The European Commission has approved durvalumab (Imfinzi®; AstraZeneca)* and olaparib (Lynparza®; AstraZeneca)**, the first immunotherapy and PARP inhibitor combination, for the treatment for certain patients with primary advanced or recurrent endometrial cancer.
In addition, durvalumab plus chemotherapy as 1st-line treatment followed by olaparib and durvalumab has been approved for patients with mismatch repair proficient (pMMR) disease. Durvalumab plus chemotherapy followed by durvalumab alone was also approved for patients with mismatch repair deficient (dMMR) disease.
This approval follows the positive opinion of the Committee for Medicinal Products for Human Use and is based on a prespecified exploratory subgroup analysis by mismatch repair (MMR) status from the DUO-E Phase 3 trial, which was presented at the 2023 European Society for Medical Oncology (ESMO) Congress in Madrid, Spain (Presentation #LBA41) and simultaneously published in the Journal of Clinical Oncology.[1]
In the trial, the olaparib and durvalumab regimen reduced the risk of disease progression or death for patients with pMMR disease by 43% (median 15.0 months versus 9.7 months, hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.44-0.73) versus the control arm.[1] The durvalumab regimen reduced the risk of disease progression or death among patients with dMMR disease by 58% (median not reached versus 7.0 months, HR 0.42; 95% CI 0.22-0.80) versus the control arm.[1]
In this study, mismatch repair (MMR) status, a biomarker of interest in endometrial cancer, was included as a prespecified exploratory subgroup analysis by MMR status, was also conducted in the DUO-E study. Results from the study analysis of mismatch repair proficient (pMMR) patients showed a reduction in the risk of disease progression or death in both the durvalumab plus olaparib and the durvalumab Arms, by 43% (HR 0.57; 95% CI 0.44-0.73) and 23% (HR 0.77; 95% CI 0.60-0.97), respectively, versus the Control Arm. Median PFS was 15 months in the durvalumab plus olaparib Arm and 9.7 months in the Control Arm.
Results from the analysis of mismatch repair deficient (dMMR) patients showed a similar reduction in the risk of disease progression or death in both the durvalumab plus olaparib and the durvalumab Arms, by 59% (HR 0.41; 95% CI 0.21-0.75) and 58% (HR 0.42; 95% CI 0.22-0.80), respectively, versus the Control Arm.
Endometrial Cancer
Endometrial cancer, a highly heterogeneous disease also referred to as uterine cancer, is a type of cancer that begins in the layer of cells that form the lining of the uterus, called the endometrium. Globally, this cancer is among the most common cancers diagnosed in women who have already been through menopause. Based on available data, the incidence of this cancer, generally diagnosed in patients between 65 and 75 years of age, is rising. [2]
Today, the standard of care, per consensus of the European Society for Medical Oncology (ESMO) Clinical Practice Guideline, for newly diagnosed advanced or recurrent endometrial cancer includes platinum-based chemotherapy with carboplatin plus paclitaxel.[3][1] While patients may initially demonstrate sensitivity to platinum-based chemotherapy, most patients subsequently experience disease progression, requiring additional lines of chemotherapy.[4][5][6][7][8]
The majority of patients diagnosed with endometrial cancer are diagnosed at an early stage of disease, where the cancer is confined to the uterus.[9] They are typically treated with surgery and/or radiation, and the five-year survival rate is high (approximately 80-90%). [10] Patients with advanced disease (Stage III-IV) usually have a much poorer prognosis, with the five-year survival rate falling to less than 20. [11] Immunotherapy combined with chemotherapy is emerging as a new standard of care for advanced endometrial cancer, particularly for patients with dMMR disease, who make up approximately 20-30% of all patients.[12][13][14][15] There is a significant need for new treatment options, especially for 70-80% of patients with pMMR disease.[16][17]
In Europe, nearly 125,000 women were diagnosed with endometrial cancer in 2022.[18][19]
DUO-E Trial
The DUO-E trial (GOG 3041/ENGOT-EN10) is a three-arm, randomized, double-blind, placebo-controlled, multicentre Phase III trial of 1st-line durvalumab plus platinum-based chemotherapy (carboplatin and paclitaxel) followed by either durvalumab monotherapy or durvalumab plus olaparib as maintenance therapy versus platinum-based chemotherapy alone as a treatment for patients with newly diagnosed advanced or recurrent endometrial cancer.
The DUO-E trial randomized 699 patients with newly diagnosed advanced or recurrent epithelial endometrial carcinoma to receive either durvalumab (1,120 mg) or placebo, given every three weeks in addition to standard-of-care platinum-based chemotherapy. After 4-6 cycles of chemotherapy, patients (whose disease had not progressed) then received either durvalumab (1,500 mg) or placebo every four weeks as maintenance, plus 300 mg olaparib (300 mg BID [2 x 150 mg tablets, twice a day]) or placebo until disease progression.
The dual primary endpoint was progression-free survival (PFS) of each treatment arm versus standard-of-care chemotherapy alone, and both arms demonstrated a statistically significant and clinically meaningful improvement in PFS compared to standard-of-care in patients with newly diagnosed advanced or recurrent endometrial cancer.[1] Secondary endpoints included overall survival (OS), safety, and tolerability. The trial continues to assess OS for both arms in the overall trial population. Mismatch repair (MMR) status, recurrence status, and geographic location were stratification factors. The trial was funded by AstraZeneca and conducted in 253 study locations across 22 countries including the United States, Europe, South America, and Asia.
Improving treatment outcomes
“This approval is welcome news for patients with advanced or recurrent endometrial cancer in Europe, especially those with mismatch repair proficient disease who have limited options,” said Els Van Nieuwenhuysen, Gynaecological Oncologist at the UZ Leuven, Belgium and DUO-E trial investigator.
“The olaparib and durvalumab as well as the durvalumab regimens now have the potential to improve outcomes for all patients in this setting in Europe, regardless of mismatch repair status,” Van Nieuwenhuysen added.
Major step forwards
“This approval of durvalumab and olaparib regimens marks the first-ever approval for a combination of an immunotherapy and PARP inhibitor in endometrial cancer and a major step forward for patients,” explained Dave Fredrickson, Executive Vice President, of the Oncology Business Unit ate AstraZeneca.
“In Europe, endometrial cancer is the fourth most common cancer in women, and until now, 70-80% of patients who have mismatch repair proficient disease have had few available treatment options,” Fredrickson further noted.
The safety profiles of both regimens were generally manageable, well-tolerated, and broadly consistent with the known profiles of the individual agents.[1]
Further regulatory approval
Regulatory submissions for durvalumab and olaparib are currently under review in Japan and several other countries based on the DUO-E trial. Durvalumab plus chemotherapy was recently approved for dMMR patients with primary advanced or recurrent endometrial cancer in the US.
Development
Olaparib is being jointly developed and commercialized by AstraZeneca and MSD, both as a monotherapy and in combination with other potential medicines. Independently, the companies are developing and will commercialize olaparib in combination with their respective PD-L1 and PD-1 medicines, durvalumab and pembrolizumab. Olaparib has been used to treat approximately 140,000 patients worldwide. Olaparib has a broad clinical trial development program, and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumors as a monotherapy and in combination across multiple cancer types. Olaparib is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.
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Note: * Durvalumab is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics and releasing the inhibition of immune responses. Durvalumab, first approved in 2017, is the only approved immunotherapy and the global standard of care in the curative-intent setting of unresectable, Stage III NSCLC in patients whose disease has not progressed after chemoradiotherapy. Durvalumab is also approved for treating extensive-stage small-cell lung cancer (SCLC) + a short course of tremelimumab (Imjudo®; AstraZeneca), and chemotherapy for treating metastatic Non-small cell Lung Cancer (NSCLC).
** Olaparib is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumors harboring a deficiency in homologous recombination-related (HRR) genes, such as those with mutations in BRCA1 and/or BRCA2, or those where deficiency is induced by other agents (such as new hormonal agents [NHAs]). Inhibition of PARP with Olaparib leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse, and the generation of DNA double-strand breaks, leading to cancer cell death. Olaparib may also help enhance immunogenicity and increase the impact of anti-tumour immune responses.
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Clinical trials
Durvalumab With or Without Olaparib as Maintenance Therapy After First-Line Treatment of Advanced and Recurrent Endometrial Cancer (DUO-E) – ClinicalTrials.gov ID NCT04269200
Summary of Product Characteristics
Olaparib lynparza®; AstraZeneca)[SmPC][Product information]
Durvalumab (Imfinzi®; AstraZeneca)[SmPC][Product Information]
Highlights of Prescribing Information
Olaparib (Lynparza®; AstraZeneca)[Prescribing Information]
Durvalumab (Imfinzi®; AstraZeneca)[Prescribing Information]
Pembrolizumab (Keytruda®; Merck & Co/MSD)[Prescribing Information]
Tremelimumab (Imjudo®; AstraZeneca)[Prescribing Information]
References
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DOI: 10.14229/onco.2024.08.14.001
