Lynparza & Imfinzi combo reduced risk of disease progression or death by 37% vs. chemo and bevacizumab in patients with advanced ovarian cancer without tumour BRCA mutations in DUO-O Phase III trial

Positive results from a planned interim analysis of the DUO-O Phase III trial showed that treatment with a combination of Lynparza (olaparib), Imfinzi (durvalumab), chemotherapy and bevacizumab demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) versus chemotherapy plus bevacizumab (control arm) in newly diagnosed patients with advanced high-grade epithelial ovarian cancer without tumour BRCA mutations. Patients were treated with Imfinzi in combination with chemotherapy and bevacizumab followed by Imfinzi, Lynparza and bevacizumab as maintenance therapy.  

These results will be presented today in an oral presentation at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago (Abstract #LBA5506).  

The combination of Lynparza, Imfinzi, chemotherapy and bevacizumab reduced the relative risk of disease progression or death by 37% versus chemotherapy and bevacizumab (hazard ratio (HR) 0.63; 95% CI 0.52-0.76; p<0.0001). Median PFS was 24.2 months versus 19.3, respectively. In the homologous recombination deficiency (HRD)-positive subgroup of patients, Lynparza, Imfinzi, chemotherapy and bevacizumab reduced the relative risk of disease progression or death by 51% versus chemotherapy and bevacizumab alone (HR 0.49; 95% CI 0.34-0.69; p<0.0001). Median PFS was 37.3 months versus 23.0, respectively.

Professor Philipp Harter, Director, Department of Gynaecology and Gynaecologic Oncology, Evangelische Kliniken Essen-Mitte, Germany, and principal investigator for the trial, said: “The primary aim of first-line treatment of patients with advanced ovarian cancer is long-term control over the disease, but still too many patients progress quickly and face poor clinical outcomes today. Data from the DUO-O trial interim progression-free survival analysis provide evidence for further improvement with olaparib and durvalumab combination versus chemotherapy and bevacizumab alone in patients without tumour BRCA mutations.”

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “These results are an important milestone in our ongoing journey to address unmet need in ovarian cancer. The DUO-O trial demonstrates the potential of combining PARP inhibition with immunotherapy and we look forward to seeing more mature data and key secondary endpoints results.”

At a pre-planned exploratory analysis of the HRD-negative subgroup of patients, Lynparza, Imfinzi, chemotherapy and bevacizumab reduced the relative risk of disease progression or death by 32% versus chemotherapy and bevacizumab (HR 0.68; 95% CI 0.54-0.86). Median PFS was 20.9 months versus 17.4. 

At the time of this interim analysis, an additional arm evaluating the combination of Imfinzi, chemotherapy and bevacizumab demonstrated a numerical improvement in PFS which was not statistically significant (HR 0.87; 95% CI 0.73-1.04; p=0.13). 

At the time of this planned interim analysis, the overall survival (OS) and other secondary endpoints were immature. OS will be formally assessed at a subsequent analysis.

Summary of results: DUO-O

*Results based on the stratified model

**Results based on the unstratified model: HR 0.51 (95% CI 0.36-0.72)

The safety and tolerability of these combinations was broadly consistent with that observed in prior clinical trials and the known profiles of the individual medicines.  

The most common adverse events (AEs) (greater than or equal to 20% of patients) for the combination of Lynparza, Imfinzi, chemotherapy and bevacizumab were nausea (57%), anaemia (55%), neutropenia (51%), fatigue/asthenia (49%), arthralgia (34%), constipation (30%), diarrhoea (30%), thrombocytopenia (28%), hypertension (26%), vomiting (26%), leukopenia (24%), headache (22%), abdominal pain (21%) and hypothyroidism (20%). Grade 3 or higher AEs were neutropenia (31%), anaemia (24%), leukopenia (8%), hypertension (7%) and thrombocytopenia (6%).

Approximately 65% of patients treated with the combination of Lynparza, Imfinzi, chemotherapy and bevacizumab who experienced AEs during chemotherapy and throughout the maintenance phase remained on treatment at the time of data cut-off, compared to 80% of patients in the control arm (chemotherapy plus bevacizumab).

Notes

Ovarian cancer

Ovarian cancer is one of the most common gynaecologic cancers and is the eighth most common cancer in women worldwide with more than 314,000 new patients diagnosed in 2020 and over 207,000 deaths. This number is expected to rise by almost 42% by 2040 to over 445,000 newly diagnosed patients and 314,000 deaths.^1,2,3

Over two thirds of patients are diagnosed with advanced disease, which can progress quickly, often within two years, diminishing their quality of life despite treatment. Unfortunately, 50-70% of patients with advanced disease die within five years.^4-7 Outcomes are generally worse in patients with homologous recombination deficiency (HRD)-negative disease, where survival at five years is approximately 30%.^5,8

DUO-O

DUO-O is a Phase III randomised, double-blind, placebo-controlled, multi-centre trial to evaluate the efficacy and safety of Imfinzi in combination with platinum-based chemotherapy and bevacizumab followed by maintenance treatment with Imfinzi and bevacizumab with or without Lynparza in newly diagnosed patients with advanced ovarian cancer without tumour BRCA mutations.

Patients were randomized 1:1:1 to: Arm 1 (control), induction therapy with platinum-based chemotherapy in combination with bevacizumab and placebo followed by maintenance treatment with bevacizumab plus placebo; Arm 2, induction therapy with platinum-based chemotherapy in combination with bevacizumab and Imfinzi followed by maintenance Imfinzi and bevacizumab plus placebo; or Arm 3, induction therapy with platinum-based chemotherapy in combination with bevacizumab and Imfinzi followed by maintenance Imfinzi and bevacizumab plus Lynparza. In all arms, platinum-based chemotherapy was administered every 3 weeks (q3w) for up to 6 cycles, bevacizumab was administered q3w for up to 15 months, Imfinzi or placebo was administered q3w for up to 24 months, and Lynparza or placebo was administered twice daily for up to 24 months.

The primary endpoint of the trial is progression-free survival (PFS) as assessed by investigator for Arm 3 compared to Arm 1 (control) in the overall trial population which included patients without tumour BRCA mutations and in the subset of these patients with homologous recombination deficiency (HRD)-positive disease. Key secondary endpoints include PFS as assessed by investigator in Arm 2 compared to control, as well as comparisons for overall survival (OS). DUO-O enrolled over 1200 patients across all treatment arms at 179 study locations. For more information about the trial, visit ClinicalTrials.gov.

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 is also approved in combination with chemotherapy in locally advanced or metastatic biliary tract cancer in the US, EU, Japan and several other countries; in combination with Imjudo in unresectable hepatocellular carcinoma in the US, EU and Japan; and 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 combinations 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 repair (HRR), 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 deficiency (HRD)-positive advanced ovarian cancer, respectively; for germline BRCA-mutated (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) in whom chemotherapy is not clinically indicated (in the EU) and as monotherapy in 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 a 1st-line maintenance therapy in BRCA-mutated advanced ovarian cancer as well as 1st-line maintenance treatment with bevacizumab for HRD-positive advanced ovarian cancer.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, has been used to treat over 75,000 patients worldwide. The companies develop Lynparza in combination with their respective PD-L1 and PD-1 medicines independently. 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.

By harnessing the power of six scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response, Antibody Drug Conjugates, Epigenetics and Cell Therapies – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment 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 and follow the Company on Twitter @AstraZeneca. 

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References

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