Durvalumab addition to chemo shows endometrial cancer benefit
Prof Shannon Westin - University of Texas MD Anderson Cancer Center, Houston, USA
DUO-E was a randomised phase III study that was exploring not only the role of checkpoint inhibition in combination with chemotherapy followed by checkpoint maintenance, but also the addition of PARP inhibition to the maintenance phase. What we know is chemotherapy and immunotherapy have been demonstrated to be active in endometrial cancer but really specifically in patients with mismatch repair deficiency, which is a proportion of patients. But there’s a larger proportion of patients with mismatch repair proficiency for whom we have no clear option. DUO-E meant to see if we could push the envelope there and improve outcomes for patients with combination strategies.
We enrolled patients with advanced stage FIGO three or four, or recurrent endometrial cancer. They could have had prior chemotherapy if it was given in the adjuvant setting and it had been more than a year since they completed it. We allowed all comers as far as histologies, including carcinosarcoma, which is a more rare and aggressive type. Once we identified those patients they were randomised to one of three arms: the chemotherapy alone arm, chemotherapy with durvalumab followed by durvalumab maintenance, or chemotherapy with durvalumab followed by durvalumab and olaparib maintenance.
Our primary endpoints were two - we had dual primary endpoints. It was investigator-assessed progression free survival by RECIST version 1.1 in either the durvalumab arm versus the control arm, or the durvalumab olaparib arm versus the control arm. A large number of patients were randomised, almost all of them made it through the chemotherapy phase. We saw more in the two interventional arms and the durvalumab arms make it to that maintenance, which was very intriguing. At a median follow up of approximately seventeen months we did meet both primary endpoints. So DUO-E was a positive study, so yay.
In those primary endpoints, the durvalumab alone did yield a progression free survival benefit in the intend to treat population of a hazard ratio of 0.71, so very large reduction in the risk of progression. But the addition of olaparib enhanced that benefit, and we saw a hazard ratio of 0.45. So a really nice reduction in the risk of progression. But, like I said, the molecular matters, so we did tease out in subset analyses looking at mismatch repair deficiency and mismatch repair proficiency.
For MMRD, the addition of olaparib to durvalumab didn’t seem to give us that much more benefit; that seems to be a place where checkpoint inhibition alone is enough. However, conversely, when we looked at the mismatch repair proficient group, that was really where the combination shone. We saw benefit of durvalumab alone, but really the most enhanced benefit to progression free survival in that group was with the addition of olaparib.
Then I would just be remiss if I didn’t mention safety because we’re adding additional drugs to standard of care. What I’ll say is overall it was well tolerated; we did see an increase in grade 3 adverse events in the combination of durvalumab olaparib, but in general the side effects we saw were as expected for each individual agent, so there were no real surprises. That grade 3 toxicity really seemed to be driven by grade 3 anaemia which we know is super-common with olaparib. As such, we did see more dose delays and dose reductions in that arm, but the majority of patients were able to stay on the study throughout, after management of those adverse effects appropriately.
How could these results impact the future treatment of advanced or recurrent endometrial cancer?
We already had regulatory approvals for the addition of dostarlimab with chemotherapy, so we knew checkpoint and chemotherapy worked, but it was specifically in this mismatch repair deficient subgroup. DUO-E provides us data for an all-comers population, but specifically in that mismatch repair proficient group, that the addition of olaparib to durvalumab does improve progression free survival in a very obviously statistically significant but more importantly clinically meaningful way. So this is an option that we should be considering for our patients.
