Positive results from the primary analysis of the DUO-E Phase III trial showed that Imfinzi (durvalumab) plus platinum-based chemotherapy, followed by either Imfinzi monotherapy or Imfinzi plus Lynparza (olaparib), both demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to chemotherapy alone in the overall trial population of patients with newly diagnosed advanced or recurrent endometrial cancer.

These results will be presented today in a proffered paper session at the 2023 European Society for Medical Oncology (ESMO) Congress in Madrid, Spain (Presentation #LBA41) and simultaneously published online in the Journal of Clinical Oncology (https://protect-de.mimecast.com/s/l_H8CLZj2GtwWnnGBfqMjLe?domain=urldefense.com).

In the overall trial population, results showed that treatment with Imfinzi plus chemotherapy followed by Imfinzi plus Lynparza (Imfinzi plus Lynparza Arm) and treatment with Imfinzi plus chemotherapy followed by Imfinzi monotherapy (Imfinzi 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 Imfinzi plus Lynparza Arm and 9.6 months in the Control Arm.

Mismatch repair (MMR) status is a biomarker of interest in endometrial cancer, therefore a prespecified exploratory subgroup analysis by MMR status was conducted in DUO-E. Results from the analysis of mismatch repair proficient (pMMR) patients showed a reduction in the risk of disease progression or death in both the Imfinzi plus Lynparza and the Imfinzi 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 Imfinzi plus Lynparza 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 Imfinzi plus Lynparza and the Imfinzi 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.

Interim overall survival (OS) data showed a favourable trend for both treatment regimens in the overall population.

Shannon N. Westin, Professor of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center, and principal investigator of the trial, said, "These findings showcase, for the first time, the potential of combining immunotherapy with a PARP inhibitor to deliver significant clinical improvements for these patients. These DUO-E data may offer oncologists novel avenues to enhance outcomes for endometrial cancer patients."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said, "The treatment options for most patients with advanced endometrial cancer are limited, especially for those with mismatch repair proficiency, and have not changed for many years. We are delighted that these DUO-E data show meaningful clinical improvements for patients when Imfinzi and Lynparza are combined or when Imfinzi is added alone. We look forward to discussing these data with global regulatory authorities and bringing these important new treatment approaches to patients as soon as possible."

PD-L1 is a known biomarker for Imfinzi in other indications and a prespecified analysis based on PD-L1 status showed, in the PD-L1 positive population, that treatment reduced the risk of disease progression or death by 58% (HR 0.42; 95% CI 0.31-0.57) and 37% (HR 0.63; 95% CI 0.48-0.83) in the Imfinzi plus Lynparza and the Imfinzi Arms, respectively, versus the Control Arm. Median PFS was 20.8 months in the Imfinzi plus Lynparza Arm and 9.5 months in the Control Arm.

In the PD-L1 negative population, treatment reduced the risk of disease progression or death by 20% (HR 0.80; 95% CI 0.55-1.16) and 11% (HR 0.89; 95% CI 0.59-1.34) in the Imfinzi plus Lynparza and the Imfinzi Arms, respectively, versus the Control Arm.

The safety and tolerability profiles of both regimens (Imfinzi plus Lynparza Arm and Imfinzi Arm) were broadly consistent with those observed in prior clinical trials and the known profiles of the individual medicines.[1,2]

The most common adverse events (AEs) (affecting 20% or more of patients) reported in the Imfinzi plus Lynparza Arm during the overall study were anaemia (62%), nausea (55%), fatigue and asthenia (54%), alopecia (51%), neutropenia (42%), constipation (33%), thrombo-cytopenia (30%), diarrhoea (28%), vomiting (26%), peripheral neuropathy (25%), peripheral sensory neuropathy (25%), arthralgia (24%), decreased appetite (23%), leukopenia (20%) and urinary tract infection (20%).

The most common AEs reported in the Imfinzi Arm during the overall study were alopecia (50%), anaemia (48%), fatigue and asthenia (43%), nausea (41%), neutropenia (36%), diarrhoea (31%), arthralgia (30%), thrombo-cytopenia (28%), constipation (27%), peripheral neuropathy (26%), peripheral sensory neuropathy (26%) and vomiting (21%).

Notes

Endometrial cancer

Endometrial cancer is a highly heterogeneous disease that originates in the tissue lining of the uterus and is most common in women who have already been through the menopause, with the average age at diagnosis being over 60 years old.[3-5] It is the 6th most common cancer in women worldwide.[6] Incidence and mortality of endometrial cancer are expected to increase by approximately 46% and 62% respectively (from 417,400 cases and 97,400 deaths in 2020 to 608,130 cases and 157,813 deaths) in 2040.[6,7]

The majority of patients with endometrial cancer are diagnosed at an early stage of disease where the cancer is confined to the uterus. They are typically treated with surgery and/or radiation and the 5-year survival rate is high (approximately 95%). Patients with advanced disease (Stage III-IV) usually have a much poorer prognosis, with the 5-year survival rate falling to around 20-30%. The standard of care for advanced endometrial cancer has traditionally been limited to chemotherapy.[5,8,9,10,11,12 ]There is a high unmet need for novel treatment options and strategies that can improve long-term outcomes in advanced or recurring endometrial cancer.[10,13]

DUO-E

The DUO-E trial (GOG 3041/ENGOT-EN10) is a three-arm, randomised, double-blind, placebo-controlled, multicentre Phase III trial of 1st-line Imfinzi (durvalumab) plus platinum-based chemotherapy (carboplatin and paclitaxel) followed by either Imfinzi monotherapy or Imfinzi plus Lynparza (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 randomised 699 patients with newly diagnosed advanced or recurrent epithelial endometrial carcinoma to receive either Imfinzi (1120mg) 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 Imfinzi (1500mg) or placebo every four weeks as maintenance, plus 300mg Lynparza (300mg BID [2x150mg 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. Key secondary endpoints included overall survival (OS), safety and tolerability. Mismatch repair status, recurrence status and geographic location were stratification factors. Mismatch repair deficient (dMMR) status reflects an inability to correct DNA replication errors and therefore results in an increased risk of cancer, while mismatch repair proficient (pMMR) status indicates when DNA repair pathways remain intact and where the mismatch repair pathway is active and functional.[14,15] The trial was sponsored independently by AstraZeneca and conducted in 253 study locations across 22 countries including the US, Europe, South America and Asia.

For more information about the trial please visit ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT04269200).

Imfinzi

Imfinzi (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 tumour's immune-evading tactics and releasing the inhibition of immune responses.

Imfinzi is the only approved immunotherapy and the global standard of care in the curative-intent setting of unresectable, Stage III non-small cell lung cancer (NSCLC) in patients whose disease has not progressed after chemoradiation therapy based on the PACIFIC Phase III trial. Imfinzi is also approved in the US, EU, Japan, China and many other countries around the world for the treatment of extensive-stage small cell lung cancer (SCLC) based on the CASPIAN Phase III trial. Additionally, Imfinzi is approved in combination with a short course of Imjudo (tremelimumab) and chemotherapy for the treatment of metastatic NSCLC in the US, EU and Japan based on the POSEIDON Phase III trial.

In addition to its indications in lung cancer, Imfinzi also is approved in combination with chemotherapy (gemcitabine plus cisplatin) in locally advanced or metastatic biliary tract cancer and in combination with Imjudo in unresectable hepatocellular carcinoma in the US, EU, Japan and several other countries based on the TOPAZ-1 and HIMALAYA Phase III trials, respectively. Imfinzi is approved in previously treated patients with advanced bladder cancer in a small number of countries.

Since the first approval in May 2017, more than 200,000 patients have been treated with Imfinzi.

As part of a broad development programme, Imfinzi is being tested as a single treatment and in combination with other anti-cancer treatments for patients with SCLC, NSCLC, bladder cancer, several gastrointestinal cancers and other solid tumours.

Lynparza

Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring 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 Lynparza 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 and cancer cell death.

Lynparza is currently approved in a number of countries across multiple tumour types including maintenance treatment of platinum-sensitive relapsed ovarian cancer and as both monotherapy and in combination with bevacizumab for the 1st-line maintenance treatment of BRCA-mutated (BRCAm) and homologous recombination repair deficient (HRD)-positive advanced ovarian cancer, respectively; for germline BRCA mutation (gBRCAm), HER2-negative metastatic breast cancer (in the EU and Japan, this includes locally advanced breast cancer); for gBRCAm, HER2-negative high-risk early breast cancer (in Japan, this includes all BRCAm HER2-negative high-risk early breast cancer); for gBRCAm metastatic pancreatic cancer; in combination with abiraterone for the treatment of metastatic castration-resistant prostate cancer (mCRPC) when chemotherapy is not clinically indicated (EU only) and for BRCAm mCRPC (US and Japan); and as monotherapy for HRR gene-mutated mCRPC in patients who have progressed on prior NHA treatment (BRCAm only in the EU and Japan). In China, Lynparza is approved for the treatment of BRCA-mutated mCRPC as well as 1st-line maintenance treatment with bevacizumab for HRD-positive advanced ovarian cancer.

Lynparza is being jointly developed and commercialised by AstraZeneca and MSD, both as a monotherapy and in combination with other potential medicines. Independently, the companies are developing and will commercialise Lynparza in combination with their respective PD-L1 and PD-1 medicines, Imfinzi (durvalumab) and Keytruda (pembrolizumab). Lynparza has been used to treat over 75,000 patients worldwide. Lynparza has a broad clinical trial development programme, and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types. Lynparza is the foundation of AstraZeneca's industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

AstraZeneca in oncology

AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.

The Company's focus is on some of the most challenging cancers. It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.

AstraZeneca has the vision to redefine cancer care and, one day, eliminate cancer as a cause of death.

AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development, and commercialisation of prescription medicines in Oncology, Rare Diseases, and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com (https://www.astrazeneca.com) and follow the Company on social media @AstraZeneca (https://www.linkedin.com/company/astrazeneca/).

Contacts

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References

1. FDA. Highlights of prescribing information - Lynparza. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208558s014lbl.pdf. Accessed October 2023.
2. FDA. Highlights of prescribing information - Imfinzi. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761069s018lbl.pdf. Accessed October 2023.
3. Dork T, et al. Genetic Susceptibility to Endometrial Cancer: Risk Factors and Clinical Management. Cancers (Basel). 2020;12(9):2407.
4. American Cancer Society. What is Endometrial Cancer? Available at https://www.cancer.org/cancer/endometrial-cancer/about/what-is-endometrial-cancer.html. (https://www.cancer.org/cancer/types/endometrial-cancer/about/what-is-endometrial-cancer.html) Accessed October 2023.
5. Oakin A, et al. ESMO Guidelines. Endometrial Cancer: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-Up. Ann Oncol. 2022;33(9):860-877.
6. World Cancer Research Fund International. Endometrial Cancer Statistics. Available at https://www.wcrf.org/cancer-trends/endometrial-cancer-statistics/ (https://www.wcrf.org/cancer-trends/endometrial-cancer-statistics/#:~:text=There%20were%20more%20than%20417%2C000,shown%20in%20the%20tables%20below.). Accessed October 2023.
7. IARC. WHO. Corpus Uteri. Estimated Numbers from 2020 to 2040, Females, Age [0-85+] World. Available at https://gco.iarc.fr/tomorrow/en/dataviz/trends (https://gco.iarc.fr/tomorrow/en/dataviz/trends?types=0_1&sexes=2&mode=cancer&group_populations=0&multiple_populations=0&multiple_cancers=1&cancers=24&populations=900) Accessed October 2023.
8. Carlson R. Advanced Endometrial Cancer Carboplatin-Paclitaxel Regimen Promising. Oncology Times. 2003;25(22):36.
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10. Matrai CE, et al. Molecular Evaluation of Low-grade Low-Stage Endometrial Cancer With and Without Recurrence. Int Gynecol Pathol. 2022;41(3):207-219.
11. Wright JD, et al. Contemporary Management of Endometrial Cancer. Lancet. 2012 Apr 7;379(9823):1352-60.
12. Monk BJ, et al. Real-World Outcomes in Patients with Advanced Endometrial Cancer: A Retrospective Cohort Study of US Electronic Health Records. Gynecol Oncol. 2022;164(2):325-332.
13. Soumerai T, et al. Clinical Utility of Prospective Molecular Characterization in Advanced Endometrial Cancer. Clin Cancer Res. 2018;24(23):5939-5947.
14. Assasi N, et al. DNA Mismatch Repair Deficiency Tumour Testing for Patients With Colorectal Cancer: Recommendations. CADTH Optimal Use Report, No. 5.3d. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health. 2016.
15. Fight Colorectal Cancer. Available at https://fightcolorectalcancer.org/blog/dna_mismatch_repair_and_5-fu_whats_the_connection/. Accessed October 2023.