ASCO 2025 | ctDNA dynamics in DUO-E: durvalumab ± olaparib in endometrial cancer

DuoE was a study looking at the treatment of advanced and recurrent endometrial cancer where we wanted to observe if the addition of durvalumab, the PD-L1 inhibitor, to chemotherapy could improve progression-free survival in that population. Then we also had an arm where we added olaparib in the maintenance setting to durvalumab, again, to determine if there was an improvement in progression-free survival in the maintenance setting. And what we found was that actually both arms met their primary endpoint. So Durvalumab with chemotherapy performed higher in progression-free survival setting as opposed to chemo alone. And then the addition of olaparib seemed to add additional benefit, especially in the mismatch repair proficient population of endometrial cancer. So that’s very exciting and has yielded FDA approval for durvalumabin the mismatch repair deficient setting. We’re still trying to do more translational work to understand what the impact of these additional drugs might be and also who might benefit the most. So we were able to obtain ctDNA testing on a proportion of the patients in the study. About 341 had effective testing of the ctDNA. And we tested it at a couple of different time points. So we tested it at baseline before they started, after cycle three, day one. So right in the middle of that chemotherapy phase. And then at cycle seven, day one, right before they were to move from the chemo combination to just maintenance. And then finally in cycle nine, day one, which was meant to be during the phase. And we were able to observe at those time points, the level of ctDNA. And the bottom line is we saw ctDNA expression across all the groups, but higher ctDNA expression or presence of ctDNA at all was associated with worse prognosis, so worse progression-free survival. And that didn’t matter what treatment the patient had received. So that’s important information because we don’t have a lot of data yet for ctDNA and endometrial cancer. But more importantly, we were able to observe the impact of the additional drugs on ctDNA. So what we found was in the arm that added durvalumab to chemo, followed by Durvalumab alone maintenance, that during that chemotherapy phase, the addition of durvalumab led to more reduction in ctDNA expression than chemotherapy alone, indicating that durvalumab itself, when added to chemo, could help enhance tumor kill and clearance. So that was interesting, and that was especially seen in the mismatch repair deficient group. Now, when we looked at the olaparib arm, we saw something very intriguing, and this was specifically in the mismatch repair proficient group, that once we got into maintenance and added the olaparib , we saw an increase in clearance of ctDNA, 35% increased clearance over chemo alone, which indicates that there’s actually novel anti-tumor activity happening in those patients that had existing ctDNA. They were able to clear it out with the addition of olaparib . So that’s really exciting to start to understand where this mechanism might lie.

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