Stephanie Percich, MS, CGC
Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer
Metastatic pancreatic cancer is especially difficult to treat. Currently, the standard of care first-line treatments for pancreatic adenocarcinoma have a median progression-free survival of 6 months and less than 10% of those with pancreatic cancer survive more than 5 years after diagnosis.1 It is estimated that 4-7% of individuals with pancreatic adenocarcinoma carry a germline pathogenic variant in the BRCA1 or BRCA2 genes.1,2 These genes aid in repair of double-strand DNA breaks via homologous recombination. Cells with deficient homologous recombination (e.g. those with BRCA1/2 pathogenic variants) are sensitive to PARP (poly adenosine diphosphate–ribose) polymerase inhibitors, such as olaparib. Olaparib has proven beneficial in patients with breast or ovarian cancer and germline BRCA1/2 mutations.3,4
The POLO (Pancreas Cancer Olaparib Ongoing) trial was a randomized, double-blinded, placebo-controlled phase 3 trial aimed at assessing the efficacy of olaparib maintenance therapy in patients with a germline BRCA1/2 mutation and metastatic pancreatic adenocarcinoma that had not progressed with first-line platinum-based chemotherapy. Patients from 119 sites in 12 countries were screened for trial eligibility. Patients were eligible if they had been diagnosed with pancreatic adenocarcinoma, carried a deleterious/suspected deleterious BRCA1/2 mutation, and were 18 years of age or older. Eligible patients were randomized in a 3:2 ratio to receive maintenance olaparib or placebo four to eight weeks after administration of their last dose of first-line chemotherapy. The primary endpoint of the POLO trial was progression-free survival (defined as the time from randomization until radiologic disease progression or death). Learn more about the POLO trial.
Throughout the trial, 90 patients received olaparib and 61 patients received placebo. Upon the data cutoff in January 2019, 30 patients were still taking olaparib and 8 were still taking placebo. The median progression-free survival was significantly longer in those receiving olaparib than in those receiving placebo (7.4 months vs. 3.8 months) and after 6 months, the percentage of patients still alive without disease progression was more than double in the olaparib group. At two years, 22.1% of those in the olaparib group did not have disease progression or death versus 9.6% in the placebo group. Grade 3 or higher adverse events occurred in 40% of those receiving olaparib and in 23% of those receiving placebo. There were no significant changes in reported quality of life between the two groups from baseline.
The POLO trial demonstrated that patients with metastatic pancreatic adenocarcinoma and a germline BRCA1/2 mutation that had not progressed during first-line platinum-based chemotherapy had a significantly longer progression-free survival when taking maintenance olaparib compared with placebo. In the POLO trial, olaparib cut the risk of disease progression or death by 47% for patients with pancreatic cancer and a germline BRCA1/2 mutation. Consequently, the National Comprehensive Cancer Network (NCCN) recommends consideration of olaparib as maintenance therapy in patients with metastatic pancreatic cancer, a germline BRCA1/2 mutation, no disease progression during >16 weeks of first-line, platinum-based chemotherapy, and a good performance status.5
Additionally, NCCN recommends that all patients with pancreatic adenocarcinoma undergo germline testing using a comprehensive panel of genes for hereditary cancer.5 Germline testing at the time of pancreatic cancer diagnosis is imperative as those found to carry a BRCA1/2 mutation may benefit from platinum-based chemotherapy (versus standard chemotherapy).5 The myRisk STAT test provides faster results for patients with pancreatic cancer in order to inform treatment decisions as soon as possible Learn more about STAT. In addition to informing treatment decisions for an individual with pancreatic cancer, genetic test results have implications for the patient’s family. Patients found to carry a germline mutation can inform their relatives of their option to undergo genetic testing and if unaffected family members are found to carry the same germline mutation, they can take steps to be more proactive with their cancer screening and prevention.
1. Golan T, et al. Maintenance olaparib for germline BRCA-Mutated metastatic pancreatic cancer. N Engl J Med. Epub 2019 Jun 2.
2. Holter S, et al. Germline BRCA mutations in a large clinic-based cohort of patients with pancreatic adenocarcinoma. J Clin Oncol. 2015;33(28):3124-9.
3. Robson M, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523-533.
4. Moore K, et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018;39(26):2495-2505.
5. NCCN Clinical Practice Guidelines in Oncology. Pancreatic Adenocarcinoma (Version 3.2019). https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed July 11, 2019.