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.

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.

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