30 December 2019 — AstraZeneca and Merck & Co., Inc., Kenilworth, N.J., US (Merck: known as MSD outside the US and Canada) today announced that Lynparza® (olaparib) has been approved in the US for the maintenance treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. Patients will be selected for therapy based on an FDA-approved companion diagnostic for Lynparza.
The approval follows the recommendation by the US FDA Oncologic Drugs Advisory Committee (ODAC) on December 17 for Lynparza in this indication and was based on results from the pivotal Phase III POLO trial published in The New England Journal of Medicine and presented at the 2019 American Society of Clinical Oncology Annual Meeting.
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 (HR 0.53 [95% CI 0.35-0.81], p=0.0035). The safety and tolerability profile of Lynparza in the POLO trial was in line with that observed in prior clinical trials.
Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: “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. Lynparza is now the only approved targeted medicine in biomarker-selected patients with advanced pancreatic cancer.”
Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, Merck Research Laboratories, said: “Lynparza embodies Merck’s and AstraZeneca’s commitment to advance the treatment of challenging types of cancer, including metastatic pancreatic cancer. The expanded approval of Lynparza represents a significant milestone for patients and supports the value of germline BRCA testing in patients with this disease.”
Hedy L. Kindler, Co-Principal Investigator of the POLO trial and Professor of Medicine, University of Chicago Medicine, said: “Today’s approval of olaparib based on the POLO results gives clinicians an important 1st-line maintenance treatment option which nearly doubled the progression-free survival benefit in patients with germline BRCA-mutated metastatic pancreatic cancer.”
Julie Fleshman, President and CEO, Pancreatic Cancer Action Network, said: “Metastatic pancreatic cancer patients have been waiting a long time for new therapy options for their devastating disease. Today’s approval of Lynparza provides an exciting new treatment option for patients with germline BRCA-mutated metastatic pancreatic cancer.”
The Pancreatic Cancer Action Network (PanCAN) is a US-based organization that supports and advocates on behalf of the patients, caregivers and communities affected by pancreatic cancer.
The most common adverse reactions (ARs) ≥10% were fatigue (60%), nausea (45%), abdominal pain (34%), diarrhea (29%), anemia (27%), decreased appetite (25%), constipation (23%), vomiting (20%), back pain (19%), arthralgia (15%), rash (15%), thrombocytopenia (14%), dyspnea (13%), nasopharyngitis (12%), neutropenia (12%), dysgeusia (11%) and stomatitis (10%). Grade 3 or above ARs were anemia (11%), fatigue (5%), neutropenia (4%), decreased appetite (3%), thrombocytopenia (3%), abdominal pain (2%), vomiting (1%) and arthralgia (1%). ARs led to dose reduction in 17% of patients on Lynparza while 6% of patients discontinued treatment.
Lynparza is currently approved for the maintenance treatment of platinum-sensitive relapsed ovarian cancer regardless of BRCA status. It is approved as first-line maintenance treatment in BRCAm advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved for germline BRCAm HER2-negative metastatic breast cancer previously treated with chemotherapy. For first-line maintenance in advanced ovarian cancer and the metastatic breast cancer setting, physicians should select patients for therapy based on an FDA-approved companion diagnostic for Lynparza.
POLO is a Phase III randomized, double-blinded, placebo-controlled, multi-center study 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 1st-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 include overall survival, time to second disease progression, overall response rate, disease control rate and health-related quality of life. Phase III POLO results were 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, 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, 0.35-0.81], p=0.0035).
The safety and tolerability profile of Lynparza in the POLO trial was in line with that observed in prior clinical trials.
Based on the results of POLO, the National Comprehensive Cancer Network (NCCN) guidelines have been updated in July 2019 to recommend Lynparza as maintenance treatment for gBRCAm pancreatic cancer.
About Pancreatic Cancer
In the U.S. this year, it is expected that more than 55,000 people will be diagnosed with pancreatic cancer and over 45,750 people will die of this disease. Early diagnosis of pancreatic cancer is difficult, as often there are no symptoms.
There are two types of pancreatic cancer. Exocrine tumors, of which the most common type is pancreatic ductal adenocarcinoma (PDAC), start in the exocrine cells, where enzymes help to digest food. Neuroendocrine tumors start in neuroendocrine cells, which produce hormones, such as insulin, that control different functions of the body.
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.
Lynparza is a first-in-class PARP inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) in cells/tumors harboring a deficiency in homologous recombination repair (HRR), such as mutations in BRCA1 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 tumor types with defects and dependencies in the DDR pathway.
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 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.
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, we are committed to advance Oncology as a growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by our investment in Acerta Pharma in hematology.
By harnessing the power of four scientific platforms – Immuno-Oncology, Tumor Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalized combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.
AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialization of prescription medicines, primarily for the treatment of diseases in three therapy areas – Oncology, Cardiovascular, Renal & Metabolism and Respiratory. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. For more information, please visit www.astrazeneca-us.com and follow the Company on Twitter @AstraZenecaUS.
Posted: December 2019