Durvalumab Plus Olaparib Approaches EU Approval for pMMR Advanced or Recurrent Endometrial Cancer

Frontline durvalumab (Imfinzi) plus chemotherapy followed by olaparib (Lynparza) and durvalumab has been recommended for approval in patients with mismatch repair–proficient (pMMR) primary advanced or recurrent endometrial cancer by the European Medicines Agency’s Committee for Medicinal Products for Human Use.1 Moreover, durvalumab plus chemotherapy followed by single-agent durvalumab has been recommended for those with mismatch repair–deficient (dMMR) disease.

The positive opinion is supported by data from a prespecified exploratory subgroup analysis by mismatch repair status from the phase 3 DUO-E study (NCT04269200).2 Data indicated that in the pMMR group, the median progression-free survival (PFS) was 15.0 months (95% CI, 12.4-18.0) with the doublet (n = 191) vs 9.7 months (95% CI, 9.2-10.1) with the control regimen (n = 192; HR, 0.57; 95% CI, 0.44-0.73). The 12-month PFS rates in the doublet and control arms were 59.4% and 40.8%, respectively; these respective rates at 18 months were 42.0% and 20.0%. In the dMMR group, those in the durvalumab arm (n = 46) experienced a median PFS that was not yet reached (NR; 95% CI, NR-NR) vs 7.0 months (95% CI, 6.7-14.8) for those in the control arm (n = 49; HR, 0.42; 95% CI, 0.22-0.80).

“Patients with advanced or recurrent endometrial cancer currently have a very poor prognosis, especially those with [pMMR] disease,” Els Van Nieuwenhuysen, MD, study investigaror and gynecologic oncologist at the UZ Leuven, in Belgium, stated in a press release.1 “This recommendation underscores the significant benefit shown with durvalumab as well as with the olaparib and durvalumab combination for patients with both [dMMR] and [pMMR] status. This marks an important step toward improving outcomes for these patients in Europe.”

The double-blind, global, placebo-controlled, phase 3 DUO-E study enrolled patients with newly diagnosed FIGO stage III/IV or recurrent endometrial cancer.³ Those with newly diagnosed stage III disease were required to have measurable disease. They needed to have known MMR status; they could not have prior exposure to frontline systemic therapy for advanced disease or PARP inhibitors and immune-mediated therapy. If at least 1 year had passed since last treatment relapse, prior adjuvant chemotherapy was permitted. All histologies were enrolled to the study with the exception of sarcomas.

Study participants were randomly assigned 1:1:1 to one of the following arms: 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 (control arm); chemotherapy plus durvalumab at 1120 mg every 3 weeks, followed by maintenance durvalumab at 1500 mg every 4 weeks (durvalumab arm); or chemotherapy plus durvalumab every 3 weeks, followed by maintenance durvalumab every 4 weeks plus olaparib at 300 mg twice daily (doublet arm). The chemotherapy phase lasted for 6 cycles and patients could only receive maintenance therapy if they had not experienced progressive disease (PD). Treatment continued until PD, intolerable toxicity, or other discontinuation criteria were met.

Stratification factors included MMR status (pMMR vs dMMR), disease status (newly diagnosed vs recurrent), and geographic region (Asia vs non-Asia). The dual primary end points included PFS by investigator assessment and RECIST 1.1 criteria for the durvalumab arm vs the control arm and the doublet arm vs the control arm. Secondary end points included overall survival, patient-reported outcomes, and safety.

Baseline characteristics were generally well balanced between the treatment arms. The median patient age in the doublet (n = 239), durvalumab (n = 238), and control (n = 241) arms was 63 years (range, 27-86), 64 years (range, 22-84), and 64 years (range, 31-85), respectively. Regarding disease status in the doublet arm, 52.3% had recurrent disease and 47.7% had newly diagnosed disease; in the durvalumab arm, these respective rates were 52.5% and 47.5%, and in the control arms, these respective rates were 52.3% and 47.7%. In terms of MMR status in the doublet arm, 79.9% had pMMR disease and 20.1% had dMMR disease; these respective rates in the durvalumab arm were 80.7% and 19.3% and were 79.7% and 20.3% in the control arm. In terms of geographic region in the doublet arm, 28.0% were from Asia and 72.0% were from a non-Asia region; these rates were 28.6% and 71.4% in the durvalumab arm and 28.2% and 71.8% in the control arm.

Previous data from the study indicated that in the intention-to-treat population, the median PFS was 10.2 months (95% CI, 9.7-14.7) in the durvalumab arm vs 9.6 months (95% CI, 9.0-9.9) in the control arm (HR, 0.71; 95% CI, 0.57-0.89; P = .003); the median PFS in the doublet arm was 15.1 months (95% CI, 12.6-20.7; HR vs the control arm, 0.55; 95% CI, 0.43-0.69; P < .0001), meeting the dual primary end points of the study.⁴

Updated data shared during the 2024 ESMO Gastrointestinal Cancers Congress showed that the objective response rate (ORR) reported in the durvalumab arm (n = 202) was 61.9% vs 55.1% in the control arm (n = 198; odds ratio [OR], 1.32; 95% CI, 0.89-1.98).3 In the doublet arm (n = 184), the ORR was 63.6% (OR vs the control arm, 1.44; 95% CI, 0.95-2.18). The median time to response was 2.1 months in all arms. In the durvalumab, doublet, and control arms, the median duration of response was 13.1 months (interquartile range, 6.0-not reached), 21.3 months (IQR, 8.1-29.9), and 7.7 months (IQR, 5.1-13.5). The respective 18-month DOR rates 46.6%, 55.7%, and 14.8%; these respective rates at 24 months were 38.0%, 47.1%, and 14.8%.

Regarding safety, the toxicity profiles of the durvalumab and doublet regimens were determined to be manageable and tolerable.¹

In June 2024, the FDA approved durvalumab plus carboplatin/paclitaxel, followed by single-agent durvalumab, for the treatment of adult patients with primary advanced or recurrent endometrial cancer and dMMR disease based on DUO-E data.⁵

References

1. Lynparza and Imfinzi combination recommended for approval in the EU by CHMP for patients with mismatch repair proficient advanced or recurrent endometrial cancer. News release. AstraZeneca. July 1, 2024. Accessed July 1, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/lynparza-and-imfinzi-positive-chmp-in-endometrial.html
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. 2024;42(3):283-299. doi:10.1200/JCO.23.02132
3. Van Nieuwenhuysen E, Chon HS, Pepin JT, et al. First-line durvalumab + carboplatin/paclitaxel followed by durvalumab ± olaparib for endometrial cancer (DUO-E): objective response rate, duration of response and time to treatment discontinuation or death by mismatch repair status. Presented at: 2024 ESMO Gynecological Cancers Congress; June 20-22, 2024; Florence, Italy. Abstract: 40MO.
4. 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.
5. FDA approves durvalumab with chemotherapy for mismatch repair deficient primary advanced or recurrent endometrial cancer. FDA. June 14, 2024. Accessed July 1, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-chemotherapy-mismatch-repair-deficient-primary-advanced-or-recurrent