Findings from the phase 2 DOMEC trial showed that although durvalumab plus olaparib was well tolerated, it missed the study’s primary end point of progression-free survival in patients with metastatic or recurrent endometrial cancer.
Durvalumab (Imfinzi) plus olaparib (Lynparza), although well tolerated, did not meet the prespecified 6-month progression-free survival (PFS) threshold of 50% for patients with metastatic or recurrent endometrial cancer, according to results from the phase 2 DOMEC trial (NCT03951415).
At 6 months, 34% of patients were progression-free. For those with low-grade endometrial cancer, the median PFS was 4.2 months (95% CI, 3.0–not reached [NR]), and for those with high-grade disease, it was 3.4 months (95% CI, 2.8-7.8; P = .82). Additionally, the median PFS for those with mismatch repair deficient (MMRd) endometrial cancer was 5.7 months (95% CI, 2.8-NR), 3.2 months for no specific molecular profile (NSMP; 95% CI, 2.6-NR), and 3.0 months for p53-abnormal disease (95% CI, 2.8-7.8; P = .67). The objective response rate was 16% (95% CI, 8.3%-28.5%), with 1 complete response (CR) and 7 partial responses (PR). The median follow-up was 17.6 months, and the median PFS was 3.4 months (95% CI, 2.8-6.2). Moreover, the median overall survival was 8.0 months (95% CI, 7.5-14.3).
“The [phase 2] DOMEC trial is the first to report the efficacy and safety of combined immune-checkpoint inhibition and PARP inhibition for patients with metastatic, persistent or recurrent endometrial cancer including uterine carcinosarcoma. In this investigator-initiated phase 2 study, the combination of PD-L1 inhibitor durvalumab and PARP inhibitor olaparib did not meet the prespecified threshold of 50% 6-month PFS,” the study’s investigators wrote.
A total of 55 patients enrolled and 50 patients were evaluable for safety and efficacy. The median age was 69 years. Most patients had received prior chemotherapy (84%), while a smaller group had received endocrine therapy (26%). Histologic subtypes included serous carcinoma (38%), endometrial carcinoma (32%), clear cell carcinoma (12%), and carcinosarcoma (14%). Most patient’s tumors were classified as p53-abnormal (58%), and others were MMRd (20%) or had NSMP (20%). No patients had POLE mutant endometrial cancer.
Durvalumab was administered at 1500 mg intravenously every 4 weeks, and oral olaparib was given at 300 mg twice daily until disease progression, treatment discontinuation due to toxicity, or patient withdrawal of consent.
Investigators did not find any difference in characteristics between responders and non-responders. Among those with BRCA1 germline mutations, 1 patient had a CR with progression after 12.9 months, 1 had a PR with progression after 8.3 months, and 1 partial responder still receiving treatment after the data cut-off at 20 months.
Treatment-related adverse effects (TRAEs) occurred in 88% of patients, the most common of which were fatigue (44%), nausea (38%), anemia (32%), and diarrhea (26%). Grade 3 TRAEs were observed in 16% of patients, with the most frequent being anemia (10%). There were no grade 4 or 5 TRAEs.
Discontinuation of olaparib because of a treatment-related renal event was necessary in 1 patient; 24% of patients had dose reductions because of TRAEs. Additionally, 6% of patients had olaparib dose interruptions but resumed treatment at the initial dose. Discontinuation of durvalumab was necessary in 1 patient because of treatment-related diarrhea.
Post CCB, Westermann AM, Boere IA, et al. Efficacy and safety of durvalumab with olaparib in metastatic or recurrent endometrial cancer (phase II DOMEC trial). Gynecol Oncol. 2022;165(2):223-229. doi:10.1016/j.ygyno.2022.02.025