Maintenance Olaparib New Standard in Pancreatic Cancer?

Maintenance olaparib (Lynparza; AstraZeneca) is likely to become a new treatment option for patients with metastatic pancreatic cancer and germline BRCA mutations following platinum-based chemotherapy, based on findings presented at the 2019 American Society of Clinical Oncology Annual Meeting in Chicago, IL, on June 2 and simultaneously published in The New England Journal of Medicine. In the phase III POLO trial, olaparib significantly extended progression-free survival (PFS) and median duration of response (DoR) compared with a placebo, and it did not adversely affect quality of life.

“Metastatic pancreatic cancer is a dismal disease—even with modern chemotherapy regimens, patients generally live less than a year,” and second-line treatment options are limited, said senior author Hedy Kindler, MD, of the University of Chicago, who presented the results. However, the 4% to 7% of patients with germline BRCA mutations are more responsive to first-line platinum-based chemotherapy, and a single-arm phase II trial, published online in 2014, suggested that these patients may also respond to the PARP inhibitor olaparib.

Kindler and her colleagues designed the phase III POLO trial to test olaparib as a maintenance therapy in patients with metastatic disease who had germline BRCA1/2 mutations following successful treatment with platinum-based chemotherapy. In total, 154 patients were assigned 3:2 to receive olaparib or a placebo.

Patients treated with the drug had a median PFS of 7.4 months and an objective response rate of 23.1%, compared with 3.8 months and 11.5% in patients receiving a placebo. Patients on olaparib also had a median DoR of 24.9 months, compared with 3.7 months in patients on a placebo, a finding that Kindler called “truly remarkable.” Interim survival data did not significantly differ between arms; final survival data are not yet available.

Adverse effects classified as grade 3 or higher occurred in 40% of patients taking olaparib and caused 5.5% to stop treatment, compared with 23% and 1.7% of those receiving a placebo. Kindler noted that the side-effect profile was similar to that seen with olaparib in other tumor types. Patients in both arms reported a similar quality of life.

“Our results are the first from a phase III trial to validate a targeted treatment in a biomarker-selected population of pancreatic cancer patients,” Kindler said, adding that she thinks maintenance olaparib could become a new standard of care. A future goal, she said, is to identify more patients with pancreatic cancer who might benefit from maintenance olaparib—ongoing trials are investigating the drug in patients with somatic BRCA mutations.

“This is a really huge step forward,” said Suzanne Cole, MD, of The University of Texas Southwestern Medical Center in Dallas, who was not involved in the trial. “This is the first time that a targeted medication has been successful in stopping the growth of metastatic pancreatic cancer in people who carry the BRCA mutation.”

However, Wells Messersmith, MD, of the University of Colorado Comprehensive Cancer Center in Aurora, who was also not connected to the study, noted that the lack of survival benefit thus far suggests that although olaparib should become an option for patients with germline BRCA mutations, “it's very reasonable to continue platinum-based therapies,” especially considering the drug's high cost.

Cole and Messersmith agree that the results highlight the need for more widespread genetic testing, as is recommended by guidelines recently released by the National Comprehensive Cancer Network. “Now that we have a targeted medication that can benefit patients who have a BRCA mutation … it is our duty to search for this genetic mutation in all patients with metastatic pancreatic cancer,” Cole said. –Catherine Caruso