The Importance and Necessity of Inherited BRCA Mutation Testing for Pancreatic Cancer

The phase-III POLO clinical trial, presented at the 2019 American Society of Clinical Oncology (ASCO) Congress and published simultaneously in NEJM on June 2, delivered noteworthy, practice-changing results for pancreatic cancer treatment.

Maintenance Treatment with Olaparib in Pancreatic Cancer

Poly (ADP-ribose) polymerase, DNA mutationsare repaired by this cellular system, which is abbreviated as PARP . Small-molecule drugs have been developed to inhibit the PARP system. Among them, olaparib (Lynparza) is the first and most widely used PARP inhibitor. Olaparib previously received FDA approval for use in ovarian and breast cancer ... The BRCA gene family is another DNA repair system.

Figure Explanation: The BRCA and PARP genes targeted by olaparib are involved in repairing DNA damage. If only one of these genes is defective, the cancer cell survives. However, if both are disrupted, the cancer cell cannot repair DNA effectively. Researchers achieved anticancer activity by targeting the PARP gene in patients with germline (inherited) BRCA gene mutations.

Summary of the POLO Study

In patients with germline BRCA mutations and metastatic (stage 4) pancreatic cancer, maintenance treatment with olaparib was found to significantly delay cancer progression compared with placebo: median progression-free survival was 7.4 months versus 3.8 months. In cancer, maintenance treatmentis an intervention given after the main treatment—which is chemotherapy for metastatic pancreatic cancer—to reduce the risk of disease progression.

In POLO, olaparib was given to patients whose cancer had not progressed after completion of first-line platinum-based chemotherapy. After 2 years, 22.1% of patients receiving olaparib had no disease progression, compared with 9.6% of those receiving placebo. Overall survival data are not yet mature.

Dr. Hedy L. Kindler, one of the study’s lead authors, said, "POLO is the first phase III randomized clinical trial to establish a biomarker -driven approach in treating metastatic pancreatic cancer and opens the door to a new era of personalized treatment for this difficult-to-treat cancer" .

• Within the study, 3315 patients with pancreatic cancer underwent genetic testing, and germline (inherited) BRCA mutations were found in 247; in other words, 7.4% were BRCA-positive .
• Researchers randomly divided 154 patients into two groups in a 3:2 ratio; 92 were assigned to olaparib and 62 to placebo.
• Treatment began 4 to 8 weeks after the patient’s last dose of platinum-based chemotherapy.
• Median treatment duration was 6 months for patients receiving olaparib and 3.7 months for those receiving placebo.
• Participants had a median age of 57; 58% of those receiving olaparib were men, while equal numbers of women and men received placebo .
• BRCA mutations were BRCA2 in two-thirds of cases, with BRCA1 accounting for the remainder.

Results of the POLO Study

• Patients were evaluated for disease progression using oncological imaging initially every 8 weeks and then every 12 weeks for 40 weeks.
• At months 6, 12, 18 and 24, patients receiving olaparib were found to be at least twice as unlikely to experience disease progression as patients receiving placebo.
• Olaparib reduced the risk of disease progression by 47% compared with placebo. • Median progression-free survival (the time cancer remained controlled with treatment) was 7.4 months in patients receiving olaparib versus 3.8 months in those receiving placebo.
• After 1 year, 33.7% of patients receiving olaparib showed no signs of disease progression, compared with 14.5% of those receiving placebo.
• After 2 years, 22.1% of patients receiving olaparib had no disease progression, compared with 9.6% of those receiving placebo.
• Severe side effects (grade 3, 4 or 5) occurred in 40% of patients receiving olaparib versus 23% of those receiving placebo. In addition, 5.5% receiving olaparib and 1.7% receiving placebo discontinued treatment because of side effects. Olaparib was well tolerated, and there was no difference in quality of life between those receiving olaparib and placebo.

Commentary

The POLO clinical trial results are likely to change our perspective on pancreatic cancer treatment. Finding germline mutations at a rate of 5-10% in a disease such as advanced pancreatic cancer involving BRCA cannot be overlooked. This is why, in May 2019, ASCO recommended germline/inherited cancer testing for all patients with pancreatic cancer. Long-term POLO results will better identify which patients benefit from olaparib treatment for pancreatic cancer.