No OS benefit? No problem. FDA panel backs use of Lynparza in pancreatic cancer
As AstraZeneca works to tighten its hold on the PARP market, an independent panel of advisors to the FDA cautiously endorsed Lynparza’s use in certain pancreatic cancer patients, even though it failed to help patients live longer.
On Tuesday, panelists voted 7-5 to recommend the drug for maintenance use in patients with germline BRCA-mutated metastatic adenocarcinoma of the pancreas, whose disease has not progressed on at least 16 weeks of first-line platinum-based chemotherapy. Globally, germline BRCAm pancreatic cancer accounts for 5-7% of all cases.
The FDA is not obliged to accept the recommendations of the panel but typically does. The agency is expected to make its final decision in the fourth quarter.
Lynparza, known chemically as olaparib, is already approved as a maintenance agent in multiple lines of therapy for ovarian cancer, as well as a metastatic breast cancer therapy. It is also expected to secure approval in prostate cancer next year.
The pancreatic cancer application was based on the 154-patient, placebo-controlled POLO trial. Lynparza induced a statistically significant improvement in progression-free survival (PFS) (95% confidence interval: 0.35, 0.81; p=0.0035) — corresponding to a 3.6-month improvement in median PFS. There was also evidence of tumor shrinkage, indicated by the difference in the overall response rate of 9.9% versus the placebo arm. However, no effect on overall survival (OS) was observed.
In a briefing document posted days earlier, FDA staff highlighted their concerns about the drug’s use in this pancreatic cancer population. Reviewers took issue that the primary endpoint was assessed on the basis of tumor measurements, which can differ among tumor settings and are subject to assessment bias. In addition, they questioned whether the trial was ‘adequately controlled’ given its small size. Another source of uncertainty, they said, was the limitations of current imaging technology to accurately measure the effect on PFS.
“Given these concerns regarding the accuracy of tumor measurement in pancreatic cancer, FDA approval of all previous drugs for the treatment of pancreatic cancer has been based on effects on OS, an endpoint for which assessment bias and limitations in the accuracy of tumor measurement by imaging technology are not present,” the report said.
“FDA acknowledges that a difference in PFS favoring the olaparib arm has been demonstrated in the POLO trial. However, there is uncertainty that the observed magnitude of the treatment effect on PFS accurately represents the true treatment effect…”
AstraZeneca and partner Merck’s Lynparza, akin to GSK’s Zejula and Clovis Oncology’s Rubraca, is a poly-ADP ribose polymerase (PARP) inhibitor. PARP is a protein used by damaged cells to initiate repair, and by thwarting it, the class of drugs is engineered to prevent cancer cells from repairing themselves, thereby catalyzing their destruction.
“While there are currently 4 approved PARP inhibitors in the US and Europe, AstraZeneca and partner Merck have established the drug as the market leader through a combination of marketing expertise and strategic trial designs,” SVB Leerink’s Andrew Berens wrote in a note last month.
“We expect the drug to remain the market leader…with potential expansion to other tumors like pancreatic, bladder and lung,” he said, adding that experts expect Lynparza to continue as the dominant PARP inhibitor until its loss of exclusivity, which is modeled for 2029.