Derby, S. et al. (2024) Concurrent olaparib and radiotherapy in elderly patients with newly diagnosed glioblastoma: the phase I dose escalation PARADIGM trial. International Journal of Radiation Oncology, Biology, Physics, (doi: 10.1016/j.ijrobp.2024.01.011) (PMID:38211641) (In Press)
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Abstract
Background : Patients with glioblastoma who are elderly or have poor performance status (PS) experience particularly poor clinical outcomes. At the time of study initiation, these patients were treated with short-course radiotherapy (40 Gy in 15 fractions). Olaparib is an oral inhibitor of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) that is well tolerated as a single agent but exacerbates acute radiation toxicity in extracranial sites. Preclinical data predicted that PARP inhibitors would enhance radiosensitivity in glioblastoma without exacerbating adverse effects on the normal brain. Methods : Phase I of the PARADIGM trial was a 3+3 dose escalation study testing olaparib in combination with radiotherapy (40 Gy 15 fractions) in patients with newly diagnosed glioblastoma who were unsuitable for radical treatment either because they were aged 70 or over (WHO PS 0-1) or aged 18-69 with PS 2. The primary outcome was the recommended phase 2 dose (RP2D) of olaparib. Secondary endpoints included safety and tolerability, overall survival (OS) and progression free survival (PFS). Effects on cognitive function were assessed by mini-mental state examination (MMSE). Results : Of 16 eligible patients (56.25% male, median age 71.5 [range 44-78 years], 75% PS 0-1), one dose-limiting toxicity was reported (grade 3 agitation). Maximum tolerated dose was not reached and the RP2D was determined as 200 mg twice daily. Median OS and PFS were 10.8 months (80% CI: 7.3-11.4) and 5.5 months (80% CI: 3.9-5.9) respectively. MMSE plots indicated that cognitive function was not adversely affected by the olaparib-radiotherapy combination. Conclusions : Olaparib can be safely combined with hypofractionated brain radiotherapy and is well tolerated in patients unsuitable for radical chemoradiation. These results enabled initiation of a randomised phase II study and support future trials of PARP inhibitors in combination with radiotherapy for patients with brain tumors.
| Item Type: | Articles |
|---|---|
| Additional Information: | This work was supported by an externally sponsored scientific research grant from AstraZeneca and by two Cancer Research UK Clinical Trials Unit Programme Awards (C1348/A15960 and C1348/A25355). |
| Status: | In Press |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Williamson, Mrs Aoife and Sweeting, Miss Lorna and Nowicki, Dr Stefan and Shad, Dr Shumaila and Williams, Dr Karin and Derby, Dr Sarah and Chalmers, Professor Anthony and Kelly, Mrs Caroline and Jackson, Dr Mark and James, Dr Allan |
| Authors: | Derby, S., Jackson, M. R., Williams, K., Stobo, J., Kelly, C., Sweeting, L., Shad, S., Herbert, C., Short, S. C., Williamson, A., James, A., Nowicki, S., Bulbeck, H., and Chalmers, A. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing |
| Journal Name: | International Journal of Radiation Oncology, Biology, Physics |
| Publisher: | Elsevier |
| ISSN: | 0360-3016 |
| ISSN (Online): | 1879-355X |
| Published Online: | 09 January 2024 |
| Copyright Holders: | Copyright © 2024 The Authors |
| First Published: | First published in International Journal of Radiation Oncology, Biology, Physics 2024 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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