Durvalumab + Olaparib for Endometrial Cancer

(DUO-E Trial)

Recruiting at 171 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Female

Trial Phase: Phase 3

Sponsor: AstraZeneca

Must not be taking: PARP inhibitors, Immune therapy

Disqualifiers: Leptomeningeal carcinomatosis, Brain metastases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 6-12 weeks

813 Participants Needed

Trial Summary

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it does mention that you should not have had prior treatment with certain types of cancer therapies, like PARP inhibitors or immune-mediated therapies.

What data supports the effectiveness of the drug combination Durvalumab and Olaparib for endometrial cancer?

Durvalumab has shown activity in advanced endometrial cancers, particularly in those with mismatch repair deficiencies, which are similar to the conditions studied in the KEYNOTE-158 trial with pembrolizumab. Additionally, Olaparib is being evaluated in combination with other drugs like pembrolizumab for its potential to improve outcomes in various cancers, suggesting a possible benefit when combined with Durvalumab. ^{1 2 3 4 5}

Is the combination of Durvalumab and Olaparib safe for humans?

Research shows that the combination of Durvalumab and Olaparib is generally safe and tolerable in humans, with no dose-limiting toxicities reported in a study involving women's cancers. However, some side effects like hypertension (high blood pressure) and fatigue were noted with other drug combinations. ^{1 5 6 7 8}

What makes the drug combination of Durvalumab and Olaparib unique for treating endometrial cancer?

The combination of Durvalumab, an immune checkpoint inhibitor that enhances the body's immune response against cancer cells, and Olaparib, a drug that targets cancer cell DNA repair mechanisms, is unique because it combines two different approaches to attack cancer cells, potentially offering a new treatment option for endometrial cancer where standard treatments may be limited. ^{1 4 5 7 8}

What is the purpose of this trial?

A study to assess the efficacy and safety of durvalumab in combination with platinum-based chemotherapy (paclitaxel + carboplatin) followed by maintenance durvalumab with or without olaparib for patients with newly diagnosed advanced or recurrent endometrial cancer.

Research Team

Shannon Westin, MD

Principal Investigator

The University of Texas MD Anderson Cancer Center

Eligibility Criteria

This trial is for women over 18 with advanced or recurrent endometrial cancer, including carcinosarcomas but not sarcomas. Participants can be newly diagnosed or have a recurrence after at least 12 months since last treatment if previously treated in the adjuvant setting. They must have an ECOG performance status of 0 or 1 and cannot have brain metastases, spinal cord compression, history of leptomeningeal carcinomatosis, prior PARP inhibitors use, or previous immune-mediated therapy.

Inclusion Criteria

I have a tumor sample available for a specific genetic test.

I have been recently diagnosed with Stage IV cancer.

I am fully active or restricted in physically strenuous activity but can do light work.

Exclusion Criteria

I have cancer that has spread to my brain or spinal cord.

I have previously received immunotherapy, excluding cancer vaccines.

I have been treated with PARP inhibitors before.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive platinum-based chemotherapy (paclitaxel + carboplatin) in combination with durvalumab

6-12 weeks

Maintenance

Participants receive maintenance therapy with durvalumab with or without olaparib

Up to 4 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 6 years

Treatment Details

Interventions

• Durvalumab
• Olaparib

Trial Overview The study tests durvalumab combined with chemotherapy (paclitaxel + carboplatin), followed by maintenance durvalumab alone or with olaparib versus placebo in patients with new or recurring endometrial cancer. The goal is to assess how well these treatments work and their safety as maintenance therapy.

Participant Groups

Group I: Arm C (durvalumab+olaparib) Experimental Treatment 4 Interventions

Platinum-based chemotherapy and durvalumab followed by maintenance durvalumab and olaparib.

Group II: Arm B (durvalumab+placebo) Experimental Treatment 4 Interventions

Platinum-based chemotherapy and durvalumab followed by maintenance durvalumab and olaparib placebo

Group III: Arm A (control) Active Control 4 Interventions

Platinum-based chemotherapy and durvalumab placebo followed by maintenance durvalumab placebo and olaparib placebo (tablets).

Durvalumab is already approved in European Union, United States, Japan for the following indications:

Approved in European Union as Imfinzi for:

• Locally advanced, unresectable non-small cell lung cancer (NSCLC)

Approved in United States as Imfinzi for:

• Extensive-stage small cell lung cancer (ES-SCLC)
• Limited-stage small cell lung cancer (LS-SCLC)
• Locally advanced or metastatic urothelial carcinoma

Approved in Japan as Imfinzi for:

• Not specified in provided sources

Who Is Running the Clinical Trial?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

The Gynecologic Oncology Group (GOG) Foundation Inc

Collaborator

Trials

1

Recruited

810+

The European Network for Gynaecological Oncological Trial groups (ENGOT)

Collaborator

Trials

2

Recruited

870+

Findings from Research

Durvalumab, a PD-L1 inhibitor, has been shown to be safe for patients with various solid tumors, with common side effects including pruritus and fatigue, based on a meta-analysis of 17 studies involving 1,529 patients.

Higher levels of PD-L1 expression in tumors are linked to better treatment responses to durvalumab, indicating that PD-L1 could serve as a useful biomarker for predicting the drug's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. Yang, H., Shen, K., Zhu, C., et al.[2022]

In a study of 71 women with advanced endometrial cancer, durvalumab showed a significant objective tumor response rate of 47% in patients with mismatch repair deficient (dMMR) tumors, compared to only 3% in those with proficient tumors (pMMR).

The median progression-free survival was notably longer in the dMMR cohort at 8.3 months versus 1.8 months in the pMMR cohort, indicating that durvalumab is more effective in treating dMMR endometrial cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical activity of durvalumab for patients with advanced mismatch repair-deficient and repair-proficient endometrial cancer. A nonrandomized phase 2 clinical trial. Antill, Y., Kok, PS., Robledo, K., et al.[2021]

In the KEYNOTE-158 study, pembrolizumab showed a clinically meaningful objective response rate in patients with advanced MSI-H/dMMR endometrial cancer, with 84 out of 90 patients completing health-related quality of life (HRQoL) assessments.

Patients receiving pembrolizumab experienced significant improvements in their quality of life, with mean scores on the QLQ-C30 and EQ-5D-3L questionnaires increasing notably, especially among those who achieved a complete or partial response to treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related quality of life with pembrolizumab monotherapy in patients with previously treated advanced microsatellite instability high/mismatch repair deficient endometrial cancer in the KEYNOTE-158 study. O'Malley, DM., Bariani, GM., Cassier, PA., et al.[2022]

The KEYLYNK-012 study is a phase III clinical trial evaluating the effectiveness of pembrolizumab combined with chemoradiotherapy in patients with stage III non-small-cell lung cancer (NSCLC), involving participants aged 18 and older with unresectable disease.

This study aims to determine if the addition of pembrolizumab, with or without olaparib, improves progression-free survival and overall survival compared to standard concurrent chemoradiotherapy, with enrollment ongoing at around 190 sites.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale and Design of the Phase III KEYLYNK-012 Study of Pembrolizumab and Concurrent Chemoradiotherapy Followed by Pembrolizumab With or Without Olaparib for Stage III Non-Small-Cell Lung Cancer. Jabbour, SK., Cho, BC., Bria, E., et al.[2022]

Durvalumab is an FDA-approved monoclonal antibody that enhances T-cell responses against cancer by blocking the PD-L1 pathway, specifically for patients with advanced urothelial carcinoma who have progressed after platinum-based chemotherapy.

The drug is currently being tested in phase III trials for various cancers, including lung and head and neck cancers, indicating its potential broad application in oncology beyond urothelial carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab: First Global Approval. Syed, YY.[2022]

The combination of durvalumab and tremelimumab in cancer treatment is associated with a higher incidence of severe adverse events (32.6%) compared to durvalumab alone (23.8%), indicating increased safety concerns with the combination therapy.

Patients receiving the combination therapy also experienced higher rates of specific side effects such as diarrhea (15.6% vs. 8.1%), rash (11.1% vs. 6.5%), and treatment discontinuation (18% vs. 3%), highlighting the need for careful monitoring and patient counseling regarding these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. Fahmy, O., Ahmed, OAA., Khairul-Asri, MG., et al.[2023]

In a study involving 34 patients with BRCA1 or BRCA2 mutated metastatic breast cancer, the combination of olaparib and durvalumab demonstrated promising antitumor activity, with 80% of patients showing disease control at 12 weeks.

The treatment was generally safe, with 32% of patients experiencing grade 3 or worse adverse events, but no treatment-related deaths were reported, indicating a manageable safety profile for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study. Domchek, SM., Postel-Vinay, S., Im, SA., et al.[2021]

In a phase I study involving 26 women with recurrent cancers, the combination of the PD-L1 inhibitor durvalumab with olaparib or cediranib was found to be tolerable and showed promising anti-tumor activity, with an 83% disease control rate for the durvalumab plus olaparib group.

The recommended phase II doses were established as durvalumab 1,500 mg every 4 weeks with olaparib 300 mg twice daily, or cediranib 20 mg on an intermittent schedule, indicating that these combinations could be viable options for further investigation in treating recurrent women's cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Clinical Activity of the Programmed Death-Ligand 1 Inhibitor Durvalumab in Combination With Poly (ADP-Ribose) Polymerase Inhibitor Olaparib or Vascular Endothelial Growth Factor Receptor 1-3 Inhibitor Cediranib in Women's Cancers: A Dose-Escalation, Phase I Study. Lee, JM., Cimino-Mathews, A., Peer, CJ., et al.[2022]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Clinical activity of durvalumab for patients with advanced mismatch repair-deficient and repair-proficient endometrial cancer. A nonrandomized phase 2 clinical trial. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Health-related quality of life with pembrolizumab monotherapy in patients with previously treated advanced microsatellite instability high/mismatch repair deficient endometrial cancer in the KEYNOTE-158 study. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Rationale and Design of the Phase III KEYLYNK-012 Study of Pembrolizumab and Concurrent Chemoradiotherapy Followed by Pembrolizumab With or Without Olaparib for Stage III Non-Small-Cell Lung Cancer. [2022]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Durvalumab: First Global Approval. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Olaparib and durvalumab in patients with germline BRCA-mutated metastatic breast cancer (MEDIOLA): an open-label, multicentre, phase 1/2, basket study. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Safety and Clinical Activity of the Programmed Death-Ligand 1 Inhibitor Durvalumab in Combination With Poly (ADP-Ribose) Polymerase Inhibitor Olaparib or Vascular Endothelial Growth Factor Receptor 1-3 Inhibitor Cediranib in Women's Cancers: A Dose-Escalation, Phase I Study. [2022]