Veliparib Is Well Tolerated When Added to Standard Treatment in Unmethylated MGMT Glioblastoma Multiforme

Mustafa Khasraw, MD, MBChB

Adding the PARP inhibitor veliparib to standard therapy for newly diagnosed patients with unmethylatedMGMT(uMGMT) glioblastoma multiforme (GBM) was well-tolerated in a phase II trial, according to findings presented by Mustafa Khasraw, MD, MBChB, at the 24th Annual Meeting and Education Day of the Society of NeuroOncology.¹

Khasraw and colleagues hypothesized that adding veliparib to DNA damaging therapies, including radiation therapy (RT) and temozolomide, could improve clinical outcomes in patients. Historically, patients with the methylated form of theMGMTpromoter responded significantly better to therapy with temozolomide as compared with those patients with unmethylatedMGMT.^2,3Khasraw, an instructor in the Department of Neurosurgery at Duke University's Preston Robert Tisch Brain Tumor Center, Durham, North Carolina, said past studies involving veliparib in combination with chemotherapy or RT have demonstrated the agent’s safety and tolerability.

The trial screened newly diagnosed patients with GBM following surgery for the unmethylatedMGMTpromoter gene who were suitable for treatment. Patients were randomized to receive veliparib 200 mg twice daily and RT at 60 Gy, 30 Gy, or 5 Gy over 6 weeks in the experimental arm (n = 84) or a standard treatment of temozolomide 75 mg/m²once daily and RT at 60 Gy, 30 Gy, and 5 Gy over 6 weeks in the standard treatment arm (n = 41). After a treatment break, patients in the experimental arm received veliparib 40 mg twice daily on days 1 through 7, and temozolomide 150 mg/m²to 200 mg/m²once daily on days 1 through 5 for 6 cycles of 28 days. The standard treatment arm received temozolomide 150 mg/m²to 200 mg/m²once daily on days 1 through 5.

“We registered 412 patients in order to identify 197 patients with unmethylatedMGMT. These patients were then randomized into the experimental- and standard-treatment arms,” Khasraw said. There were 72 patients who failed screening. Baseline characteristics were similar between the 2 groups, but the investigators reported that the standard arm had slightly more macroscopic resections than the experimental arm (90% vs 86%). Biopsy-only resections were less frequent in the standard arm than in the experimental arm (10% vs 14%).

Grade 3/4 adverse events were similar between the 2 groups, with common AEs in the experimental arm including low platelet count (16%), neutropenia (12%), seizures (11%), and fatigue (7%). Patients in the standard treatment arm experienced low platelet count (8%), hyperglycemia (5%), seizures (5%), and diarrhea (5%) as the most common AEs. Khasraw acknowledged the incidence of seizures during the presentation.

Regarding quality-of-life analysis, Khasraw said there were no major differences between the experimental arm and the standard treatment arm. In addition, “adding veliparib to standard of care for newly diagnosed uMGMTGBM did not appear to compromise health-related quality of life,” Khasraw said.

Khasraw reported no significant difference in progression-free survival (PFS) between the 2 arms, with median PFS reported at 5.7 months (95% CI, 3.9-6.5) for the experimental arm and 4.2 months (95% CI, 2.5-5.9) for the standard treatment arm (HR, 0.82; 95 CI, 0.56-1.20).

The overall survival (OS) was similar for both arms, with patients in the experimental arm reporting an OS of 12.7 months (95% CI, 11.4-14.5) versus 12.8 months (95% CI, 11.0 -15.8) in the standard treatment arm (HR, 1.13; 95% CI, 0.74-1.71).

At a median follow-up of 24.9 months, 105 patients on the trial had died. The 6-month PFS rate was 46% (95% CI, 36%-57%) in the experimental arm and 34% (95% CI, 20%-48%) in the standard treatment arm. The rate of PFS at 12-month was 56% (95% CI, 45%-66%) in the experimental arm and 57% (95% CI, 40%-70%) in the standard treatment arm.

“The 6-month PFS did not meet the prespecified primary end point, however, the trial demonstrated that the addition of veliparib to standard treatment was feasible and well-tolerated,” Khasraw said. “Subset analyses are underway to identify patients who may have benefited.”

Khasraw reported that current research is looking at the use of PARP inhibitors in patients with methylatedMGMTas well as the potential for use in combination with immunotherapy. He concluded by stating that a phase II/III trial is currently investigating temozolomide with or without veliparib treatment in patients with newly diagnosed GBM (NCT02152982).

References

1. Khasraw M, McDonald LM, Rosenthal M, et al. A randomized phase 2 trial of veliparib (V), radiotherapy (RT) and temozolomide (TMZ) in patients (pts) with unmethylated MGMT (uMGMT) glioblastoma (GBM). Presented at: 24th Annual Meeting and Education Day; Nov 20-24, 2019; Phoenix, Arizona.
2. Hegi M, Diserens A-C, Gorlia T. MGMT gene silencing and benefits from temozolomide in glioblastoma.N Engl J Med. 2005;352(10):987-996. doi: 10.1056/NEJMoa043330.
3. Wick W, Hartmann C, Engel C, et al. NOA-04 randomized phase III trial of sequential chemoradiotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide.J Clin Oncol. 2009;27(35):5874