Practice-Changing Results: Olaparib Maintenance Therapy Extends Progression-Free Survival in Metastatic Pancreatic Cancer with BRCA Mutations

TOP - August 2019, Vol 12, No 3 - Pancreatic Cancer
Phoebe Starr
Chicago, IL—Maintenance therapy with the targeted drug olaparib (Lynparza) after first-line platinum-based chemotherapy prolonged progression-­free survival (PFS) in patients with metastatic pancreatic cancer and a germ­line BRCA mutation, according to results of the phase 3 POLO clinical trial presented at the plenary session at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting. Lead investigator Hedy L. Kindler, MD, FASCO, Medical Director, Gastrointestinal Oncology, University of Chicago Medicine, IL, presented the results.

The median PFS was 7.4 months with olaparib versus 3.8 months for placebo (P = .0038), for a 47% reduction in disease progression. At 2 years, 22.1% of patients who received olaparib therapy remained progression free compared with 9.6% of those in the placebo arm. The survival data are not yet mature, but these findings represent a significant advance; the current median survival for patients with metastatic pancreatic cancer is <1 year.

“Our results are the first from a phase 3 trial to validate a targeted treatment in a biomarker-selected population of patients with pancreatic cancer, highlighting the importance of germline BRCA mutation testing in this setting,” said Dr Kindler.

“A strategic approach of first-line platinum-based chemotherapy followed by olaparib maintenance should become a new standard of care for patients with metastatic pancreatic cancer who have a germline BRCA mutation,” Dr Kindler added. According to her, anywhere from 4% to 7% of all patients with metastatic pancreatic cancer harbor a BRCA mutation.

“This is a huge step forward,” said ASCO Expert Suzanne Cole, MD, Director, University Hospital Simmons Cancer Clinic, The University of Texas Southwestern Medical Center at Richardson/Plano, speaking at a press conference held during the meeting.

“This is the first time that a targeted medication has been successful at stopping the growth of metastatic pancreatic cancer in people who carry the BRCA mutation. In the study, more patients with a BRCA mutation saw their disease go dormant when they received olaparib,” Dr Cole told listeners.

“It is now our duty to test for this mutation in all patients with metastatic pancreatic cancer to identify those who can benefit from treatment with this oral agent,” Dr Cole added.

Olaparib, a poly (ADP-ribose) polymerase inhibitor, received an orphan drug designation from the FDA for pancreatic cancer in October 2018.

The POLO Study Details

Among the 3315 patients with metastatic pancreatic cancer who were screened for genetic mutations at the POLO study, 247 had a germline BRCA mutation; of these, 154 were randomized in a 2:1 ratio to treatment with olaparib (N = 92) or to placebo (N = 62). All participating patients had received first-line treatment with platinum-based chemotherapy for at least 16 weeks and had no disease progression.

Treatment with olaparib (300 mg twice daily) or with placebo started 4 to 6 weeks after the last dose of platinum-based chemotherapy and was continued until disease progression. The median duration of treatment was 6 months with olaparib and 3.7 months with placebo.

The patients’ median age was 57 years; 66% had BRCA2 mutations, and 33% had BRCA1 mutations.

At the time of data cutoff, 30 (32.6%) patients in the olaparib group and 12 (19.4%) patients in the placebo group remained progression free. From 6 months on, more than double the number of patients in the olaparib arm were progression free compared with the placebo arm.

At the interim survival analysis, the median overall survival (OS) did not differ significantly between the 2 treatment arms—18.9 months with olaparib versus 18.1 months with placebo. The final OS analysis will be presented when the data are mature.

Severe adverse events (grades 3-5) were reported in 40% of patients in the olaparib arm and in 23% of patients in the placebo arm. Treatment discontinuations because of adverse events were 5.5% with olaparib and 1.7% with placebo. No difference in quality of life was observed between the 2 treatment arms.

“Roughly 1 in 5 patients responded to olaparib for a median of 2 years, which is truly remarkable for metastatic pancreatic cancer. For patients with BRCA ­driven metastatic pancreatic cancer, we may be seeing a change in patients’ disease trajectory,” Dr Kindler said.

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Last modified: July 29, 2019