Addition of veliparib to temozolomide fails to extend survival in glioblastoma
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Key takeaways:
- The 3.3-month improvement in median OS in the investigational arm did not reach statistical significance.
- Researchers characterized the combination as well tolerated.
The addition of veliparib to adjuvant temozolomide failed to improve OS for patients with newly diagnosed, MGMT-hypermethylated glioblastoma, according to randomized phase 2/phase3 study results.
Patients assigned the investigative combination achieved a 3.3-month improvement in median OS; however, the difference did not reach statistical significance.
“While we were disappointed that there was not a statistically significant benefit, there seems to be a ‘bubble’ in the survival curve that is highly unusual and is suggestive of benefit in a subset of patients,” Jann N. Sarkaria, MD, radiation oncologist at Mayo Clinic in Rochester, Minnesota, told Healio. “However, given the aggressive nature of glioblastoma, ultimately the survival curves converged as we approached 5 years.”
Standard treatment for glioblastoma consists of surgical resection, radiation, temozolomide and tumor-treating fields. Outcomes remain poor, highlighting the need for more effective therapies.
Veliparib (ABT-888, AbbVie) is a poly(ADP-ribose) polymerase (PARP) inhibitor.
Preclinical data suggested the addition of veliparib to temozolomide had significant chemosensitizing effects. They conducted their trial to further evaluate the combination.
The trial included 447 adults (median age, 60 years; 57.5% men) with newly diagnosed glioblastoma with MGMT promoter hypermethylation. All patients had completed concomitant radiation and temozolomide.
Researchers randomly assigned patients to receive 150 to 200 mg/m2 oral adjuvant temozolomide on days 1 to 5, plus either 40 mg oral veliparib or placebo twice daily on days 1 to 7. Treatment continued for six 28-day cycles.
OS served as the primary endpoint for the phase 3 portion of the study.
Median follow-up was 73.6 months (95% CI, 71.6-78.9).
Results showed numerical improvement in median OS with veliparib but the difference did not reach statistical significance (28.1 months vs. 24.8 months; multivariable HR = 0.93; 90% CI, 0.78-1.12).
Researchers observed a trend for improved survival in the veliparib group from 24 months to 48 months of follow-up, with the largest difference in OS observed at 3 years (36.8% vs. 29%).
“It remains a suggestion that a subset of [patients with glioblastoma] could benefit from the combination of a [PARP] inhibitor and temozolomide, but we need either a larger trial or a better biomarker to enrich for patients most likely to benefit from the combination,” Sarkaria told Healio.
Analyses of patients who received at least one dose of protocol treatment showed a higher rate of grade 3 or grade 4 hematologic adverse events in the veliparib group (49.8% vs. 23.5%), but a slightly lower rate of grade 3 or higher nonhematologic adverse events in the veliparib group (22.6% vs. 27.7%).
Researchers reported four grade 5 adverse events in the veliparib group and two in the placebo group. Investigators deemed one of the grade 5 events in the veliparib group — a thromboembolic event — to be potentially related to treatment
Researchers acknowledged study limitations, including the fact they did not determine trial participants’ isocitrate dehydrogenase mutation status. Also, participants underwent radiotherapy prior to trial enrollment, and researchers did not perform a retrospective quality assurance review for the radiotherapy administered.
For more information:
Jann N. Sarkaria, MD, can be contacted at sarkaria.jann@mayo.edu.
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