AstraZeneca (LON:AZN) and MSD Inc., Kenilworth, N.J., US (MSD: known as Merck & Co., Inc. inside the US and Canada) today announced that the companies have received marketing authorisation from China’s National Medical Products Administration for Lynparza as a 1st-line maintenance treatment of adult patients with newly diagnosed advanced germline or somatic BRCA mutated epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to 1st-line platinum-based chemotherapy.
The approval in China is based on the results from the Phase III SOLO-1 trial, which were published in The New England Journal of Medicine. Results showed that Lynparza significantly reduced the risk of disease progression or death by 70% (equal to a hazard ratio of 0.30) vs. placebo in women with BRCAm advanced ovarian cancer following response to platinum-based chemotherapy. Of those women receiving Lynparza, 60% remained progression-free at three years vs. 27% of women receiving placebo.
For newly diagnosed advanced ovarian cancer patients, the primary aim of treatment is to delay progression of the disease for as long as possible, with the intent of achieving complete remission or cure. Of women diagnosed with ovarian cancer, 15% have a germline (inherited) mutation and 7% have a somatic (acquired) mutation in their BRCA1/2 genes.
Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: “This approval marks a new era for women with BRCA-mutated advanced ovarian cancer in China, where the prevalence of BRCA mutations in advanced disease is higher than the international average. Currently, 70% of women relapse within three years of initial treatment, representing the highest reoccurrence rate among gynaecological cancers worldwide. The progression-free survival benefit of Lynparza observed in SOLO-1 is a significant step towards helping these women achieve long-term remission.”
Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: “Today’s approval of Lynparza reinforces the importance of patients knowing their BRCA mutation status at diagnosis. We are proud to provide a new option for the treatment of this devastating disease in China, and we will continue to collaborate with the Chinese government and healthcare organisations to provide Lynparza to patients who need it as quickly as possible.”
Lynparza is the first PARP inhibitor approved in China for 1st-line maintenance in BRCAm advanced ovarian cancer. AstraZeneca and MSD are exploring additional trials in ovarian cancer and recently announced positive results from the Phase III PAOLA-1 trial, which tested Lynparza in combination with bevacizumab as a 1st-line maintenance treatment for women with newly-diagnosed advanced ovarian cancer, regardless of their biomarker status or surgical outcome.
SOLO-1 was a Phase III, randomised, double-blinded, placebo-controlled, multi-centre trial to evaluate the efficacy and safety of Lynparza tablets (300mg twice daily) as a maintenance monotherapy compared with placebo in patients with BRCAm advanced ovarian cancer following 1st-line platinum-based chemotherapy. The trial randomised 391 patients with a deleterious or suspected deleterious germline or somatic BRCA1 or BRCA2 mutation who were in clinical complete or partial response following platinum-based chemotherapy.
Patients were randomised (2:1) to receive Lynparza or placebo for up to two years or until disease progression. Patients who had a partial response at two years were permitted to stay on therapy at the investigator’s discretion. The primary endpoint was progression-free survival (PFS) and key secondary endpoints included time to second disease progression or death, time to first subsequent treatment and overall survival.
The SOLO-1 safety profile was in line with that observed in prior clinical trials, and with no detriment to quality of life. The most common adverse events (AEs) ≥ 20% were nausea (77%), fatigue (63%), vomiting (40%), anaemia (39%) and diarrhoea (34%). The most common ≥ Grade 3 AEs were anaemia (22%) and neutropenia (9%). Some 71% of patients on Lynparza remained on the recommended starting dose. Additionally, 88% of patients on Lynparza continued treatment without an AE-related discontinuation.
The data were presented on 21 October 2018, at the Presidential Symposium of the European Society of Medical Oncology (ESMO) 2018 Congress in Munich, Germany.
About ovarian cancer
Ovarian cancer is the eighth most common cause of death from cancer in women worldwide. In 2018, there were nearly 300,000 new cases diagnosed and around 185,000 deaths.1 China has the highest prevalence of ovarian cancer globally, with more than 52,000 new cases diagnosed in 2018 and approximately 30,886 deaths.1,2 Most women are diagnosed with advanced (Stage III or IV) ovarian cancer and have a five-year survival rate of approximately 30%.3 Of women diagnosed with ovarian cancer, 15% have a germline mutation and 7% have a somatic mutation in their BRCA1/2 genes.4,5 For newly-diagnosed advanced ovarian cancer, the primary aim of treatment is to delay progression of the disease for as long as possible with the intent of achieving complete remission or cure.6,7,8,9
About BRCA mutations
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 in 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 such as breast and ovarian cancer.10
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 mutations in BRCA1 and/or BRCA2. 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 PARP-dependent tumour types with defects and dependencies in the DDR pathway.
Lynparza is currently approved in 65 countries, including those in the EU, for the maintenance treatment of platinum-sensitive relapsed ovarian cancer, regardless of BRCA status. It is approved in the US, the EU, Japan and several other countries as 1st-line maintenance treatment of BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in 44 countries, including the US and Japan, for germline BRCA-mutated, HER2-negative, metastatic breast cancer, previously treated with chemotherapy; in the EU, this includes locally advanced breast cancer. Regulatory reviews are underway in other jurisdictions for ovarian, breast and pancreatic cancers.
Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, is approved for advanced ovarian cancer and metastatic breast cancer and has been used in over 25,000 patients worldwide. Lynparza has the broadest and most advanced clinical trial development programme of any PARP inhibitor, 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.
About the AstraZeneca and MSD strategic oncology collaboration
In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the United States and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza, the world’s first PARP inhibitor, and potential new medicine selumetinib, a MEK inhibitor, for multiple cancer types. Working together, the companies will develop Lynparza and selumetinib in combination with other potential new medicines and as monotherapies. Independently, the companies will develop Lynparza and selumetinib in combination with their respective PD-L1 and PD-1 medicines.