Impact on Survival of Durvalumab +/- Olaparib Investigated in Endometrial Cancer

Shannon N. Westin, MD, MPH, FACOG

Endometrial cancer, when caught early, has a high cure rate. However, if it recurs or is caught in the later stages, the curative rate is a lot lower, prompting the need for new novel therapies in this space.

The DUO-E trial (NCT04269200) aims to determine if durvalumab (Imfinzi) with or without olaparib (Lynparza) can prolong progression-free survival (PFS) in patients with advanced and recurrent endometrial cancer. The trial has an estimated enrollment of 699 participants and an estimated completion date of March 2025. The primary end point of the study is PFS. Secondary end points include overall survival (OS), second progression, objective response rate, duration of response, time to first subsequent therapy, time to second subsequent therapy, time to discontinuation or death, and safety and tolerability.

The study has 3 arms. In arm 1, the control, patients received platinum-based chemotherapy and a durvalumab placebo followed by maintenance durvalumab placebo and olaparib placebo. During arm 2, patients received platinum-based chemotherapy and durvalumab followed by maintenance durvalumab and olaparib placebo. In arm 3, patients received platinum-based chemotherapy and durvalumab followed by durvalumab and olaparib.

In order to participate, patients must be female 18 years of age or older and have confirmed epithelial endometrial cancer. Patients must be stage III or IV or have recurrent disease where the potential for a cure by surgery alone is poor. Patients with a history of leptomeningeal carcinomatosis, brain metastases, prior treatment with PARP inhibitors, or treatment with prior immune checkpoint inhibitors are not eligible to participate.

The study is currently recruiting in 240 locations across the globe.

In an interview with Targeted Oncology™, Shannon N. Westin, MD, MPH, FACOG, discusses the DUO-E trial, its design, end points, and the need for novel endometrial cancer therapies. 

TARGETED ONCOLOGY™: Can you explain the need for novel treatment strategies for patients with endometrial cancer?

WESTIN: The thing about endometrial cancer is for those patients that are diagnosed at an early stage, it can be cured with surgery and maybe just a little bit of additional adjuvant therapy like radiotherapy or chemotherapy. For the remainder of the patients that are either diagnosed at an advanced stage, or have a recurrence, it can be difficult to have a successful therapy. The combination of chemotherapy, specifically paclitaxel and carboplatin has been the standard of care for some time. But we have a need to improve upon those outcomes, because we know, in general, patients will not be cured with this regimen.

Are newly diagnosed, advanced, or recurrent patients more in need of novel approaches?

Both of these populations have a huge unmet need. Those patients that do have advanced-stage disease at diagnosis have a very high rate of recurrence. So, what we're trying to do is act earlier in their disease course, so that we can prevent that recurrence and hopefully achieve more cures. For the patients that have recurrence, again, it's very hard to cure these patients. This is an area where we have a lot of opportunity to improve outcomes.

What has been observed historically with maintenance durvalumab that rationalizes its use with or without olaparib in these patients?

There has been quite a bit of activity of immune checkpoint inhibitors in endometrial cancer. Some of that is driven based on the prevalence of microsatellite instability. About 30% or so of patients will have that abnormality in their tumor. However, we do see that there is the opportunity for synergy between chemotherapy and immunotherapies, specifically with checkpoint inhibitors like durvalumab.

If we give the immunotherapy with the chemotherapy, then it makes it more likely that the tumor will respond to both of those agents. That's the rationalization for utilizing it in a combination fashion. Now, we know that 1 of the ways that cancer tends to recur, or 1 of the mechanisms that it uses to be able to recur is evading the immune system. Continuing an agent that will stimulate the immune system makes a lot of sense once you have a complete response to therapy or response to therapy with chemotherapy.

The addition of olaparib is very interesting. PARP inhibitors have had a lot of activity in specific cancer types like breast cancer and ovarian cancer. It seems to be mainly driven by homologous recombination deficiencies. What we actually have found in our work is that endometrial cancer has quite high levels of homologous recombination deficiency, both with mutations in the pathway as well as aberrations in other pathways like ARID1A. It would seem that upwards of about 50% of patients with endometrial cancer could stand to benefit and maybe even more with the addition of olaparib. So, what we're doing is adding that olaparib as a potential our maintenance strategy for one of the arms.

Can you discuss the study design and the methods utilized in this study?

This is a randomized, placebo, blinded, controlled trial. It's got 3 arms and patients are randomized either to get chemotherapy alone, followed by placebo maintenance or the chemotherapy with durvalumab followed by durvalumab maintenance and a placebo. The third arm has all of the interventions, which is the chemotherapy, durvalumab, and olaparib maintenance. It'll be about 699 patients that are randomized, the primary end point is PFS. So, we're well on our way the enrollments going beautifully. Hopefully, we'll have some answers over the next few years.

Is there anything else unique about this patient population that you're enrolling?

We include several patients that are even at a higher risk. Many of these types of trials will exclude patients who have the histology carcinosarcoma, which is one of the more aggressive subtypes. But we are including that in our trials. So, we're excited to see if we can get benefit for that patient population. In addition, we are allowing patients to have prior chemotherapy, so those patients that have a recurrent endometrial cancer, can have had prior chemotherapy if it's been more than a year. So that's a few of the unique pieces of this trial that will hopefully expand eligibility and also really give us an idea of activity in all these different populations.

Is there anything else that you'd like to discuss about the objectives of the study?

This is a large study. In addition to looking at clinical outcomes, like PFS and OS, there's also a very strong patient-reported outcomes component, which matters because if we are going to be prescribing maintenance, for some years after the completion of therapy, we want to make sure that quality-of-life is not negatively impacted. So, we are collecting those data as well to ensure that if we see a benefit, from a survival standpoint, that it's not at a cost of poor quality of life.