PARP Inhibitors Shows Promise as Treatment for Pancreatic Cancer
by Dr. C.H. Weaver M.D. updated 12/2019
A precision cancer medicine developed for the treatment of ovarian cancer in women with BRCA1 and BRCA2 genetic mutations has been demonstrated to be effective in the management of some individuals with pancreatic cancer who have the same mutations.(1,2,3)
The results of the phase III "POLO" clinical trial were presented at the 2019 annual meeting of the American Society of Clinical Oncology (ASCO) and showed that the Lynparza (olaparib) PARP inhibitor delays cancer progression and improves survival when used to treat BRCA-mutated pancreatic cancer and appears to represent a new treatment option for this hard to treat cancer. (2) The results of POLO led to FDA approval of Lynparza for maintenance therapy of pancreatic cancer in Dec. 2019. (7)
About Pancreatic Cancer
Pancreatic cancer is one of the deadliest forms of cancer and is projected to become the second leading cause of cancer death by 2020. Each year, approximately 43,000 people are diagnosed with pancreatic cancer in the United States and close to 37,000 die from the disease. The disease is often diagnosed at an advanced stage, treatment remains challenging, and new treatment approaches are required. About 7% - 9 % of pancreatic patients have a BRCA mutation.(4-6)
About PARP Inhibitors
Not all cancer cells are alike: Cancer cells may differ from one another based on what genes have mutations. Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. This “genomic testing” is performed on a biopsy sample of the cancer and increasingly in the blood using a “liquid biopsy”
Once a genetic abnormality is identified, a specific precision cancer medicine or targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed.
The poly ADP-ribose polymerase (PARP) enzyme plays a role in DNA repair, including the repair of DNA damage from chemotherapy. Precision cancer medicines that target and inhibit this enzyme may contribute to cancer cell death and increased sensitivity to chemotherapy and are called PARP inhibitors. By blocking this enzyme, DNA inside the cancerous cells is less likely to be repaired, leading to cell death and possibly a slow-down or stoppage of tumor growth.
About the POLO Clinical Trial
The POLO clinical trial evaluated the effectiveness of Lynparza tablets as 1st-line maintenance therapy in 154 patients with gBRCAm metastatic pancreatic cancer whose disease had not progressed following treatment with 1st-line platinum-based chemotherapy. Patients were treated with Lynparza or placebo and directly compared and the initial trial results report that Lynparza significantly delays cancer progression.(2)
The "POLO" clinical trial, was conducted at 119 sites in 12 countries in patients with metastatic pancreatic cancer who tested positive for a BRCA mutation and whose tumors had been responding to treatment with a platinum-based chemotherapy for at least four months. Patients were randomized in a double-blind fashion. (This means neither the investigators nor the patients knew which group they belonged to.) Groups were assigned to treatment with either Lynparza or a placebo. The study monitored progression-free survival, which is the amount of time a person’s cancer either shrinks or doesn’t get worse. When the study data were unblinded, the investigators found that progression-free survival was significantly longer in the Lynparza treated patients. It took about twice as long for cancer to progress in people treated with Lynparza compared with those on a placebo After two years, the cancer in 22.1% of the people taking Lynparza had not progressed versus 9.6% of those taking a placebo.
About BRCA Mutated Pancreatic Cancer
Pancreatic cancer has the worst survival rate of the most common cancers and less than seven percent of patients survive more than five years after diagnosis. Germline BRCA-mutated pancreatic cancer accounts for ~7% of all pancreatic cancers.(2)BRCA1 and BRCA2 are human genes that produce proteins responsible for repairing damaged DNA. When either of these genes is mutated, or altered DNA damage may not be repaired properly, and the cells are more likely to develop additional genetic alterations that can lead to cancer.
Lynparza is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for the treatment of selected patients with ovarian, fallopian tube, or primary peritoneal cancer. The PARP enzyme plays a role in DNA repair, including the repair of DNA damage from chemotherapy. Precision cancer medicines that target and inhibit this enzyme may contribute to cancer cell death and increased sensitivity to chemotherapy and are called PARP inhibitors. By blocking this enzyme, DNA inside the cancerous cells is less likely to be repaired, leading to cell death and possibly a slow-down or stoppage of tumor growth.(3)
Compared with chemotherapy, PARP inhibitors are better tolerated over the long term. The most common side effects of PARP inhibitors are anemia and fatigue. Common side effects of platinum-based chemotherapy include neuropathy (weakness, numbness, or pain in the hands and feet), nausea, and anemia. Lynparza is a pill, whereas chemotherapy is given by IV.(3)
This report demonstrating activity of PARP inhibitors in pancreatic cancer is encouraging and clinical trials evaluating these medicines should be performed in combination with chemotherapy and in earlier stage patients. Individuals with pancreatic cancer should discuss the role of genomic testing and clinical trials with their treating physician.
- Ovarian Cancer Drug Shows Promise in Pancreatic Cancer Patients with BRCA Mutation
- Lynparza significantly delayed disease progression as 1st-line maintenance treatment in germline BRCA-mutated metastatic pancreatic cancer
- US FDA grants Lynparza Orphan Drug Designation for pancreatic cancer
- World Cancer Research Fund International. Pancreatic cancer statistics. Accessed February 2019
- Holter S et al. Journal of Clinical Oncology. 2015; 33; 3124-3129.
- Pancreatic Cancer Action. Facts and statistics. Accessed February 2019 from pancreaticcanceraction.org/about-pancreatic-cancer/medical-professionals/stats-facts/facts-and-statistics/
- Lynparza recommended by FDA advisory committee for 1st-line maintenance treatment of germline BRCA-mutated metastatic pancreatic cancer