NEW YORK – AstraZeneca's PARP inhibitor olaparib (Lynparza) failed to stave off cancer progression for six months in recurrent, IDH-mutant, high-grade glioma patients in the Phase II OLAGLI trial, researchers reported on Monday.
At the American Society of Clinical Oncology's virtual annual meeting, researchers led by Francois Ducray, a neuro-oncologist at the Hospices Civils de Lyon, showed that the single-arm trial did not meet its primary endpoint, which was progression-free survival for a six-month period in 45 percent of enrolled patients.
Researchers enrolled 35 patients with recurrent, high-grade gliomas who harbored an IDH mutation and gave them olaparib. If 16 patients reached six months without progression, the study would be successful. However, the six-month progression-free survival rate in the OLAGLI study was 31 percent, with only 11 of 35 patients reaching six months without disease progression.
The median progression-free survival was 2.3 months, and median overall survival was 15.9 months. Only two patients had a partial response from olaparib treatment, and 14 patients achieved stable disease. Among the partial responders and stable disease patients, the median duration of response was nine months.
In the study abstract, the authors wrote that at a median follow-up of 11 months, 30 patients had stopped treatment due to tumor progression. Only two patients were still on treatment 16 to 18 months after the start of therapy.
"Olaparib was well tolerated, however, the progression-free survival rate did not meet the predefined threshold for success," Ducray said. "There was evidence of activity in this heavily pretreated population of IDH-mutant, high-grade gliomas. However, PARP inhibition alone doesn't seem sufficient." He hypothesized that it may be necessary to combine PARP inhibitors with chemotherapy if this class of treatments is tested in this setting in the future.
The researchers decided to investigate olaparib in IDH-mutant glioma because a study published in Science Translational Medicine in 2017 showed that IDH mutations produce a homologous recombination repair defect in tumor cells, which make them "particularly sensitive to PARP inhibition," Ducray said.
That study also examined the effect of olaparib on IDH-mutant glioma cells in vitro and found it inhibited growth compared to a control. Ducray also cited other preclinical studies that have demonstrated olaparib's activity in glioma and other tumor types, such as cholangiocarcinoma and acute myeloid leukemia, with IDH mutations.
The 2017 study also found that the way in which IDH mutations hobbled tumor cells' DNA repair mechanisms was similar to how BRCA1/2 mutations hindered homologous recombination repair in cancer cells, giving IDH-mutant tumors a "BRCAness." Because olaparib is approved to treat BRCA1/2-mutated breast and ovarian cancer, the researchers decided to explore whether the PARP inhibitor would similarly exploit the "BRCAness" of IDH-mutant tumors.
Based on these earlier studies, Ducray said his team set out to test the activity of a 300-mg twice-daily dose of olaparib, which is the same dose at which the drug is approved for BRCA1/2-mutant tumors.
Ultimately, the results from the OLAGLI trial were inferior to other studies where high-grade glioma patients were treated with chemotherapy but similar to recent studies exploring other targeted therapies including palbociclib (Pfizer's Ibrance) and imatinib (Novartis's Gleevec). For example, in a Phase I/II study of imatinib in recurrent oligodendroglial tumors the six-month progression-free survival rate was 33 percent.
Extensive prior treatments may have also diminished patients' ability to fully benefit from olaparib, Ducray said. In the OLAGLI study, all patients had received radiation therapy and a median of two lines of prior chemotherapy.
"I have the feeling that we included patients who were too heavily pretreated, and for the next step, I would consider including patients at first recurrence," Ducray said. "This would be a more realistic design."
The researchers are still analyzing what characteristics the patients who responded to olaparib had in common. During his presentation at the meeting, Ducray highlighted two patients with exceptional responses. One patient with oligodendroglioma with an IDH mutation and 1p/19q codeletion had a partial response for eight months while on olaparib. Another patient with an IDH-mutant oligoastro tumor and no 1p/19q codeletion had stable disease for more than 18 months on the PARP inhibitor.
However, the heterogenous patient population in the OLAGLI trial may make it difficult to determine why some patients responded while others did not, Evanthia Galanis, a consultant in the division of medical oncology at the Mayo Clinic, reflected in reviewing the data.
Still, Ducray is not giving up on testing out this approach. He said he is considering doing a Phase II randomized trial comparing a PARP inhibitor plus chemotherapy with an isolated chemotherapy control arm.