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EU CHMP recommends approval of Lynparza as adjuvant treatment for germline BRCA-mutated, HER2-negative high-risk early breast cancer

Rahway, New Jersey
Tuesday, June 28, 2022, 09:00 Hrs  [IST]

AstraZeneca and Merck, known as MSD outside the United States and Canada, announced that the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion recommending approval of Lynparza for the adjuvant treatment of patients with germline BRCA-mutated (gBRCAm), human epidermal growth factor receptor 2 (HER2)-negative high-risk early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy.

The CHMP based its positive opinion on results from the phase 3 OlympiA trial presented during the 2021 American Society of Clinical Oncology Annual Meeting and published in The New England Journal of Medicine in June 2021.

Breast cancer is the most commonly diagnosed cancer worldwide, with an estimated 2.3 million patients diagnosed in 2020. In the European Union (EU), one in seven people who were assigned female at birth will develop breast cancer in their lifetime. Approximately 75% of breast cancer patients worldwide are diagnosed with early breast cancer; however, a quarter of these patients will experience disease recurrence following surgery. In Europe, germline BRCA mutations are found in approximately 9% of patients.

Professor Andrew Tutt, Global Chair of the OlympiA phase III trial and Professor of Oncology at The Institute of Cancer Research, London and King’s College London, said: “For patients with high-risk, early-stage breast cancer, the risk of recurrence remains unacceptably high, and cancer will return for more than one in four of these patients. Today’s recommendation is hopeful news for patients in Europe, as we move closer to setting a potential new standard of care that improves overall survival in patients suitable for treatment with olaparib.”

Susan Galbraith, executive vice president, oncology R&D, AstraZeneca, said, “If approved, Lynparza will provide a new targeted treatment option for patients with germline BRCA-mutated, HER2-negative early breast cancer in Europe. By treating patients as early as possible in their disease, we hope to avoid life-threatening recurrence and give people more time with their loved ones.”

Dr. Eliav Barr, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories, said, “Patients with germline BRCA-mutated, HER2-negative early breast cancer will often develop breast cancer at an earlier age than those without BRCA mutations, impacting people in their prime. Today’s positive opinion brings us closer to our goal of offering a much-needed new treatment option to these patients in Europe.”

In the trial, Lynparza demonstrated a statistically significant and clinically meaningful improvement in the primary endpoint of invasive disease-free survival (IDFS), reducing the risk of invasive breast cancer recurrences, second cancers or death by 42% (HR=0.58 [99.5% CI, 0.41-0.82]; p<0.0001) versus placebo. Overall survival (OS) data presented in March 2022 at the European Society for Medical Oncology Virtual Plenary showed Lynparza demonstrated a statistically significant and clinically meaningful improvement in the key secondary endpoint of OS, reducing the risk of death by 32% (HR=0.68; 98.5% CI 0.47-0.97; p=0.0091) versus placebo. The safety and tolerability profile of Lynparza in this trial was in line with that observed in prior clinical trials. The most common adverse reactions (ARs) =10% for Lynparza were nausea (57%), fatigue (42%), anaemia (24%), vomiting (23%), headache (20%), diarrhea (18%), leukopenia (17%), neutropenia (16%), decreased appetite (13%), dysgeusia (12%), dizziness (11%) and stomatitis (10%). Approximately 10% of patients who received Lynparza discontinued treatment due to an AR. The most common Grade =3 ARs for Lynparza were anaemia (9%), neutropenia (5%), leukopenia (3%) and fatigue (1.8%). The safety and tolerability profile of Lynparza in this trial was in line with that observed in prior clinical trials. The most common adverse reactions (ARs) =10% for Lynparza were nausea (57%), fatigue (42%), anaemia (24%), vomiting (23%), headache (20%), diarrhoea (18%), leukopenia (17%), neutropenia (16%), decreased appetite (13%), dysgeusia (12%), dizziness (11%) and stomatitis (10%). Approximately 10% of patients who received Lynparza discontinued treatment due to an AR. The most common Grade =3 ARs for LYNPARZA were anaemia (9%), neutropenia (5%), leukopenia (3%) and fatigue (1.8%).

In March 2022, Lynparza was approved in the US for the adjuvant treatment of patients with gBRCAm, HER2-negative high-risk early breast based on results from the OlympiA trial. Lynparzais also approved in the US, EU, Japan and several other countries for the treatment of adult patients with gBRCAm, HER2-negative metastatic breast cancer previously treated with chemotherapy and, if hormone receptor-positive, endocrine therapy if appropriate based on results from the phase 3 OlympiAD trial. In the EU and Japan, this indication also includes patients with locally advanced breast cancer.

About OlympiA OlympiA is a phase 3, double-blind, parallel-group, placebo-controlled, international trial evaluating the efficacy and safety of Lynparza versus placebo as adjuvant treatment in patients with gBRCAm, HER2-negative high-risk early breast cancer who have completed definitive local treatment and neoadjuvant or adjuvant chemotherapy. The primary endpoint is IDFS, defined as the time from randomization to the date of the first loco-regional or distant recurrence or new cancer or death from any cause. A key secondary efficacy outcome measure is OS.

The OlympiA trial is led by BIG in partnership with the Frontier Science & Technology Research Foundation, NRG Oncology, AstraZeneca and Merck.

Lynparza is a first-in-class PARP inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells. 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 being tested in a range of tumour types with defects and dependencies in the DDR.

Lynparza, which is being jointly developed and commercialized by AstraZeneca and Merck, has a broad and advanced clinical trial development programme, and AstraZeneca and Merck are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types.

Early breast cancer is defined as disease confined to the breast with or without regional lymph node involvement and the absence of distant metastatic disease. For women in the US, the five-year survival is 99% for localized breast cancer (cancer that is found only in the breast area) and 86% for regional breast cancer (cancer that has spread outside the breast to nearby structures or lymph nodes). Breast cancer is one of the most biologically diverse tumour types with various factors fuelling its development and progression. The discovery of biomarkers in the development of breast cancer has greatly impacted scientific understanding of the disease.

BRCA1 and BRCA2 (breast cancer susceptibility genes 1/2) are human genes that produce proteins responsible for repairing damaged DNA and play an important role maintaining the genetic stability of cells. When either of these genes is mutated or altered such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly, and cells become unstable. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer.

In July 2017, AstraZeneca and Merck, known as MSD outside the United States and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialize certain oncology products including Lynparza, the world’s first PARP inhibitor, for multiple cancer types. Working together, the companies will develop these products in combination with other potential new medicines and as monotherapies. Independently, the companies will develop these oncology products in combination with their respective PD-L1 and PD-1 medicines.

 

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