DUO-E Trial Data Support Durvalumab Combo as Potential Frontline Option in Advanced Endometrial Cancer

Regardless of mismatch repair status, patients with advanced or recurrent endometrial cancer experienced a progression-free survival (PFS) benefit and durable responses when treated with first-line durvalumab (Imfinzi) plus carboplatin and paclitaxel, followed by maintenance durvalumab with or without olaparib (Lynparza), vs chemotherapy alone (CP), according to findings from the phase 3 DUO-E/GOG-3041/ENGOT-EN10 trial (NCT04269200) presented during the 2024 SGO Annual Meeting on Women's Cancer.

Data showed that in the intent-to-treat (ITT) population, the median PFS in patients who received CP was 9.6 months (95% CI, 9.0-9.9) compared with 10.2 months (95% CI, 9.7-14.7) in the chemotherapy/durvalumab arm (CP+D; HR, 0.71; 95% CI, 0.57-0.89; P = .003).

When maintenance olaparib was added to the CP+D regimen (CP+D+O), the median PFS was 15.1 months (95% CI, 12.6-20.7), leading to a 45% reduction in the risk of disease progression or death compared with CP alone (HR, 0.55; 95% CI, 0.43-0.69; P <.0001). When compared with the CP+D arm, the HR was 0.78 (95% CI, 0.61-0.99).

The 1-year PFS rates with CP, CP+D, and CP+D+O were 41.1%, 48.5%, and 61.5%, respectively; the 18-month PFS rates were 21.7%, 37.8%, and 46.3%, respectively.

Additional data in the ITT population showed that the objective response rate (ORR) in the CP arm was 55.1%, which comprised a 45.5% partial response (PR) rate and a 9.6% complete response (CR) rate. The ORR in the CP+D arm was 61.9%, with a 49.0% PR rate and a 12.9% CR rate (OR vs CP, 1.32; 95% CI, 0.89-1.98); in the CP+D+O arm, the ORR was 63.6% with a 47.3% PR rate and a 16.3% CR rate (OR vs CP, 1.44; 95% CI, 0.95-2.18).

In the CP arm, the median duration of response (DOR) was 7.7 months (IQR, 5.1-13.5) compared with 13.1 months (IQR, 6.0-NR) in the CP+D arm. In the CP+D+O arm, the median DOR was 21.3 months (IQR, 8.1-29.9). The median time to onset of response was 2.1 months (IQR, 2.0-2.3) in all 3 arms. The 18-month and 24-month rates of patients in response were 14.8% and 14.8%, 46.6% and 38.0%, and 55.7% and 47.1% in the CP, CP+D, and CP+D+O arms, respectively.

At the SGO meeting, response data with the mismatch repair deficient (dMMR) and mismatch repair proficient (pMMR) subpopulations were also presented, highlighting the benefit with the two regimens.

“DUO-E results support potential new treatment options for patients with endometrial cancer: chemotherapy plus durvalumab for dMMR disease and chemotherapy plus durvalumab plus olaparib for pMMR disease,” lead study author Hye Sook Chon, MD, a gynecologic oncologist at Moffitt Cancer Center in Tampa, Florida, said in an oral presentation during the meeting.

In the double-blind, placebo-controlled, phase 3 DUO-E trial, investigators evaluated adding durvalumab to frontline chemotherapy, followed by durvalumab alone or with olaparib in patients with newly diagnosed advanced or recurrent endometrial cancer.

A total of 718 patients were first randomized 1:1:1 to receive carboplatin at area under the curve of 5 or 6 mg/mL/min plus paclitaxel at 175 mg/m2 twice daily every 3 weeks followed by maintenance placebo (CP arm); CP every 3 weeks plus intravenous (IV) durvalumab at 1120 mg every 3 weeks followed by maintenance durvalumab at 1500 mg every 4 weeks (CP+D arm); or CP every 3 weeks plus IV durvalumab every 3 weeks followed by maintenance durvalumab every 4 weeks plus oral olaparib at 300 mg twice daily (CP+D+O arm). All treatments in the chemotherapy phase were given for 6 cycles. Treatment was administered until disease progression, unacceptable toxicity, or other discontinuation criteria occurred.

To be eligible for enrollment, patients had to have newly diagnosed FIGO 2009 stage III (measurable disease)/IV or recurrent endometrial cancer with known MMR status, be naïve to frontline systemic anticancer treatment for advanced disease, and could not have previously received PARP inhibitors and immunotherapy. Adjuvant chemotherapy was permitted if it was administered at least 12 months from their last treatment relapse. Patients could have any histology except sarcomas.

Stratification factors included MMR status (proficient vs deficient), disease status (recurrent vs newly diagnosed), and geographic region (Asia vs non-Asia).

The primary end point was investigator-assessed PFS via RECIST in the CP+D and CP+D+O arms vs the chemotherapy-alone arms. Secondary end points were overall survival (OS), ORR, DOR, and safety. Exploratory outcomes were PFS in the CP+D+O arm vs the CP+D arm, as well as a prespecified subpopulation analysis of PFS and post hoc analysis of ORR and DOR by MMR status.

Regarding baseline characteristics, the median age in the CP, CP+D, and CP+D+O arms was 64 years, 64 years, and 63 years, respectively. Additionally, 28%, 29%, and 28% of patients were from Asia; 59%, 57%, and 56% were White; 8%, 12%, and 13% were Hispanic or Latino; and 20%, 19%, and 20% of patients had dMMR disease.

In the dMMR population, the median PFS for those in the CP arm (n = 49) was 7.0 months (95% CI, 6.7-14.8) compared with not reached (NR; 95% CI, NR-NR) in the CP+D arm (n = 46; HR, 0.42; 95% CI, 0.22-0.80). The median PFS in the CP+D+O arm (n = 48) was 31.8 months (95% CI, 12.4-NR), leading to a HR of 0.41 (95% CI, 0.21-0.75) when compared with the CP arm. When the CP+D+O arm was compared with the CP+D arm, the HR was 0.97 (95% CI, 0.49-1.98). The 1-year and 18-month PFS rates were 43.3%, 67.9%, and 70.0% and 31.7%, 67.9%, and 62.7% with the CP, CP+D, and CP+D+O arms, respectively.

In the dMMR subgroup, the ORR in the CP arm was 40.5%, which included a 31.0% PR rate and a 9.5% CR rate; in the CP+D arm, these rates were 71.4%, 42.9%, and 28.6% (OR vs CP, 3.68; 95% CI, 1.51-9.39). The ORR in the CP+D+O arm was 73.0% with a 54.1% PR rate and an 18.9% CR rate (OR vs CP, 3.97; 95% CI, 1.57-10.65). The median DOR was 10.5 months (IQR, 4.6-NR), NR (IQR, 22.0-NR), and 29.9 months (IQR, 9.7-29.9) in the CP, CP+D, and CP+D+O arms, respectively. The median time to onset of response was 2.1 months in all 3 arms.

The 18- and 24-month rates of patients remaining in response included 48.2% and 48.2% for the CP arm, 75.2% and 60.2% for the CP+D arm, and 73.6% and 73.6% in the CP+D+O arm, respectively.

Investigators also evaluated the immunotherapy/PARP inhibitor additions in the pMMR subpopulation. In the CP arm of this subgroup (n = 192), the median PFS was 9.7 months (95% CI, 9.2-10.1) compared with 9.9 months (95% CI, 9.4-12.5) with CP+D (n = 192; HR, 0.77; 95% CI, 0.60-0.97). The addition of olaparib (n = 191) led to a median PFS of 15.0 months (95% CI, 12.4-18.0), which yielded a 43% reduction in the risk of disease progression or death compared with CP (HR, 0.57; 95% CI, 0.44-0.73). When compared with the CP+D arm, the HR with CP+D+O was 0.76 (95% CI, 0.59-0.99). The 1-year and 18-month PFS rates were 40.8% and 20.0%, 44.4% and 31.3%, and 59.4% and 42.0% in the CP, CP+D, and CP+D+O arms, respectively.

The ORR in the CP arm of patients in the pMMR subgroup was 59.0%, which included a 49.4% PR rate and a 9.6% CR rate. In the CP+D arm, these rates were 59.4%, 50.6%, and 8.8%, respectively (OR vs CP, 1.02; 95% CI, 0.65-1.59); in the CP+D+O arm, these rates were 61.2%, 45.6%, and 15.6%, respectively (OR, 1.10; 95% CI, 0.69-1.74).

The median DOR with CP was 7.6 months (IQR, 5.1-13.1), 10.6 months (IQR, 5.6-NR) with CP+D, and 18.7 months (IQR, 8.0-NR) with CP+D+O. The median time to onset of response was 2.1 months (IQR, 2.0-2.3) in all arms. The 18-month and 24-month rates of patients in response were 12.1% and 12.1%, 37.4% and 32.4%, and 50.0% and 37.8% for the CP, CP+D, and CP+D+O arms, respectively.

Chon also noted that the PFS benefits in the ITT, dMMR, and pMMR populations were consistent across prespecified patient subgroups.

Regarding safety, patients across the CP, CP+D, and CP+D+O arms and across the chemotherapy and maintenance phases experienced any-grade anemia (54.2% vs 47.7% vs 61.8%, respectively), alopecia (50.0% vs 50.2% vs 50.8%), nausea (44.5% vs 40.9% vs 54.6%), and fatigue and asthenia (44.5% vs 43.0% vs 54.2%). Grade 3 or higher neutropenia occurred in 23.3%, 21.7%, and 26.9% of patients in the CP, CP+D, and CP+D+O arms, respectively; grade 3 or higher anemia occurred in 14.4%, 15.7%, and 23.5%, respectively.

Immune-mediated adverse effects (AEs) occurred in 6.8% of patients who received CP compared with 28.1% on CP+D and 23.5% on CP+D+O. Pure red cell aplasia occurred in 3 patients on CP+D+O, and autoimmune hemolytic anemia occurred in 1 patient on CP+D and 2 patients on CP+D+O. AEs that led to study treatment discontinuation occurred in 18.6%, 20.9%, and 24.4% of patients on CP, CP+D, and CP+D+O.

The median overall duration of treatment was 9.0 months with CP, 9.9 months with CP+D, and 13.1 months with CP+D+O. In the maintenance phase alone, the median duration of treatment was 5.7 months, 7.6 months, and 9.2 months, respectively.

Editor’s Note: Chon cited honoraria from Curio Science, Envision Communications Group, MJH Healthcare Holdings, and Guidepoint Global; consulting or advisory roles from Envision Communications Group and Eisai; speakers’ bureaus from Clinical Care Options; and travel, accommodation, and expenses from Agenus.

Reference

Chon HS, Thomas-Pepin J, Sundborg MJ, et al. Durvalumab plus carboplatin/paclitaxel followed by durvalumab with or without olaparib as first-line treatment for endometrial cancer (DUO-E/GOG-3041/ENGOT-EN10): objective response rate and duration of response by mismatch repair status. Presented at: SGO 2024 Annual Meeting on Women’s Cancer; March 16-18, 2024; San Diego, CA.