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Lynparza Delays Progression in Metastatic Pancreatic Cancer Patients With Germline BRCA Mutations

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CHICAGO (GenomeWeb) – A clinical trial of a PARP inhibitor in metastatic pancreatic cancer patients has yielded "practice changing" results, according to some oncologists, and will likely lead to more widespread testing for germline mutations in the inherited cancer risk genes BRCA1 and BRCA2.

"Our results are the first from a Phase III trial to validate a targeted treatment in a population of biomarker-selected patients, highlighting the importance of germline BRCA mutation testing in this setting," said Hedy Kindler, medical director of the University of Chicago's gastrointestinal oncology program, during a press briefing here at the American Society of Clinical Oncology annual meeting on Sunday. Kindler is the senior author of a paper describing the results of the study that was published yesterday in the New England Journal of Medicine.

For their trial, called POLO, she and her colleagues looked at using AstraZeneca and Merck's PARP inhibitor olaparib (Lynparza) as a maintenance treatment in metastatic pancreatic cancer patients who carry germline BRCA1/2 mutations.

"Olaparib is a PARP inhibitor that targets cancer cells that have a defect in DNA damage repair," Kindler explained. That activity has led to a series of PARP inhibitor trials focused on cancer patients with hereditary BRCA1/2 mutations and other DNA damage repair problems.

The POLO investigators randomized eligible BRCA mutation carriers with metastatic pancreatic cancer in a three-to-two ratio to receive either oral olaparib maintenance treatment or a placebo, following 16 or more weeks of platinum-based, first-line chemotherapy. The patients continued treatment until their doctors documented either disease progression or untenable toxicity.

Across a group of 3,315 metastatic pancreatic cancer patients screened with the Myriad Genetics BRACAnalysis CDx test, or local genetic testing followed by confirmatory testing with BRACAnalysis CDx, the investigators identified 247 individuals with germline BRCA mutations. Inherited BRCA2 mutations were more frequent than BRCA1 mutations, and one individual had germline mutations in both genes.

Of the BRCA mutation carriers, the team randomized 92 to olaparib maintenance treatment and 62 to placebo. Kindler noted that 38 percent of the POLO participants with deleterious or suspected deleterious BRCA1/2 germline mutations were either not eligible for the trial, showed progression before randomization, or declined randomization.

For those who did participate, the researchers found that olaparib extended the average post-randomization, progression-free survival time (the trial's primary endpoint) to 7.4 months, compared to 3.8 months in the trial's placebo arm. They estimated that olaparib reduced the risk of progression or death in that metastatic pancreatic cancer subgroup by some 47 percent.

Just over 23 percent of patients in the olaparib maintenance group who had measurable disease when starting the treatment showed an objective response, as gauged by a blinded review. Two individuals had a complete response that persisted past the most recent data collection.

In contrast, Kindler explained, objective responses turned up in only 11.5 percent of patients on the placebo. Those responses tended to occur during the first few months after treatment, she noted, and likely reflect ongoing response to the chemotherapy.

The average response duration reached nearly 25 months in the olaparib group, but just shy of four months in the placebo group.

The POLO trial team did not see an overall survival difference in an interim analysis they performed at 46 percent data maturity, though they plan to assess survival again once the data has reached 69 percent maturity.

The trial investigators did not find significant health-related quality of life differences between the maintenance treatment and placebo arms, as measured with a standard European Organization for Research and Treatment of Cancer questionnaire.

Based on these and other trial results, Kindler argued that "a strategic approach of first-line platinum-based chemotherapy, followed by maintenance olaparib treatment, should become a new standard of care for patients with metastatic pancreatic cancer who have a germline BRCA mutation."

Richard Schilsky, deputy director of the University of Chicago Comprehensive Cancer Center and ASCO's senior vice president and chief medical officer, told reporters during the press briefing he is "quite sure" the findings "will change the face of treatment for at least this population of patients with pancreatic cancer."

Until now, no targeted therapies for biomarker-selected metastatic pancreatic cancer patients had been validated by a Phase III trial. And despite the abysmal five-year survival rates for metastatic pancreatic cancer, there have been no new therapies approved for those patients in five years, noted Olivier Nataf, vice president of AstraZeneca's US oncology unit.

"I hope we will have enough with the results of this trial to actually submit the dossier to the authorities and share the great results that we're seeing," Nataf said in an interview.

Last month, Myriad said that it is seeking US Food and Drug Administration approval for the BRACAnalysis CDx test as a companion diagnostic to olaparib maintenance treatment in metastatic pancreatic cancer patients. With its supplemental Premarket Approval application, the firm aims to start identifying advanced pancreatic cancer patients who might respond to olaparib maintenance in the future.

In addition, the FDA previously expanded the indication for Myriad's BRACAnalysis CDx for use in conjunction with first-line olaparib maintenance treatment after chemotherapy based on results from a Phase III, randomized, double blind clinical trial known as SOLO-1 that were reported in a NEJM paper last year.

Still, it remains to be seen how quickly the results will spur widespread testing for inherited BRCA mutations in pancreatic cancer patients. Past estimates suggest some 4 percent to 7 percent of individuals with metastatic pancreatic cancer carry pathogenic BRCA1/2 mutations in their germlines.

The National Comprehensive Cancer Network recently recommended hereditary cancer testing for all individuals with pancreatic cancer. But until now, that testing was focused on identifying at-risk family members rather than finding patients who might respond to a particular treatment.

"The [NCCN] guidelines changed in February and the approval may not come for the drug until later in the fall," Nicole Lambert, president of Myriad Oncology, a unit of Myriad Genetics, said in an interview. "That gives us a window to help raise awareness across these patients and providers, and hopefully get them tested to figure out who would be eligible for the drug before the drug launches."

Based on the trial data, though, "it is our duty to search for this genetic mutation in all patients with metastatic pancreatic cancers," said ASCO-designated expert Suzanne Cole, a medical oncologist at UT Southwestern Medical Center.

She brought home the importance of germline BRCA mutation testing in this patient population by sharing a story of a POLO participant from Kindler's clinic, a BRCA mutation carrier with pancreatic cancer that had metastasized to his liver.

As in many families affected by inherited BRCA mutations, the patient watched a close family member succumb to cancer — a brother who developed pancreatic cancer and died just months after diagnosis.

"Because this patient wanted to have a different outcome than what had happened to his brother, he decided to enroll in a clinical trial to see if he could get a better outcome," Cole said.

More than two years after his diagnosis, he has a high quality of life with stable and, in some cases, shrinking liver metastases, Cole said.

"I can't wait to go back to my clinic on Tuesday and look for [BRCA mutations] in my own patients," she added.

During the ASCO plenary session, Wells Messersmith, co-head of the University of Colorado's medical oncology division and associate director of translational research, discussed findings from the POLO trial in the context of other pancreatic cancer and PARP inhibitor studies.

He agreed that the POLO trial marks a first in terms of targeted treatments for metastatic pancreatic disease, which will push germline BRCA testing to become the standard of care in advanced pancreatic cancer.

But he also raised concerns over the interim overall survival, which was no different between the maintenance treatment and placebo arms, and emphasized the large number of patients screened to find the germline BRCA-mutated patient group.

"Finding these patients was challenging," he said, "and the investigators should be commended for taking this on."

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