting, decreased appetite, leukopenia, and urinary tract infection.

“The safety profiles across treatment arms were generally consistent with the known profiles of each individual agent,” Westin added.

Enrollment Criteria

In the global, double-blind, placebo-controlled trial, investigators randomly assigned patients 1:1:1 to receive either of the following regimens in a chemotherapy phase and then a maintenance phase:

• carboplatin/paclitaxel plus placebo every 3 weeks, followed by placebo maintenance therapy (control arm)
• carboplatin/paclitaxel plus durvalumab 1200 mg intravenously (IV) every 3 weeks, followed by maintenance therapy with durvalumab 1500 mg IV every 4 weeks plus placebo (durvalumab arm)
• carboplatin/paclitaxel plus durvalumab 1200 mg IV every 3 weeks, followed by maintenance therapy with durvalumab 1500 mg IV every 4 weeks plus oral olaparib 300 mg twice daily (durvalumab plus olaparib arm)

Patients were treated until disease progression, unacceptable toxicity, or other discontinuation criteria were met. Of note, those without evidence of disease progression during the chemotherapy stage were transitioned to the maintenance phase.

Patients with newly diagnosed FIGO 2009 stage III/IV or recurrent endometrial cancer and known MMR status were eligible for the trial if they were naive to first-line systemic anticancer treatment for advanced disease and naive to PARP inhibitors as well as immune-mediated therapy. In addition, adjuvant chemotherapy was allowed if 12 months or more had passed from the patient’s last treatment to relapse, and all histologies were allowed, except sarcomas. Patients were stratified by MMR status, disease status, and geographic region.

PFS for the durvalumab and durvalumab plus olaparib arms vs the control arm served as the primary end points. Key secondary end points included OS and safety; PFS in the durvalumab plus olaparib arm vs durvalumab alone arm and subgroup analyses of PFS, including MMR, PD-L1, and HRRm status, were exploratory end points.

In total, 169 patients (70%) in the control arm, 183 patients (77%) in the durvalumab monotherapy arm, and 192 patients (80%) in the combination maintenance therapy arm started the maintenance phase of the trial. Further, 147 (61%), 159 (67%), and 170 (71%) patients in each arm, respectively, were ongoing in the study at data cutoff on April 12, 2023.

Editor’s Note: Dr Westin reports research funding for AstraZeneca, Avenge Bio, Bayer, Bio-Path, Clovis, Genentech/Roche, GSK, Jazz Pharmaceuticals, Mereo, Novartis, Nuvectis, and Zentalis; and consulting and advisory roles for AstraZeneca, Caris, Clovis, Eisai, EQRx, Genentech/Roche, Gilead, GSK, Immunocore, ImmunoGen, Lilly, Merck, Mersana, Mereo, NGM Bio, Nuvectis, Seagen, Verastem, Vincerx, Zentalis, and ZielBio.

Reference

Westin SN, Moore KN, Chon HS, et al. Durvalumab (durva) plus carboplatin/paclitaxel (CP) followed by maintenance (mtx) durva ± olaparib (ola) as a first-line (1L) treatment for newly diagnosed advanced or recurrent endometrial cancer (EC): results from the phase III DUO-E/GOG-3041/ENGOT-EN10 trial. Ann Oncol. 2023;34(S2):S1282-S1283. doi:10.1016/j.annonc.2023.10.035