In August 2019, the FDA accepted the supplemental New Drug Application (sNDA) for Lynparza for this indication with Priority Review and set a Prescription Drug User Fee Act (PDUFA) date for the fourth quarter of 2019.
José Baselga, Executive Vice President, Oncology R&D, said: "We are pleased with the ODAC’s recommendation for Lynparza and the potential to bring a personalised, biomarker-targeted medicine to patients with germline BRCA-mutated metastatic pancreatic cancer. Patients with advanced pancreatic cancer historically have faced poor outcomes due to the aggressive nature of the disease and limited treatment advances over the last few decades. We look forward to working with the FDA as it completes the review of our application."
Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "We are encouraged by the ODAC’s favourable vote for Lynparza as a 1st-line maintenance therapy in germline BRCA-mutated metastatic pancreatic cancer. This recommendation is a significant step towards reaching our goal to help patients with this deadly disease."
The sNDA submission was based on the positive results from the Phase III POLO trial published in The New England Journal of Medicine and presented at the 2019 American Society of Clinical Oncology Annual Meeting. The results showed a statistically significant and clinically meaningful improvement in progression-free survival and reduced the risk of disease progression or death by 47% based on a hazard ratio of 0.53 (p=0.0038). Lynparza nearly doubled the time patients with gBRCAm metastatic pancreatic cancer lived without disease progression or death to a median of 7.4 months vs. 3.8 months on placebo.
The benefit of maintenance with Lynparza was seen consistently across a range of clinically meaningful endpoints. At each time point, from six months onwards, more than twice as many patients treated with Lynparza showed no disease progression vs. those on placebo. In patients with measurable disease at baseline, 23% responded to Lynparza vs.12% on placebo and had a median duration of treatment in excess of two years (24.9 months) vs 3.7 months on placebo. Overall survival (OS), a secondary endpoint, at interim analysis was 18.9 months for Lynparza vs. 18.1 months for placebo but did not reach statistical significance (HR=0.90; p=0.68). The safety and tolerability profile of Lynparza in the Phase III POLO trial was in line with that observed in prior clinical trials.
The ODAC provides the FDA with independent, expert advice and recommendations on marketed and potential new medicines for use in the treatment of cancer. The FDA will consider the vote as it reviews the submission and is not bound by the Committee's recommendation.
In addition to the US, Lynparza is currently under regulatory review in the EU, Canada and other jurisdictions as a 1st-line maintenance treatment for patients with gBRCAm metastatic pancreatic cancer.
Pancreatic cancer is a rare, life-threatening disease that accounts for about 3% of all cancers in the US. The FDA granted Lynparza Orphan Drug Designation in October 2018, which is for medicines intended to treat, diagnose or prevent rare diseases or disorders that affect fewer than 200,000 people in the US.
Lynparza was the first PARP inhibitor to be approved and has been used in over 25,000 patients worldwide. Lynparza is currently approved in 65 countries including the US 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.
About pancreatic cancerPancreatic cancer is a deadly cancer with a high unmet medical need. It is the 12th most commonly occurring cancer(2) and the 7th leading cause of cancer death globally.(3) The disease has the lowest survival rate of the most common cancers(4,5) and is the only major cancer with a single-digit five-year survival rate (2-9%) in nearly every country.(5) There were approximately 460,000 new cases worldwide in 2018(6). As there are often no symptoms, or symptoms may be non-specific in the early stages(7), it is most commonly diagnosed at an incurable stage.(8) Around 80% of pancreatic cancer patients are diagnosed when the disease has metastasised and for these the average survival is less than a year.(9) Despite advances in treatment(10), few improvements have been made in diagnosis and treatment over the decades.(11,12) Current treatment is surgery (for which approximately only 10-20% of patients are eligible), chemotherapy and radiotherapy, highlighting a critical unmet medical need for more effective treatment options.(13)
About POLOPOLO is a Phase III randomised, double-blinded, placebo-controlled, multi-centre trial of Lynparza tablets (300mg twice daily) as maintenance monotherapy vs. placebo. The trial randomised 154 patients with gBRCAm metastatic pancreatic cancer whose disease had not progressed on 1st-line platinum-based chemotherapy. Patients were randomised (3:2) to receive Lynparza or placebo until disease progression. The primary endpoint was PFS and key secondary endpoints included overall survival, time to second disease progression, overall response rate and health-related quality of life.(1)
The results showed a statistically significant and clinically meaningful improvement in progression-free survival, where Lynparza nearly doubled the time patients with gBRCAm metastatic pancreatic cancer lived without disease progression or death to a median of 7.4 months vs. 3.8 months on placebo and reduced the risk of disease progression or death by 47% (HR 0.53 [95% CI, 0.35-0.82], p=0.004). The benefit of maintenance with Lynparza was seen consistently across a range of clinically meaningful endpoints. From six months onwards, more than twice as many patients receiving Lynparza showed no disease progression vs. those receiving placebo. In patients with measurable disease at baseline, 23% responded to Lynparza vs.12% on placebo (odds ratio, 2.30; 95% CI, 0.89 to 6.76) and had a median duration of treatment in excess of two years (24.9 months; 95% CI, 14.8 to could not be calculated) vs 3.7 months on placebo (95% CI, 2.1 to could not be calculated). Overall survival (OS), a secondary endpoint, at interim analysis was 18.9 months for Lynparza vs. 18.1 months for placebo but did not reach statistical significance (HR=0.90; p=0.68).
The safety and tolerability profile of Lynparza in the POLO trial was in line with that observed in prior clinical trials. The most common adverse events (AEs) ≥20% were fatigue/asthenia (60%), nausea (45%), abdominal pain (29%), diarrhoea (29%), anaemia (28%), decreased appetite (25%) and constipation (23%). The most common ≥ grade 3 AEs were anaemia (11%), fatigue/asthenia (5%), decreased appetite (3%), abdominal pain (2%), vomiting (1%) and arthralgia (1%). AEs led to dose reduction in 16% of patients on Lynparza while 5% of patients discontinued treatment.
There are currently no precision medicine treatment options for gBRCAm pancreatic cancer patients. However, based on the results of POLO, the National Comprehensive Cancer Network (NCCN) guidelines were updated in July 2019 to recommend Lynparza as maintenance treatment for gBRCAm pancreatic cancer.(14)
About BRCA mutationsBRCA1 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.
About LynparzaLynparza (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, China 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, prostate 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 collaborationIn 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.
About AstraZeneca in oncologyAstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company's future. With at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to AstraZenec's main capabilities, the Company is actively pursuing innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by the investment in Acerta Pharma in haematology.
By harnessing the power of four scientific platforms - Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates - 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.
About AstraZenecaAstraZeneca (LSE/STO/NYSE: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal and Metabolism, and Respiratory. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide.
2. World Cancer Research Fund International. Pancreatic cancer statistics. Available at: www.wcrf.org/dietandcancer/cancer-trends/pancreatic-cancer-statistics Accessed October 2019.
3. World Health Organization. IARC. (2019). Estimated number of deaths in 2018, worldwide, both sexes, all ages. Website available here. Accessed October 2019.
4. Pancreaticcancer.org.uk. Pancreatic cancer statistics. Available at: www.pancreaticcancer.org.uk/statistics/ Accessed October 2019.
5. Worldpancreaticcancerday.org. Available at: www.worldpancreaticcancerday.org/about-pancreatic-cancer/ Accessed October 2019.
6. World Health Organization. IARC. (2019). Estimated number of new cases in 2018, worldwide, both sexes, all ages. Website available here. Accessed October 2019.
7. Pancreaticcancer.org.uk. Signs and symptoms of pancreatic cancer. Available at: www.pancreaticcancer.org.uk/information-and-support/facts-about-pancreatic-cancer/signs-and-symptoms-of-pancreatic-cancer/ Accessed October 2019.
8. DaVee (2018). Pancreatic cancer screening in high-risk individuals with germline genetic mutations. Gastrointestinal Endoscopy. 87(6), pp.1443-1450.
9. Azar et al. (2019). Treatment and survival rates of stage IV pancreatic cancer at VA hospitals: a nation-wide study. Journal of Gastrointestinal Oncology, 10(4), pp.703-711.
10. Sheahan et al. (2018). Targeted therapies in the management of locally advanced and metastatic pancreatic cancer: a systematic review. Oncotarget. 9(30): 21613-21627.
11. Adamska et al. (2017). Pancreatic ductal adenocarcinoma: current and evolving therapies. International Journal of Molecular Science. 18(7): 1338.
12. Yongxing et al. (2017). Molecular subtyping of pancreatic cancer: translating genomics and transcriptomics into the clinic. Journal of Cancer. 8(4):513-522.
13. Stunt, A. (2016). Pancreatic cancer: GPs can help prognosis by identifying early signs. Guidelines in Practice. Available at: www.guidelinesinpractice.co.uk/cancer/pancreatic-cancer-gps-can-help-prognosis-by-identifying-early-signs/352855.article Accessed October 2019.
14. NCCN. (2019). NCCN Guidelines for Patients® | Pancreatic Cancer. Nccn.org. Available at: https://www.nccn.org/patients/guidelines/pancreatic/12/ Accessed December 2019.