Improving the standard of care: Inside the DUO-E trial

Professor Shannon Westin is principal investigator of the DUO-E trial, here she speaks to DDW’s Megan Thomas about why the standard of care needs improving and the impact of therapeutic antibodies such as durvalumab.

The DUO-E trial is a three-arm, randomised, double-blind, placebo-controlled, multicentre Phase III trial assessing the combination of durvalumab with platinum-based chemotherapy followed by durvalumab with or without olaparib maintenance therapy as a treatment for patients with newly diagnosed advanced or recurrent endometrial cancer. In the DUO-E trial, patients were randomised 1:1:1 to Control arm – platinum- based chemotherapy and durvalumab placebo followed by durvalumab placebo and olaparib placebo; durvalumab arm – platinum-based chemotherapy and durvalumab followed by durvalumab and olaparib placebo; and durvalumab plus olaparib arm – platinum-based chemotherapy and durvalumab followed by durvalumab and olaparib. The dual primary endpoint was progression free survival (PFS) comparing durvalumab plus olaparib arm vs Control arm and durvalumab arm vs Control arm.

Dr Shannon Westin says: “I am very excited about the DUO-E trial results as they showed that durvalumab plus platinum-based chemotherapy, followed by either durvalumab monotherapy or durvalumab plus olaparib, both demonstrated a statistically significant and clinically meaningful improvement in progression-free survival compared to chemotherapy alone in the overall trial population of patients with newly diagnosed advanced or recurrent endometrial cancer.”

Dr Westin explains that the results showed that treatment with durvalumab plus chemotherapy followed by durvalumab plus olaparib (durvalumab plus olaparib Arm) and treatment with durvalumab plus chemotherapy followed by durvalumab monotherapy (durvalumab Arm) demonstrated a reduction in the risk of disease progression or death, by 45% (hazard ratio [HR] 0.55; 95% confidence interval [CI] 0.43-0.69; p<0.0001) and 29% (HR 0.71; 95% CI 0.57-0.89; p=0.003), respectively, versus chemotherapy alone (Control Arm). Median PFS was 15.1 months in the durvalumab plus olaparib Arm. Interim overall survival (OS) data showed a favourable trend for both treatment regimens versus control in the overall population. Therefore, DUO-E confirms the clinical benefit of adding immunotherapy to chemotherapy in the treatment of advanced or recurrent endometrial cancer and is the first Phase III study to demonstrate that the addition of olaparib confers benefit in this setting.

In addition, in a prespecified exploratory analysis by mismatch repair status, similar results were achieved with both treatment arms in dMMR patients: 59% (HR 0.41; 95% CI 0.21-0.75) and 58% (HR 0.42; 95% CI 0.22-0.80) for the durvalumab plus olaparib Arm and durvalumab-only Arm, respectively, compared with chemotherapy alone. However, in patients with mismatch repair proficient disease (pMMR) the durvalumab-only arm saw a reduction in the risk of progression or death of 23% (HR 0.77; 95% CI 0.60-0.97), which was increased to 43% (HR 0.57; 95% CI 0.44-0.73) when olaparib was added to durvalumab and median PFS was 15 months in the durvalumab plus olaparib Arm versus 9.7 months in the Control Arm.

“These DUO-E data offer clinical community evidence for novel avenues to provide incremental benefit for endometrial cancer patients”, Dr Westin adds.

Standard of care

According to Dr Westin, endometrial cancer is the sixth most common cancer in women worldwide and the only cancer where incidence and mortality continue to rise driven in part by an ageing population and the obesity epidemic. This, she says, is why the standard of care requires improvement and why new treatment options that can better serve a wide range of patients are needed, particularly at advanced stages. She says: “Most patients with endometrial cancer are diagnosed at an early stage and the five-year survival rate is high in this setting (approximately 95%). However, for patients with advanced disease (Stage III-IV), prognosis remains poor, with a five-year survival rate of approximately 20-30%.”

dMMR and pMMR patient results

On the topic of how important it is that the study saw results in both mismatch repair deficient (dMMR) and mismatch repair proficient (pMMR) patients, Dr Westin says: “Currently, the global standard-of-care treatment for advanced or recurrent endometrial cancer is hormonal therapy or platinum-based combination chemotherapy, specifically carboplatin and paclitaxel. Recently, we have seen immunotherapy combined with chemotherapy emerging as a new standard of care, particularly for patients with mismatch repair deficient (dMMR) disease. But there remains a high unmet need for new treatment options for patients with mismatch repair proficient (pMMR) disease, who comprise approximately 80% of patients with endometrial cancer.”

She continues to say that what this is why the results of DUO-E are so interesting, as they build on these recent advancements with immunotherapies by adding a PARP inhibitor to the combination and are important as there is a high unmet need for new treatment options for patients with pMMR endometrial cancer.

She adds: “As I mentioned in a prespecified exploratory analysis by mismatch repair status, similar results were achieved with both treatment arms in dMMR patients: 59% (HR 0.41; 95% CI 0.21-0.75) and 58% (HR 0.42; 95% CI 0.22-0.80) for the durvalumab plus olaparib Arm and durvalumab-only Arm, respectively, compared with chemotherapy alone. However, in patients with mismatch repair proficient disease (pMMR) the durvalumab-only arm saw a reduction in the risk of progression or death of 23% (HR 0.77; 95% CI 0.60-0.97), which was increased to 43% (HR 0.57; Therapeutic antibodies: DUO-E trial 95% CI 0.44-0.73) when olaparib was added to durvalumab and median PFS was 15 months in the durvalumab plus olaparib Arm versus 9.7 months in the Control Arm.”

PD-L1 for tumours

PD-L1 has become an important biomarker for tumours responding to immunotherapies but this study still saw some benefit in PD-L1 negative patients. When asked if this is due to the combination approach of both the immunotherapy and PARP inhibitor, Dr Westin says: “Durvalumab enhances the anti-tumour immune response by overcoming PD-L1- mediated inhibition of T cells. Chemotherapy complements durvalumab through its potential to enhance immune priming and through direct tumour cell killing. Olaparib leads to the accumulation of DNA damage in tumour cells through the inhibition of PARP, which can lead to tumour cell death. In addition, inhibition of PARP can also have immunomodulatory effects that work together with durvalumab to further enhance the anti-tumour immune response.

“PD-L1 is a known biomarker for durvalumab in other indications and a prespecified analysis based on PD-L1 status showed that in the PD-L1 positive population (tumour area positivity score [TAP] ≥1%), treatment in the durvalumab and the durvalumab plus olaparib Arms reduced the risk of disease progression or death by 37% (HR 0.63; 95% CI 0.48-0.83) and 58% (HR 0.42; 95% CI 0.31-0.57), respectively, versus the Control Arm. Median PFS was 20.8 months in the durvalumab plus olaparib Arm versus 9.5 months in the Control Arm. In the PD-L1 negative population (TAP<1%), treatment in the durvalumab and the durvalumab plus olaparib Arms reduced the risk of disease progression or death by 11% (HR 0.89; 95% CI 0.59-1.34) and 20% (HR 0.80; 95% CI 0.55-1.16) respectively, versus the Control Arm.”

Opportunities and challenges

Dr Westin says that this study is indicative of other successful therapeutic antibody combination therapy approaches we’ve seen in cancer, highlighting that in recent years we have seen the successful emergence of antibody combination therapy approaches across a variety of tumour types. She notes: “What is different about DUO-E is by building on this foundation we are also bringing in PARP inhibition, expanding the effect to patients who wouldn’t normally see as great a benefit with the addition of immunotherapy alone. I’m looking forward to seeing additional DUO-E trial results which will be presented at upcoming medical meetings.”

Dr Westin says that resistance to therapy remains a critical challenge and one of the biggest unmet needs for these patients. She says: “To understand mechanisms of resistance, we build in translational endpoints including assessment of liquid and tissue biospecimens. This allows us to develop future trials and treatments that will prevent or overcome this resistance.”

DDW Volume 25 – Issue 1, Winter 2023/2024 – Therapeutic Antibodies Guide

Professor Shannon WestinBiography:

Professor Shannon Westin is the Professor of Gynecologic Oncology and Reproductive Medicine in the Division of Surgery at The University of Texas MD Anderson Cancer Center, and principal investigator of the DUO-E trial.

 

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