Pancreatic Cancer Patients with BRCA1/BRCA2 Respond to PARP Inhibitor

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A three-protein biomarker panel has been established that is able to screen urine samples for signs of early-stage pancreatic cancer. [iStock/© David Marchal]
A three-protein biomarker panel has been established that is able to screen urine samples for signs of early-stage pancreatic cancer. [iStock/© David Marchal]

In the first Phase III trial ever to test maintenance treatment with a PARP inhibitor in pancreatic cancer, patients with germline BRCA1 or BRCA2 mutations showed significantly improved progression free survival (PFS) on the PARP inhibitor Lynparza (olaparib) versus placebo.

These findings come of the heels of the National Comprehensive Cancer Network’s (NCCN) updated guidelines to recommend universal germline BRCA testing for all pancreatic cancer patients.

The study used Myriad Genetics’ BRACAnalysis CDx companion diagnostic test to identify metastatic pancreatic cancer patients who benefitted from treatment with AstraZeneca’s olaparib in the Phase III POLO (Pancreas cancer OLaparib Ongoing) study.  Patients with a germline mutation, and whose disease had not progressed on first-line platinum-based chemotherapy, had clinically-meaningful and statistically-significant improvement in PFS of 7.4 months on Lynparza compared to 3.8 months on placebo.

“Our long-standing collaboration with Myriad Genetics Inc. has enabled us to deliver the positive POLO study in pancreatic cancer patients, demonstrating our shared ambition to target precision medicines to the right patients across different cancer,” said Ruth March, Ph.D., senior vice president and head of Precision Medicine, Oncology R&D, AstraZeneca.  Myriad and AstraZeneca have been collaborating on numerous studies of olaparib since 2007, leading to multiple regulatory approvals.

POLO is a Phase III randomized, double-blinded, placebo-controlled, multicenter trial of 300mg of olaparib twice daily as maintenance monotherapy vs. placebo. The trial randomized 154 patients with gBRCAm metastatic pancreatic cancer whose disease had not progressed on 1st-line platinum-based chemotherapy. Patients were randomized (3:2) to receive Lynparza or placebo until disease progression. Of those patients, 151 were treated.

Pancreatic cancer is the seventh leading cause of cancer death worldwide, and the third most common cause of cancer-related death in the United States.  There are few targeted therapies available for these patients but it is estimated that seven percent of cases involve germline BRCA mutations.

Lynparza is a PARP inhibitor and the first targeted treatment to block DNA damage response in cells/tumors harboring a deficiency in homologous recombination repair (HRR), such as mutations in BRCA1 and/or BRCA2. Inhibition of PARP with olaparib traps PARP bound to DNA single-strand breaks, stalls of replication forks, and leads to their collapse and the generation of DNA double-strand breaks and cancer cell death. The drug is being tested in a range of PARP-dependent tumors.

Olaparib is not yet approved by the U.S. Food and Drug Administration (FDA) for gBRCAm pancreatic cancer. But several years ago, it became the first PARP inhibitor to be approved by the FDA as a monotherapy for patients with BRCA-mutated advanced ovarian cancer, as detected by the BRACAnalysis CDx.

Myriad has announced it will file a supplementary Premarket Approval (sPMA) application with the FDA to authorize BRACAnalysis as a companion diagnostic for olaparib in pancreatic cancer patients. “Based on the new NCCN guidelines, clinicians should order a BRACAnalysis CDx test for their patients with pancreatic cancer at the time of diagnosis,” said Jonathan Lancaster, M.D. Ph.D., chief medical officer, Myriad Genetics.

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