ASCO 2019: PARP Inhibitors Benefit People with Pancreatic Cancer Who Have a BRCA Mutation

MSK medical oncologist Eileen O'Reilly with a patient

MSK medical oncologist Eileen O'Reilly specializes in treating people with pancreatic cancer.

Pancreatic cancer that has spread, or metastasized, is difficult to treat. Outcomes are often poor, and new treatment options are needed.

Standard treatment is usually a combination chemotherapy regimen consisting of several different drugs. This approach is effective at controlling the cancer and prolonging survival, but the drugs have side effects that can build up over time.

Previous studies have shown that people with pancreatic cancer who have mutations in the cancer-predisposition genes BRCA1 or BRCA2 may benefit from a type of targeted therapy called a PARP inhibitor. These drugs work by exploiting a weakness in cancer cells’ ability to repair DNA damage.

Now, scientists are reporting that a large phase III study has found that the PARP inhibitor olaparib (Lynparza®) is effective at delaying disease progression in people with metastatic pancreatic cancer who have an inherited BRCA mutation. The results were presented on June 2 at the annual meeting of the American Society of Clinical Oncology. They are being published simultaneously in the New England Journal of Medicine.

This study defines a new treatment option for certain people with pancreatic cancer.
Eileen M. O'Reilly medical oncologist

“This study defines a new treatment option for certain people with pancreatic cancer,” says Eileen O’Reilly, a medical oncologist at MSK and co-author on the study. “We expect it will lead to an application to the US Food and Drug Administration to expand olaparib’s approved indications to include people with pancreatic cancer who have an inherited BRCA mutation.”

Currently, no targeted therapies are approved specifically for this group.

A Wide-Ranging Study

The trial, dubbed POLO, was conducted at 119 sites in 12 countries. It enrolled 151 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 either olaparib 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 olaparib group versus the placebo group. It took about twice as long for cancer to progress in people on olaparib compared with those on a placebo (a median of 7.4 versus 3.8 months). After two years, the cancer in 22.1% of the people taking olaparib had not progressed versus 9.6% of those taking a placebo.

“These results are significant and meaningful in terms of what this targeted drug brings to the table,” Dr. O’Reilly says.

BRCA Mutations in Pancreatic Cancer

Inherited BRCA mutations are known to increase the rates of both breast and ovarian cancer, two cancers for which PARP inhibitors are already FDA approved. About 4 to 7% of people with pancreatic cancer have an inherited BRCA mutation. In this study, 7.5% of participants had such a mutation.

BRCA mutations can hinder a cell’s ability to repair breaks in DNA. PARP inhibitors further hobble cells’ ability to repair DNA breaks, leading to unsustainable amounts of DNA damage and eventually the death of the cell. Normal cells are much less affected by PARP inhibitors than cancer cells.

Platinum-based chemotherapy also works through DNA damage. This is why the study required that patients were benefiting from platinum chemotherapy before enrolling.

About 4 to 7% of people with pancreatic cancer have an inherited BRCA mutation.

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. Olaparib is a pill, whereas chemotherapy is given by IV.

“I think if you polled a hundred people, probably 95 would favor taking a pill as maintenance rather than having intravenous treatment,” Dr. O’Reilly says.

An important takeaway, she says, is that testing for BRCA mutations in pancreatic cancer is valuable. The results could determine what treatment is best.

“At MSK, we’ve been recommending routine testing for BRCA mutations in pancreatic cancer for about five years. But it’s not yet common practice in the general community,” she notes.  

This study was sponsored by AstraZeneca and is part of an alliance between AstraZeneca and Merck Sharp & Dohme, a subsidiary of Merck. This research was funded in part through a National Institutes of Health and National Cancer Institute Cancer Center Support Grant (P30-17 CA008748).