Journal of clinical oncology : Official Journal of the American Society of Clinical Oncology 2023 Oct 21
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.
Abstract
Purpose
Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)-deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease.
Methods
This phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control.
Results
Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P < .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1-positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents.
Conclusion
Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer.
Related Questions
What do you view as the future role for the combination of durvalumab + olaparib + chemotherapy in the management of patients with advanced/recurrent endometrial cancer following the DUO-E trial results?
The results of DUO-E are very exciting and will serve a number of purposes. I was encouraged to continue to see that the combo of chemo IO performed better than chemo alone confirming the class effect that was seen in GY018 and RUBY. I wish there was a pre-planned comparison of the chemo/IO/Olaparib...
Would you consider offering immunotherapy +/- olaparib to a patient with early-stage endometrial carcinoma for whom you are recommending adjuvant chemotherapy based on improved outcomes seen in RUBY/DUO-E/NRG-GY018?
I hesitate to offer the chemo/IO combination to patients with stage I disease as this is likely an overtreatment. The majority of the patients who require chemotherapy for stage I disease are those with serous and carcinosarcoma histology. Most of those patients are not even MMRd. It is unclear what...
For patients with advanced endometrial cancer, are the improved outcomes in PFS from DUO-E/RUBY/NRG-GY018 sufficient to move immunotherapy to the frontline for all presuming FDA approval?
The standard of care for metastatic endometrial cancer is systemic therapy with chemotherapy and now with or without immunotherapy. With this approach to therapy, there is a roughly 70% reduction in the risk of progression or death across three separate trials for the dMMR population (RUBY, GY018, A...
In a patient with HER2+ advanced endometrial cancer, do you include IO(+/- olaparib) in their treatment regimen, or only trastuzumab in addition to carboplatin/paclitaxel?
This is a data-free zone and an excellent question. We don't yet know the efficacy of checkpoint inhibitor therapy in pMMR, HER2-positive, p53 mutated tumors, although the ad hoc RUBY data presented at ESMO suggest that p53 mutated tumors are responsive to immunotherapy. I eagerly await the histolog...
In light of the improved outcomes seen in patients receiving IO +/- olaparib, what role, if any, do you think pelvic radiation still plays in the management of patients with advanced endometrial cancer?
The study included a wide spectrum of patients including advance stage with residual disease or recurrent with or without residual disease. Prior RT when indicated was allowed and about 40% had RT as part of care.
Would you recommend adjuvant chemo+IO +/- olaparib for patients with occult stage III disease identified after staging surgery with no measurable residual disease?
Although most of those patients were not included in the trial, it is definitely a discussion I would have for patients with MMRd tumors and would recommend it to them. I would for MMRd patients although they were not included in the trial if they had stage 3 endometrioid histology. More data on thi...