December 17, 2019
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FDA panel narrowly supports approval of maintenance olaparib in BRCA-mutated pancreatic cancer

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An FDA panel today supported approval of olaparib as maintenance treatment for adults with deleterious or suspected deleterious germline BRCA-mutated metastatic pancreatic cancer.

The final vote of 7-5 by the Oncologic Drugs Advisory Committee reflected concerns of some panelists who sought more survival data and questioned whether olaparib (Lynparza; AstraZeneca, Merck), a first-in-class poly(ADP-ribose) polymerase (PARP) inhibitor, conferred meaningful clinical benefit.

Panelists also debated whether the activity demonstrated by olaparib led to quality-of-life improvements.

“I voted yes because I think the evidence does show that this drug has activity in advanced pancreatic cancer,” Matthew Kulke, MD, chief of the section of hematology/oncology in the department of medicine at Boston Medical Center and Zoltan Kohn professor of medicine at Boston University School of Medicine, said in an open session after the vote. “If you think about this from a patient standpoint, would you want the option of being at home for an average of 7.4 months while taking an oral agent, or [would you rather] take a short treatment break and then go right back to the clinic for [IV] chemotherapy? I think many patients would [take] the option of an oral drug to be able to stay home longer, and I think that is a benefit.”

The approval of olaparib would apply to patients whose metastatic pancreatic cancer did not progress following first-line platinum-based chemotherapy.

“This was a challenge because we don’t want our patients to be harmed by drugs, and we absolutely don’t want our patients to refrain from platinum-based therapy, which is a home run in this treatment,” Diane Reidy Lagunes, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, said after the vote. “This drug is not a home run for the vast majority of patients, but I do think it was done in a way that we could enrich the patient population that could derive benefit, and I think they deserve the opportunity to have the drug.”

Results of the POLO3 trial, presented at ASCO Annual Meeting in June and published in The New England Journal of Medicine, showed maintenance therapy with olaparib improved PFS among patients with metastatic pancreatic cancer who harbored germline BRCA mutations.

Researchers randomly assigned 154 patients (median age, 57 years) with pancreatic adenocarcinoma and a germline BRCA mutation to 300 mg twice-daily maintenance olaparib (n = 92) or placebo (n = 62). Two-thirds of patients harbored BRCA2 mutations, whereas the others had BRCA1 mutations.

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Treatment with olaparib or placebo began 4 to 8 weeks after the last chemotherapy dose.

Results showed patients in the olaparib group demonstrated longer PFS compared with patients assigned placebo (7.4 months vs. 3.8 months; HR = 0.53; 95% CI, 0.35-0.82).

These results were consistent regardless of response to previous chemotherapy.

At 6 months, the percentage of progression-free patients in the olaparib arm was double that of the placebo arm (53% vs. 23%). This PFS trend continued at 1 year (33.7% vs. 14.5%), 18 months (27.6% vs. 9.6%) and 2 years (22.1% vs. 9.6%).

The interim OS analysis, at 46% maturity, showed an HR of 0.91 (95% CI, 0.56-1.46), with a median OS of 18.9 months in the olaparib group and 18.1 months in the placebo group.

“I do believe PFS is an important endpoint, but I think it needs to be supported by a difference in OS or at least a trend toward a difference in OS — or some hint in that direction or additional evidence like health care quality of life,” Anthony Sung, MD, assistant professor of medicine at Duke University, said during the open session. “In a year or two with additional data, I could see myself changing my vote. But at this time, with the data we have, I don’t think it’s sufficient.”

Other panelists said there was a lack of data to show a favorable risk-benefit ratio for these patients.

Christian Hinrichs, MD
Christian Hinrichs

“I reject the argument that an OS endpoint is impossible,” Christian Hinrichs, MD, clinical researcher at NCI Center for Cancer Research, said after the vote. “It’s impossible if the agent is only marginally active. For a highly active agent, OS is a feasible endpoint.” – by John DeRosier

Reference:

Golan T, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1903387.