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2019 ASCO: POLO: Maintenance Olaparib in Germline BRCA-Mutated Pancreatic Cancer

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Key Points

  • At 6, 12, 18, and 24 months after randomization, patients who received olaparib were at least twice as likely to have no disease progression compared with those who received placebo.
  • Olaparib reduced the risk of disease progression by 47% compared with placebo.
  • The median progression-free survival for patients receiving olaparib was 7.4 months, compared with 3.8 months for patients who received a placebo.
  • After 1 year, 33.7% of patients receiving olaparib showed no signs of disease progression compared with 14.5% of those who received a placebo; after 2 years, 22.1% of patients receiving olaparib had no disease progression compared with 9.6% of those receiving a placebo.

The randomized phase III POLO trial found that maintenance therapy with the poly (ADP-ribose) polymerase inhibitor olaparib significantly delayed the progression of metastatic pancreatic cancer in patients with germline BRCA gene mutations compared with placebo (median progression-free survival = 7.4 months vs 3.8 months, respectively). In the trial, olaparib was administered to patients with cancer that had not progressed after completion of initial platinum-based chemotherapy, and after 2 years, 22.1% of patients receiving olaparib had no disease progression vs 9.6% of those treated with placebo. Overall survival data are not yet mature. These findings were presented during the 2019 ASCO Annual Meeting Plenary Session by Kindler et al (Abstract LBA4).

“POLO is the first phase III randomized study to establish a biomarker-driven approach in the treatment of metastatic pancreatic cancer, and it opens the door to a new era of personalized care for this difficult-to-treat cancer,” said lead study author Hedy L. Kindler, MD, FASCO, Professor of Medicine, University of Chicago Medicine. “Roughly one in five 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.”

In January 2019, ASCO issued a Provisional Clinical Opinion (PCO) recommending that people with pancreatic cancer undergo risk assessment for hereditary syndromes that increase pancreatic cancer risk. The PCO also states that germline genetic testing for cancer susceptibility—including testing for BRCA mutations—may be discussed with individuals diagnosed with pancreatic cancer, even if family history does not clearly suggest an inheritable cancer-related syndrome.

Study Background and Methods

The current trial builds on phase II data from a 2015 trial published by Kaufman et al in the Journal of Clinical Oncology, which reported 22% response rates in pancreatic cancers with BRCA1/2 gene mutations treated with olaparib following chemotherapy with gemcitabine. The POLO trial examined whether olaparib could delay disease progression after 16 weeks or more of initial platinum-based chemotherapy. The use of an oral, nonchemotherapeutic medicine with lower toxicities—such as olaparib—would provide an important option, according to the study authors.

After screening 3,315 patients with pancreatic cancer, the investigators identified 247 with germline BRCA mutations. The researchers randomly assigned 154 patients on a 3:2 basis, with 92 people assigned to olaparib and 62 assigned to placebo. Treatment started 4 to 8 weeks after a patient’s last dose of platinum-based chemotherapy. The median duration of treatment was 6 months for those taking olaparib and 3.7 months for people who received a placebo.

Enrollees were a median age of 57 years; 58% of patients who received olaparib were men; and equal numbers of men and women received placebo. Two-thirds of those enrolled had BRCA2 mutations, and the remainder had BRCA1 mutations.

Results

Patients were initially evaluated for disease progression every 8 weeks, then subsequently for 40 weeks, and every 12 weeks thereafter. At 6, 12, 18, and 24 months after randomization, patients who received olaparib were at least twice as likely to have no disease progression compared with those who received placebo.

Olaparib reduced the risk of disease progression by 47% (hazard ratio = 0.53) compared with placebo. The median progression-free survival for patients receiving olaparib was 7.4 months, compared with 3.8 months for patients who received a placebo. After 1 year, 33.7% of patients receiving olaparib showed no signs of disease progression compared with 14.5% of those who received a placebo. After 2 years, 22.1% of patients receiving olaparib had no disease progression compared with 9.6% of those receiving a placebo.

Serious side effects (grade 3, 4, or 5) occurred in 40% of patients taking olaparib compared with 23% of those taking a placebo. In addition, 5.5% of those taking olaparib and 1.7% of those on placebo discontinued treatment due to toxicity. Olaparib was well tolerated, and there was no difference in quality of life between those taking olaparib and placebo.

Dr. Kindler noted that the results of this trial are likely practice-changing. The long-term goal is to demonstrate the utility of olaparib in pancreatic cancer beyond the patients who benefitted from the medicine in the POLO trial.

Disclosure: This study received funding from AstraZeneca and Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, New Jersey. For full disclosures of the study authors, visit coi.asco.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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