First Phase III Trial Validates Biomarker-Selected Therapy for Pancreatic Cancer

CHICAGO-Maintenance therapy with the PARP inhibitor olaparib yielded a clinically meaningful improvement in progression-free survival (PFS) in metastatic pancreatic cancer patients with a germline BRCA mutation, according to the results of the POLO trial (abstract LBA4), which were presented in a plenary session at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, held May 31–June 4 in Chicago. The study is the first phase III trial to validate a biomarker-selected treatment for patients with pancreatic cancer.

“Metastatic pancreatic cancer is a dismal disease,” said Hedy L. Kindler, MD, of The University of Chicago, who presented the results. “Even with modern chemotherapy regimens, patients generally live less than a year. Historically, most do not receive second-line treatment.”

However, it is known that the 4% to 7% of pancreatic cancer patients who have germline BRCA mutations benefit more from platinum-based chemotherarpy, explained Kindler. “There are no targeted therapies for this disease in a biomarker-selected population validated by a phase III trial,” Kindler told Cancer Network.

POLO is an international, randomized, double-blind, placebo-controlled trial of patients with a germline BRCA mutation and metastatic pancreatic cancer who received ≥ 16 weeks of first-line platinum-based chemotherapy without progression. Patients were randomized to maintenance olaparib (300-mg tablet twice daily) or placebo, and continued therapy until progression or unacceptable toxicity occurred. The primary endpoint was progression-free survival (PFS). Secondary endpoints included duration of response and health-related patient quality of life.

The investigators screened 3,315 patients for germline BRCA mutations; a total of 247 (7.4%) were identified for randomization (3:2) to the study. However, 38% of these patients had disease progression, were ineligible, or declined randomization. Thus, there were 92 patients assigned to the olaparib arm (median age, 57 years; range, 37–84 years; 58% male) and 62 to the placebo arm (median age, 57 years; range, 36–75; 50% male). As expected, more patients had a mutation in BRCA2 than in BRCA1 (olaparib: 67.4% vs 31.5%, respectively; placebo: 74.2% vs 25.8%, respectively). Only one patient, who was in the olaparib group, had mutations in both genes.

“This is one of the first examples of a successful biomarker study in this disease,” said the discussant of the study, Wells Messersmith, MD, of the University of Colorado Comprehensive Care Center.

PFS was significantly longer in the olaparib group compared with the placebo group (hazard ratio [HR], 0.53; 95% CI 0.35–0.82; P = .0038; median PFS, 7.4 vs 3.8 months, respectively), a 47% improvement. Additionally, a subgroup analysis revealed that PFS improvement with olaparib was consistent across patients who were grouped based on response to prior platinum-based chemotherapy (complete/partial response HR, 0.62; stable disease HR, 0.50).

“What is truly remarkable is that the median duration of response to olaparib treatment in these patients who had metastatic pancreatic cancer was more than 2 years,” said Kindler, referring to an interim analysis (46% maturity).

In a global health-related patient quality-of-life assessment, there was no change in either arm from baseline, nor was there a difference between the arms. Grade ≥ 3 adverse events rates were 40% and 23% in the olaparib and placebo groups, respectively; treatment discontinuation rates due to adverse events were 5.5% and 1.7%, respectively.

“Maybe olaparib should be an option for patients with germline BRCA mutations, although, in my view, it is very reasonable to continue platinum-based therapies such as FOLFIRINOX or gemcitabine combined with cisplatin,” said Messersmith.