Study: Results from the POLO trial: Olaparib may delay cancer progression in metastatic pancreatic cancer patients with BRCA mutations.

IN-DEPTH REVIEW OF RESEARCH

Study background:

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.

Researchers of this study wanted to know:

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.

Populations looked at in this study:

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.

Study design:

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). 

Study findings:

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.

• Participants taking olaparib had 7.4 months on average before disease progression occurred.
   
• Participants taking placebo had 3.8 months on average before disease progression occurred.

The data on overall survival was not fully complete at the time of this publication (46% of patients had died).

• At this interim evaluation point, there was no difference in the overall survival among the olaparib and placebo groups (18.9 months survival with olaparib and 18.1 months survival with placebo).

The objective response rate (ORR)—whether the cancer decreased in size during the trial was evaluated by blinded, independent reviewers.

• 18 of 78 patients (23%) in the olaparib group had decreased tumor size.
• 6 of 52 patients in the placebo group (12%) had decreased tumor size.
   
• Two patients from the olaparib group had a complete response. No cancer was observable in these two patients at the time of publication.

Quality of life evaluations were similar in both groups:

• There was no difference in health-related quality of life between participants taking olaparib and those taking placebo.

Adverse events including toxic side effects were more common among participants taking olaparib than among those taking placebo:

•  40% of participants taking olaparib had severe adverse events.
• 23% of participants taking placebo had severe adverse events.

Limitations:

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.

Conclusions:

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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Posted 7/3/19

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