CHICAGO—Maintenance therapy with the PARP inhibitor olaparib prolonged progression-free survival (PFS) after platinum-based chemotherapy in patients with metastatic pancreatic cancer who had mutated germline BRCA 1/2 genes in findings from the international POLO study reported at the 2019 ASCO Annual Meeting (Abstract LBA4).
“What we observed was a clinically significant improvement in progression-free survival in those patients who received olaparib. [It was] 7.4 months in those on olaparib and 3.8 months [for patients] on placebo,” said first author Hedy Lee Kindler, MD, Professor of Medicine from the University of Chicago. “That is a 47 percent decrease in the risk of progression or death.”
The POLO results were the first from a phase III randomized, double-blinded, placebo-controlled trial to validate a targeted treatment in biomarker-selected patients with metastatic pancreatic cancer. The findings highlighted the importance of testing for BRCA1/2 genetic mutations in patients with pancreatic cancer, which was associated with this biomarker in up to 7 percent of cases, Kindler said.
Patients with pancreatic cancer who had germline BRCA mutations had already been viewed as candidates for PARP inhibitors because these drugs target cells without normal DNA damage repair and had been approved as standard of care in germline BRCA-mutated breast and ovarian cancers. Also a phase II trial in heavily pretreated patients with pancreatic cancer had demonstrated significant activity in those who had a germline BRCA mutation.
For recruitment into POLO, patients needed to have had a germline BRCA mutation and metastatic pancreatic adenocarcinoma and have received at least 16 weeks of first-line platinum-based chemotherapy without progression. They were randomized to maintenance therapy with olaparib or placebo beginning 4-8 weeks after the final chemotherapy dose. Treatment was continued until progression or unacceptable toxicity, and the primary endpoint was PFS.
The study screened 3,315 patients for BRCA mutation in four continents, and 7.5 percent tested positive. “These patients had all received at least 4 months of platinum-based chemotherapy and were then randomized to receive either olaparib or placebo,” said Kindler. Among the 247 patients randomized, there were 104 events in the active arm and POLO reported significantly improved PFS on olaparib with a hazard ratio of 0.53 (p=0.003) compared to placebo.
The objective response rate to olaparib was 23.1 percent. Kindler emphasized that even though the patients' cancers were metastatic they had long responses. “What is really remarkable in these patients [was that] the median duration of response was over 2 years,” she said. “Truly remarkable in a population of patients who shouldn't even live that long.” After 6 months of treatment, the percentage of patients who were progression-free in the olaparib arm was more than twice that in the placebo arm.
Grade 3 or higher adverse events occurred in 40 percent of patients treated with olaparib and 23 percent of those on placebo. But more patients needed to discontinue treatment in the active treatment arm (5.5%) than among those taking placebo (1.7%).
Suzanne Cole, MD, Assistant Professor at the University of Texas Southwestern Medical Center in Dallas, said the POLO result was a huge step forward for patients with metastatic pancreatic cancer. Since 20 percent of patients were still alive 2 years after taking olaparib, she said the drug had succeeded in rendering the disease “dormant” in many patients and this meant there was a new imperative for clinicians.
“It is our duty to search for this genetic mutation in all patients with metastatic pancreatic cancer so that we can identify those people who have the BRCA mutation and can benefit from being treated with an oral agent that can extend their life,” she said.
Kindler said metastatic pancreatic cancer was an “absolutely abysmal disease” that was due to become the second-leading cause of cancer death in the U.S. by 2020. “This is a disease that's highly symptomatic and where most patients at diagnosis will live less than a year—even with contemporary chemotherapy regimens. So now we have a treatment option that can offer at least a select population of patients the ability to receive a maintenance treatment that can help prolong their time off toxic chemotherapy, and that can delay the time to disease progression. It really is a major advance,” she told Oncology Times.
In the light of emerging knowledge about the relevance of BRCA testing in patients with pancreatic cancer, Kindler said both the National Comprehensive Cancer Network (NCCN) guidelines and a recent ASCO provisional clinical opinion had suggested that patients with the relevant family history should be tested for BRCA mutations, and that all pancreatic cancer patients could be offered the option of testing.
“I think in the future—with the data that we now have—all patients should be offered the option of germline testing,” she said.
Cancer doctors need to think about this and look for mutations in order to identify these patients, Kindler noted. “We have changed our standard of care practice in our clinics. At the first visit, we now bring up the notion of germline BRCA testing to all of our patients.” She was anticipating that, as patients became aware of the relevance of this biomarker, they would be “knocking down the doors and saying: ‘Yes, we need to get this testing early.’”
Kindler also said it's important to understand that having a BRCA mutation meant that patients would also respond better to platinum-based chemotherapy.
“With the option of receiving either FOLFIRINOX (or something similar) or gemcitabine/paclitaxel protein-bound, if you have a BRCA mutation, you want to start with a platinum-based chemotherapy and then receive olaparib,” she explained. “This is a transformation of outlook for patients with metastatic pancreatic cancer who have a germline mutation. They now have a treatment option that could potentially put their disease into control for years.”
Since early detection of pancreatic cancer was very difficult with “vague, nebulous” symptoms (such as abdominal pain, weight loss, and new onset diabetes), it was “very challenging to diagnose this disease early,” Kindler noted, bringing the focus even more strongly on the importance of germline testing.
“If you already know that you have a hereditary syndrome, you may then be able to diagnose it early. So perhaps the families of our current patients who are being germline tested will be able to be screened in the future and then perhaps those diseases will be found earlier,” she said.
Her take-home message for doctors was to draw attention to the BRCA biomarker in patients with metastatic pancreatic cancer. “All patients with this disease need to have germline testing at diagnosis so that they can take advantage of this new treatment option.”
Cole commented that they were eagerly awaiting longer-term data to understand the full impact of the results from the POLO trial.
“It's encouraging to see that olaparib is consistently delaying the progression of metastatic pancreatic cancer in patients with a BRCA mutation,” she said. “We're potentially on the cusp of a new age of treatment for pancreatic cancer, where for the first time we can tailor therapy based on a biomarker and where having a BRCA mutation opens up more treatment options.”
Peter M. Goodwin is a contributing writer.