[caption id="attachment_9277" align="aligncenter" width="747"] Press Release[/caption]

ODAC voted that Lynparza demonstrated a clinically meaningful and favourable risk-benefit profile for patients based on Phase III POLO trial results

AstraZeneca and MSD Inc., Kenilworth, NJ, US (MSD: known as Merck & Co., Inc. inside the US and Canada) today announced that the US Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) voted 7 to 5 to recommend?Lynparza?(olaparib) as a 1st-line maintenance monotherapy for patients with germline BRCA-mutated (gBRCAm) metastatic adenocarcinoma of the pancreas (pancreatic cancer), whose disease has not progressed following 1st-line platinum-based chemotherapy. 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. Jos? 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 cancer Pancreatic 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 20186. As there are often no symptoms, or symptoms may be non-specific in the early stages⁷, 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 treatment¹⁰, 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 POLO POLO 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 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. About?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 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 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. About AstraZeneca in oncology AstraZeneca 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 AstraZeneca?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 AstraZeneca AstraZeneca (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. Please visit?astrazeneca.com?and follow the Company on Twitter?@AstraZeneca.  

Contacts

Media Relations
Gonzalo Vi?a		+44 203 749 5916
Rob Skelding	Oncology	+44 203 749 5821
Rebecca Einhorn	Oncology	+1 301 518 4122
Matt Kent	BioPharmaceuticals	+44 203 749 5906
Jennifer Hursit	Other	+44 203?749 5762
Christina Malmberg H?gerstrand	Sweden	+46 8?552 53 106
Michele Meixell	US	+1 302 885 2677
Investor Relations
Thomas Kudsk Larsen		+44 203 749 5712
Henry Wheeler	Oncology	+44 203 749 5797
Christer Gruvris	BioPharmaceuticals (Cardiovascular, Metabolism)	+44 203 749 5711
Nick Stone	BioPharmaceuticals (Renal) Environmental, Social and Governance	+44 203 749 5716
Josie Afolabi	BioPharmaceuticals (Respiratory) Other medicines	+44 203 749 5631
Craig Marks	Finance Fixed income	+44 7881 615 764
Jennifer Kretzmann	Corporate access Retail investors	+44 203 749 5824
US toll-free		+1 866 381 72 77

 

References

1.???? Golan?et al?(2019). Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer.?New England Journal of Medicine. 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.  

Adrian Kemp Company Secretary AstraZeneca PLC