Date: 10-Jul-2020

EU Approves Lynparza For Patients With Germline BRCA-mutated Metastatic Pancreatic Cancer

AstraZeneca and Merck announced that Lynparza (olaparib) has been approved in the European Union (EU) for patients with germline BRCA-mutated (gBRCAm) metastatic pancreatic cancer.

Pancreatic cancer is a rare, life-threatening disease with the lowest survival rate among the most common cancers. Approximately 5-7% of patients with metastatic pancreatic cancer have a germline BRCA mutation.

The approval by the European Commission was based on results from the phase III POLO trial, which were published in The New England Journal of Medicine. It follows the recommendation for approval by the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA).

Hedy L. Kindler, Co-Principal Investigator of the POLO trial and Professor of Medicine, University of Chicago Medicine, said: “Today’s approval opens the door to a new era of biomarker-led care for patients with metastatic pancreatic cancer in the EU, which has the highest incidence of any region globally. Lynparza now provides clinicians with a targeted, well-tolerated treatment option for patients with germline BRCA-mutated metastatic pancreatic cancer.”

Dave Fredrickson, executive vice president, Oncology Business Unit, said: “Patients with metastatic pancreatic cancer historically have faced poor outcomes due to the aggressive nature of the disease and few treatment advances have been made over the last few decades. In the POLO trial, Lynparza nearly doubled median progression-free survival versus placebo after 1st-line chemotherapy for patients with germline BRCA-mutated metastatic pancreatic cancer. This approval underscores the importance of testing all patients for germline BRCA mutations at the time of diagnosis, as it will help inform personalised treatment options for patients in the EU.”

Roy Baynes, senior vice president and head of global clinical development, chief medical officer, MSD Research Laboratories, said: “MSD and AstraZeneca are committed to advancing research into the treatment of patients with challenging types of cancer, including those with metastatic pancreatic cancer. Lynparza is now the only approved PARP inhibitor in biomarker-selected patients with metastatic pancreatic cancer. We look forward to making this targeted treatment option available for patients across the EU as quickly as possible.”

The POLO trial demonstrated that Lynparza nearly doubled the time patients with gBRCAm metastatic pancreatic cancer lived without disease progression or death to a median of 7.4 months versus 3.8 months on placebo. The safety and tolerability profile of Lynparza in the trial was consistent with previous trials.

Lynparza is indicated as monotherapy for the maintenance treatment of adult patients with germline BRCA1/2 mutations who have metastatic adenocarcinoma of the pancreas and have not progressed after a minimum of 16 weeks of platinum treatment within a 1st-line chemotherapy regimen.

Lynparza is approved in the US and several other countries as a 1st-line maintenance treatment for patients with gBRCAm metastatic pancreatic cancer based on the phase III POLO trial, with ongoing regulatory reviews in other regions.

Pancreatic cancer is a deadly cancer with a high unmet medical need. Globally, pancreatic cancer is the 11th-most commonly occurring cancer and the seventh leading cause of cancer death. There were approximately 460,000 new cases worldwide in 2018. 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 has metastasised, at which point average survival is less than a year. Despite advances, few improvements have been made in diagnosis and treatment in the past few 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.

POLO is a randomised, double-blinded, placebo-controlled, multi-centre phase III trial of Lynparza tablets (300mg twice daily) as maintenance monotherapy versus 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 progression-free survival and key secondary endpoints included overall survival, time to second disease progression, overall response rate and health-related quality of life.

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 (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, 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.