ESTRO 2024 - Abstract Book

S876

Clinical - CNS

ESTRO 2024

References:

1. Oehlke O, Mix M, Graf E, Schimek-Jasch T, Nestle U, Götz I, Schneider-Fuchs S, Weyerbrock A, Mader I, Baumer BG, Short SC, Meyer PT, Weber WA, Grosu AL. Amino-acid PET versus MRI guided re-irradiation in patients with recurrent glioblastoma multiforme (GLIAA) - protocol of a randomized phase II trial (NOA 10/ARO 2013-1). BMC Cancer. 2016; 16(1):769.

1938

Proffered Paper

Results of PARADIGM-2: a phase I study of olaparib-radiotherapy in MGMT unmethylated glioblastoma

Sarah J Derby 1 , Mark R Jackson 1 , Lorna Sweeting Sweeting 2 , Shumaila Shad 2 , Lucy Paterson 2 , Jamie Stobo 3 , Stefan Nowicki 4 , Aoife Williamson 4 , Helen Bulbeck 4 , Susan C Short 5 , Catherine McBain 6 , Christopher Herbert 7 , James Powell 8 , Caroline Kelly 2 , Anthony J Chalmers 1 1 University of Glasgow, School of Cancer Sciences, Glasgow, United Kingdom. 2 University of Glasgow, Cancer Research UK Glasgow Clinical Trials Unit, Glasgow, United Kingdom. 3 University of Dundee, School of Medicine, Dundee, United Kingdom. 4 NHS Greater Glasgow & Clyde, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom. 5 University of Leeds, Leeds Institute of Cancer and Pathology, Leeds, United Kingdom. 6 Christie NHS Foundation Trust, Oncology, Manchester, United Kingdom. 7 University Hospitals Bristol NHS Foundation Trust, Oncology, Bristol, United Kingdom. 8 Velindre Cancer Centre, Oncology, Cardiff, United Kingdom Glioblastoma (GBM) is a primary brain tumour with very poor outcomes despite aggressive standard-of-care treatment comprising maximal safe neurosurgical resection followed by radical radiotherapy (RT) with concomitant and adjuvant temozolomide (TMZ) chemotherapy. Radioresistance in GBM is associated with upregulation of the DNA damage response (DDR) and recent studies have identified TGFb and alternative end-joining (a DNA repair pathway) gene expression signatures that associate with survival and response to DNA damaging agents across multiple tumour types including GBM. These studies indicate that signature gene expression is independent of MGMT gene promoter methylation, which is a well-established biomarker in GBM. Poly(ADP-ribose) polymerase (PARP) is a key DNA repair protein that is over-expressed in GBM but barely detectable in normal brain. The PARP inhibitor olaparib has radio- and chemosensitising effects in preclinical models and penetrates GBM in patients at radiosensitising concentrations. PARP inhibitors sensitise proliferating tumour cells to TMZ but exacerbate haematological toxicity. Patients with MGMT unmethylated tumours do not benefit from TMZ so it can be withheld, enabling continuous olaparib dosing with RT. Patients with MGMT methylated tumours benefit from TMZ so olaparib must be combined with chemoradiation (CRT) in an intermittent, low-dose manner. PARADIGM-2 is a clinical trial comprising two parallel phase I studies of olaparib/RT or olaparib/RT/TMZ in newly diagnosed GBM patients stratified by MGMT status. Purpose/Objective:

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