In an interview with Targeted Oncology™, Shannon N. Westin, MD, MPH, FACOG, discussed the need for the DUO-E trial in the endometrial cancer space and the unique patient population the study will evaluate.
Sites across the United States are recruiting patients with newly diagnosed advanced or recurrent endometrial cancer for the assessment of the safety and efficacy of maintenance durvalumab (Imfinzi) in combination with platinum-based chemotherapy maintenance durvalumab with or without olaparib (Lynparza).
DUO-E is a randomized, multicenter, double-blind, placebo-controlled, phase 3 looking for adult women with histologically confirmed diagnosis of epithelial endometrial carcinoma (excluding sarcoma), as well as newly diagnosed stage III, newly diagnosed stage IV, or recurrent endometrial cancer. These patients are required to be previously untreated with systemic anti-cancer agents, have an ECOG performance status of 0 or 1, and have a tumor sample available for testing. The study is excluding individuals who have a history of leptomeningeal carcinomatosis, have brain metastases, or spinal cord compression, received prior treatment with PARP inhibitors, and those who received prior immune checkpoint inhibitors or an agent directed to a stimulatory or co-inhibitor T-cell receptor other than anti-PD-1, anti-PD-L1, or anti-PD-L2 agents.
Efficacy in DUO-E will be determined by the primary end point of progression-free survival and secondary end point including, overall survival, second progression, objective response rate, duration of response, and others. Safety will be determined through an assessment of adverse events and serious adverse events according to the National Cancer Institute criteria.
In an interview with Targeted Oncology™, Shannon N. Westin, MD, MPH, FACOG, an associate professor, Department of Gynecologic Oncology and Reproductive Medicine, Division of Surgery at the University of Texas MD Anderson Cancer Center, discussed the need for the DUO-E trial in the endometrial cancer space and the unique patient population the study will evaluate.
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. But for the remainder of the patients that are either diagnosed at 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 need to improve upon those outcomes because we know, in general, patients will not be cured from this regimen.
Your study looks at patients who are newly-diagnosed, advanced, and recurrent. Is any of these populations more in need of these novel approaches?
Both of these populations are huge unmet needs. 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 early in their disease course, so that we can prevent that recurrence and hopefully achieve more cures. For the patients that have a recurrence, again it's very hard to cure these patients. So, this is an area where we have a lot of opportunities 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. Now, 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. So, 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 combined fashion.
Now, we know that one of the ways that cancer tends to recur, or one of the mechanisms that it uses to be able to recur is evading the immune system. So, 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 and so that's the rationale for including the durvalumab both with the chemotherapy as well as a maintenance strategy.
The addition of olaparib is very interesting because PARP inhibitors have had a lot of activity and specific cancer types like breast cancer and ovarian cancer.
Now the addition of elaborate is very interesting, you know, PARP inhibitors have had a lot of activity and specific cancer types like breast cancer and ovarian cancer. It also seems to be mainly driven by homologous recombination deficiencies. What we actually have found in our work is that an in vitro cancer has quite high levels of homologous recombination deficiency, both with mutations in the pathway as well as aberrations in other pathways like A-ROD 1A, so 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. What we're doing is adding that olaparib as a potential maintenance strategy for one of the arms.
Can you explain the study design and methods used 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. Then in the third arm, all the interventions are used, which are the chemotherapy, and durvalumab and olaparib maintenance. It'll be about 699 patients that are randomized in this study. The primary end point is progression-free survival. So, we're well on our way to the enrollments going beautifully. Hopefully, we'll have some answers over the next few years.
Is there anything unique about the patient population being enrolled in this study?
One of the things that we made sure of is to include several patients that are even at higher risk. Many of these types of trials will exclude patients who have 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 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 give us an idea of the activity and all these different populations.
What else is important for referring oncologists to know about this study?
This is a large study, and in addition to looking at clinical outcomes, like progression-free survival and overall survival, there's also a very strong patient-reported outcomes component. This is really 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.
Durvalumab with or without olaparib as maintenance therapy after first-line treatment of advanced and recurrent endometrial cancer (DUO-E). Clinicaltrials.gov. Accessed August 13, 2021.