US FDA Approval Of Lynparza For Pancreatic Cancer Opens Door For PFS Endpoint In Disease
Executive Summary
AstraZeneca's PARP inhibitor Lynparza becomes first US FDA-approved drug for pancreatic cancer based on progression-free survival endpoint, providing regulatory precedent for other sponsors to use that development approach; all other pancreatic cancer drugs had been approved based on an overall survival benefit.
The US Food and Drug Administration has opened the door for sponsors to use a progression-free survival (PFS) endpoint in developing pancreatic cancer drugs with the agency's 27 December 2019 supplemental approval of AstraZeneca PLC's Lynparza (olaparib) for the disease.
Lynparza, a PARP inhibitor, is now specifically labeled for the maintenance treatment of adult patients with deleterious or suspected deleterious gBRCAm metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. It's the first FDA-approved targeted medicine in biomarker-selected patients with advanced pancreatic cancer. (Also see "Lynparza Gets US OK For Pancreatic Cancer " - Scrip, 30 Dec, 2019.)
The indication is Lynparza's fifth overall; the drug also holds three indications in ovarian cancer and one in breast cancer.
AstraZeneca opted to use PFS as the primary endpoint in its pivotal POLO trial to support the pancreatic cancer indication despite advice from FDA to use overall survival (OS). The agency generally recommends that sponsors developing new pancreatic cancer drugs use OS as the primary endpoint due to concerns regarding the accuracy of tumor measurement in the disease. OS data from POLO were not yet mature at the time of the PFS analysis. (Also see "AstraZeneca's Risky Lynparza Endpoint In Pancreatic Cancer Goes Before Advisory Cmte. " - Pink Sheet, 15 Dec, 2019.)
However, the Oncologic Drugs Advisory Committee narrowly voted in favor of approval for the indication by a 7-5 margin at a 17 December 2019 meeting. Panelists agreed with the FDA's view that Lynparza's overall impact on PFS was clinically modest, although a small majority felt the drug demonstrated meaningful benefit in a small subset of patients and that it should be approved. (Also see " Lynparza For Pancreatic Cancer: ODAC's Narrow Support Leaves US FDA In Quandary" - Pink Sheet, 17 Dec, 2019.)
AstraZeneca will submit the final OS analysis and datasets to the agency as part of a 506B postmarketing commitment. According to the approval letter, AstraZeneca will complete the trial by December 2020 and submit the final report by June 2021.
Nevertheless, sponsors now have regulatory precedent to support pancreatic cancer applications with a PFS primary endpoint, which is generally assessed earlier and with a smaller patient sample size compared with survival endpoints.
According to Biomedtracker, there are nearly 20 pancreatic cancer candidates in Phase II and that have not yet begun a pivotal trial. The sponsors of these products may have the option of studying their candidates using a PFS primary endpoint in pivotal development.