KENILWORTH - AstraZeneca and Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) voted 7-5 to recommend LYNPARZA as a first-line maintenance monotherapy for patients with germline BRCA-mutated (gBRCAm) metastatic adenocarcinoma of the pancreas (pancreatic cancer), whose disease has not progressed on at least 16 weeks of first-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.
Dr. Jose Baselga, executive vice president, oncology R&D, AstraZeneca, said, 'We are pleased with the ODAC's recommendation for LYNPARZA and the potential to bring a personalized, 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.'
Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said, 'We are encouraged by the ODAC's favorable vote for LYNPARZA as a first-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 3 POLO trial published in the New England Journal of Medicine and presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting. The results showed a statistically significant and clinically meaningful improvement in progression-free survival (PFS) and reduced the risk of disease progression or death by 47% (HR 0.53 [95% CI, 0.35-0.82], p=0.004). 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 most common adverse events (AEs) 20% were fatigue/asthenia (60%), nausea (45%), abdominal pain (29%), diarrhea (29%), anemia (28%), decreased appetite (25%) and constipation (23%). The most common grade 3 AEs were anemia (11%), fatigue/asthenia (5%), decreased appetite (3%), abdominal pain (2%), vomiting (1%) and arthralgia (1%). Around 84% of patients on LYNPARZA remained on the recommended starting dose, while 16% had a dose reduction vs. 97% who remained on the recommended dose with placebo, while 3% had a dose reduction. Additionally, 95% of patients on LYNPARZA continued treatment without an AE-related discontinuation, while 5% had an AE-related discontinuation vs. 98% who continued treatment without an AE-related discontinuation and 2% that had an AE-related discontinuation with placebo.
The ODAC provides the FDA with independent, expert advice and recommendations on marketed and investigational medicines for use in the treatment of cancer. The FDA is not bound by the committee's guidance but takes its advice into consideration when deciding whether or not to approve the application.
In addition to the U.S., LYNPARZA is currently under regulatory review in the European Union (EU), Canada and other jurisdictions as a first-line maintenance treatment for patients with gBRCAm metastatic pancreatic cancer.
Germline BRCAm pancreatic cancer accounts for 5-7% of all cases globally. The FDA granted LYNPARZA orphan drug designation on October 18, 2018 for gBRCAm metastatic pancreatic cancer. Orphan drug designation is for medicines intended to treat, diagnose or prevent rare diseases or disorders that affect fewer than 200,000 people in the U.S.
LYNPARZA is currently approved in 65 countries, including the U.S., for the maintenance treatment of platinum-sensitive relapsed ovarian cancer, regardless of BRCA status. It is approved in the U.S., EU, Japan and several other countries as first-line maintenance treatment of BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in 44 countries, including the U.S. and Japan, for gBRCAm, HER2-negative metastatic breast cancer previously treated with chemotherapy; in the EU, this includes locally advanced breast cancer.
About POLO
POLO is a Phase 3 randomized, double-blinded, placebo-controlled, multi-center trial of LYNPARZA tablets (300 mg twice daily) as maintenance monotherapy vs. placebo. The trial randomized 154 patients with gBRCAm metastatic pancreatic cancer whose disease had not progressed on first-line platinum-based chemotherapy. Patients were randomized (3:2) to receive LYNPARZA or placebo until disease progression. The primary endpoint was PFS and key secondary endpoints included OS, time to second disease progression, overall response rate and health-related quality of life.
Results showed a statistically significant and clinically meaningful improvement in PFS, 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. LYNPARZA reduced the risk of disease progression or death by 47% (HR 0.53 [95% CI, 0.35-0.82], p=0.004).
About LYNPARZA (olaparib)
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 tumor 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 program, and AstraZeneca and Merck are working together to understand how it may affect multiple PARP-dependent tumors as a monotherapy and in combination across multiple cancer types.
About Pancreatic Cancer
Pancreatic cancer is a deadly cancer with a high unmet medical need. It is the 12th most commonly occurring cancer and the seventh leading cause of cancer death globally. The disease has the lowest survival rate of the most common cancers and is the only major cancer with a single-digit five-year survival rate (2-9%) in nearly every country. There were approximately 460,000 new cases in 2018 and this number is expected to rise to over 800,000 by the year 2040. As there are often no symptoms, or symptoms may be non-specific in the early stages, it is most commonly diagnosed at an incurable stage. Around 80% of pancreatic cancer patients are diagnosed when the disease is metastatic, and for these the average survival is less than a year. Despite advances in therapy, few improvements have been made in diagnosis and treatment over the decades. 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. Germline BRCA-mutated pancreatic cancer accounts for 5-7% of all cases globally.
About BRCA Mutations
BRCA1 and BRCA2 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 the AstraZeneca and Merck 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-commercialize 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.
Merck's Focus on Cancer
Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers.
About Merck
For more than a century, Merck, a leading global biopharmaceutical company known as MSD outside of the United States and Canada, has been inventing for life, bringing forward medicines and vaccines for many of the world's most challenging diseases. Through our prescription medicines, vaccines, biologic therapies and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to health care through far-reaching policies, programs and partnerships. Today, Merck continues to be at the forefront of research to advance the prevention and treatment of diseases that threaten people and communities around the world - including cancer, cardio-metabolic diseases, emerging animal diseases, Alzheimer's disease and infectious diseases including HIV and Ebola.
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