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Special populations: BRCA mutation carriers with pancreatic cancer
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whether olaparib prolongs disease-free survival for patients with metastatic pancreatic cancer who have BRCA mutations
People with metastatic pancreatic cancer have poor survival rates and do not respond well to current treatments. Olaparib is a type of drug known as a PARP inhibitors that has received FDA approval to treat advanced breast and ovarian cancers in people with BRCA mutations. This clinical trial looked at whether the PARP inhibitor olaparib can improve outcomes for men and women with pancreatic cancer after platinum-based chemotherapy.
If you or a relative have metastatic pancreatic cancer, you may want to consider BRCA testing, because testing positive for a BRCA mutation may change treatment options.
While olaparib is not yet approved for use for treatment of metastatic pancreatic cancer, the data from this clinical trial will likely be submitted to the FDA for evaluation and the drug may be available in the future for maintenance therapy for pancreatic cancer.
Olaparib has been approved by the FDA for treatment of breast, ovarian, fallopian tube or primary peritoneal cancer for individuals with BRCA mutations.
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Pancreatic cancer has already metastasized in over half of people who are diagnosed . Metastatic pancreatic cancer does not respond well to current standard of care treatment, which is surgery followed by radiation or chemotherapy, often modified with FOLFIRINOX (leucovorin/5-FU/irinotecan/oxaliplatin). On average, standard chemotherapy care produces progression-free survival of 6 months. About 9% of patients survive 5 years after initial diagnosis. Given the poor response of metastatic pancreatic cancer, researchers have been exploring treatments that can improve outcomes.
In people with BRCA mutation who have breast or ovarian cancer, PARP inhibitors, in particular olaparib (also called Lynparza), can be an effective first-line and maintenance treatments that prolong progression-free survival. The POLO trial (Pancreas Cancer Olaparib Ongoing) was designed to test whether olaparib is useful in treating metastatic pancreatic cancer after platinum-based chemotherapy. Between 5 and 10% of patients with pancreatic cancer have an inherited BRCA gene mutation.
Whether olaparib as a maintenance treatment after platinum-based chemotherapy improved progression-free survival of metastatic pancreatic cancer patients who had an inherited BRCA mutation.
Patients were eligible for this clinical trial if they had an inherited BRCA1 or BRCA2 mutation and had confirmed metastatic pancreatic cancer that did not progress during their initial platinum-based chemotherapy.
This study involved 3,315 confirmed pancreatic cancer patients from 119 medical sites in 12 countries who were screened for BRCA mutations.
Of the 3,315 patients, 247 (7.5%) had an inherited BRCA mutation. Patients whose disease progressed while on chemotherapy during the evaluation process were ineligible for the clinical trial.
About two-thirds of the 154 eligible male and female participants had a mutation in BRCA2 and one-third had a mutation in BRCA1. Average age was 57 years.
Participants were randomly assigned to receive olaparib (90 of 92) or placebo (61 of 62). One participant assigned to olaparib and one assigned to placebo did not meet eligibility at the start of the trial (due to disease progression), and one assigned to olaparib withdrew prior to the start of the trial.
This clinical trial was a randomized, double-blind, placebo-controlled phase 3 trial.
Participants were randomly assigned to take either olaparib or placebo; they were unaware during the trial which they received.
Participants receiving olaparib took 300 mg tablets twice a day. Those receiving placebo had look-alike tablets but without olaparib. Treatment with both pills continued until the participant's cancer progressed, they had unacceptable toxic side effects or the participant died.
The primary end point of this trial was progression-free survival. Participants were evaluated for disease progression by MRI or CT imaging every 8 weeks for 40 weeks and then every 12 weeks until disease progression was observed. The imaging data was evaluated by an independent reviewer who did not know whether participants were receiving olaparib or placebo.
Secondary end points included health-related quality of life, overall survival and objective response rate. Participants filled out a questionnaire every 4 weeks to evaluate health-related quality of life.
This clinical trial was funded by AstraZeneca, a division of Merck, and others and run under FDA oversight as POLO ClinicalTrials.gov (NCT02184195).
The main finding of this clinical trial was that participants taking olaparib experienced prolonged progression-free survival that was twice as long as those on placebo.
The data on overall survival was not fully complete at the time of this publication (46% of patients had died).
The objective response rate (ORR)—whether the cancer decreased in size during the trial was evaluated by blinded, independent reviewers.
Quality of life evaluations were similar in both groups:
Adverse events including toxic side effects were more common among participants taking olaparib than among those taking placebo:
This trial had several limitations.
Participants did not include anyone who had cancer that grew during their first platinum-based chemotherapy treatment or anyone who had extended chemotherapy. For this reason, the patients in this trial may not completely represent all of those that would be treated with this drug.
Participants were screened for BRCA mutations. Other mutations that may affect metastatic pancreatic cancer were not evaluated to determine whether olaparib might be useful as a treatment.
Initial results showed that overall survival was not improved among those taking olaparib compared to those taking placebo. Patients in the placebo group who had cancer that grew during the trial sometimes took other drugs. Changes in which therapy some participants received may affect their survival: 9 patients who were in the placebo group (15%) took a PARP inhibitor after disease progression during the trial.
This clinical trial shows that olaparib may improve progression-free survival for patients with metastatic pancreatic cancer that had not progressed on platinum-based chemotherapy.
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FORCE Information: Portal for people with pancreatic cancer
FORCE Information: Pancreatic cancer treatment
FORCE Information: PARP inhibitors for pancreatic cancer
FORCE Research Study Search Tool: Pancreatic cancer treatment
Let's Win Pancreatic Cancer offers pancreatic cancer information and a support network for people living with pancreatic cancer and their caregivers.
Goaln T, Hammel P, Reni M, et al. “Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer.” New England Journal of Medicine. June 2, 2019. DOI: 10.1056/NEJMoa1903387
Pihlak R, Valle JW, McNamara MG. "Germline mutations in pancreatic cancer and potential new therapeutic options." Oncotarget. 2017 Sep 22; 8(42): 73240–73257