# Phase Ib/II Study of Pamiparib Plus Radiation Therapy and/or Temozolomide in Adult Patients with Treatment-Naïve or Recurrent/Refractory Glioblastoma

## TL;DR

This study tested a new drug combination for glioblastoma, a type of brain cancer, and found it to be safe and effective in both newly diagnosed and recurrent cases.

## Contribution

The study introduces a novel treatment combination of pamiparib with radiation and/or temozolomide for glioblastoma patients.

## Key findings

- The drug combination was well-tolerated with manageable side effects like fatigue and nausea.
- Tumor growth was controlled in 67.9% of newly diagnosed patients and 40.9% of recurrent patients.
- Median overall survival was 12.8 months for newly diagnosed and 7.3 months for recurrent patients.

## Abstract

Glioblastoma is an aggressive brain cancer with poor survival rates, particularly in patients whose tumors lack a specific genetic marker (chemically modified or methylated O-6-methylguanine-DNA methyltransferase [MGMT]). This study tested pamiparib, a drug that blocks DNA repair, combined with radiation therapy and/or low-dose chemotherapy with temozolomide in 116 patients with newly diagnosed or recurrent glioblastoma. Patients received one of three treatments: pamiparib with radiation, pamiparib with both radiation and temozolomide, or pamiparib with temozolomide for recurrent tumors. The study found that these combinations were well-tolerated regardless of whether the glioblastoma was newly diagnosed or recurrent. The most common side effects were tiredness and nausea. In newly diagnosed patients, 67.9% had their tumor stop growing with 11.3% showing tumor shrinkage, and median overall survival (length of time patients are alive after the start of treatment) of 12.8 months. In patients with recurrent glioblastoma, 40.9% had their tumor stop growing with 13.6% showing tumor shrinkage, and median overall survival of 7.3 months. These results suggest pamiparib combinations may offer a promising treatment approach for patients with glioblastoma, particularly those newly diagnosed with unmethylated MGMT tumors who typically have fewer effective treatment options.

Pamiparib, a small-molecule poly (ADP-ribose) polymerase (PARP) 1/2 inhibitor, demonstrates strong PARP-DNA complex trapping, antitumor activity, and blood–brain barrier penetration. This phase Ib/II dose-escalation study (NCT03150862) investigated pamiparib’s tolerability/safety and efficacy when combined with radiotherapy and/or low-dose temozolomide (TMZ) in patients with treatment-naïve (Arms A and B) and recurrent/refractory (Arm C) glioblastoma. The recommended phase II dose for Arm A was pamiparib 60 mg twice daily (BID) for 6 weeks with 6–7 weeks radiotherapy; the recommended dose for Arm C was pamiparib 60 mg BID plus 60 mg TMZ (days 1–7; 28-day cycle). The Arm B escalation cohort completed enrollment; the expansion cohort was not opened. Grade ≥3 treatment-emergent adverse events (TEAEs)/serious TEAEs were observed in 55.0%/36.7% (Arm A), 44.4%/22.2% (Arm B), and 66.0%/38.3% (Arm C) of patients. Disease control and objective response rates were 67.9% and 11.3%, respectively, for treatment-naïve patients in the dose-escalation and -expansion studies, and 40.9% and 13.6%, respectively, for recurrent/refractory patients. Median overall survival for treatment-naïve MGMT unmethylated patients was 12.8 months and 7.3 months for recurrent/refractory MGMT methylated and unmethylated patients. Pamiparib with radiotherapy and/or low-dose TMZ was tolerable for treatment-naïve or recurrent/refractory glioblastoma. Treatment-emergent cytopenia was manageable and reversible with dose reductions/interruptions. Combination regimens demonstrated antitumor activity.