Adding the PARP inhibitor veliparib to treatment with temozolomide did not significantly extend overall survival (OS) in patients with newly diagnosed, MGMT-hypermethylated glioblastoma, according to findings from a randomized, phase 2/3 clinical trial published in JAMA Oncology.
Although the investigational combination was well tolerated and had an acceptable elevation in grade 3 or 4 hematologic toxicities, the median overall survival (OS) in patients treated in the phase 3 analysis was 24.8 months for the placebo arm compared with 28.1 months in the veliparib arm. Therefore, this difference in survival did not meet the investigation’s prespecified efficacy end point. Notably, study authors added that there was separation of the survival curves that favored the investigational arm over 24 and 48 months of follow-up.
Additionally, there was no significant difference in progression-free survival (PFS) between the treatment groups and no identified statistically significant differences regarding OS across stratification variables of age, ECOG performance status, extent of resection, and tumor-treating field (TTF) use.
“This randomized clinical trial did not demonstrate a significant OS benefit for patients with MGMT-hypermethylated glioblastoma treated with adjuvant temozolomide combined with veliparib. While PFS was superimposable, there was a trend for higher survival with veliparib plus temozolomide treatment at intermediate points,” study authors wrote in the JAMA Oncology article. “The results for each of these studies could be explained if a more effective experimental treatment produced a deeper nadir in tumor cell burden.”
Standard treatments for glioblastoma, which is the most common primary malignant brain tumor, includes surgery and radiotherapy with concurrent temozolomide followed by adjuvant temozolomide and TTFs. Even in patients with MGMT-hypermethylated glioblastoma, therapy resistance leads to tumor progression and death. However, there is a strong rationale to evaluate PARP1 inhibitors as chemosensitizing agents due to prior improvement in survival following treatment of patients with breast, ovarian or prostates cancers.
“Veliparib is in a category of drugs called a PARP inhibitor, which works by not allowing cancer cells to repair damaged DNA. When these damages build up in a cell, it can lead to cell death which is the goal of these types of drugs,” Dr. Priya U. Kumthekar explained in a news release from Northwestern University.
Kumthekar, who is one of the study authors, currently serves as an associate professor of medicine in the Division of Hematology and Oncology and is a member of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University Feinberg School of Medicine, in Evanston, Illinois.
“When glioblastoma is MGMT promoter-methylated, this means that it is more susceptible or more sensitive to the effects of alkylating chemotherapy, or in this case temozolomide. While patients who have tumors that are MGMT promoter-methylated fare better than those whose tumors do not possess this, the current treatment regimen remains a noncurative option,” she added in the same news release.
Based on this rationale, investigators aimed to answer this question: Does the PARP inhibitor veliparib enhance the efficacy of temozolomide in patients with newly diagnosed, MGMT promoter hypermethylated glioblastoma?
Taking a Deeper Dive into the Phase 2/3 Trial
Patients aged 18 and older were eligible for enrollment onto the phase 2/3 study so long as they had MGMT-hypermethylated glioblastoma without 1p/19q co-deletion, completion of concurrent temozolomide treatment and radiotherapy with recovery from treatment, platelet nadir levels of 75,000/mm3 or greater, an ECOG performance status of 2 or less, and adequate organ function and seizure control.
Eligible participants were enrolled and randomly assigned between treatment arms between Dec. 15, 2014, and Dec. 15, 2018, onto the study. Patients were stratified by age, ECOG status, extent of resection and planned use of TTF.
PFS served as the primary end point of the phase 2 portion of the study while OS served as the primary end point for phase 3.
Notably, study authors noted that, “The treatment groups were well balanced regarding baseline variables.”
In the phase 2 portion of the study, 322 patients were randomized to treatment, while 125 patients were added in the phase 3 accrual, making a total of 447 patients in the final analysis of the phase 3 trial. The median age range for these patients was 60 years old and a majority of patients were male.
"The results reported in this randomized clinical trial highlight the importance of developing more precise predictive biomarkers to identify the subset of patients with the greatest temozolomide-sensitizing potential. ... The present study potentially provides a road-map for a highly efficient clinical evaluation strategy for PARP1-selective or other novel chemosensitizing strategies in newly diagnosed glioblastoma,” study authors concluded.
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