Results of the OPARATIC trial: a phase I dose escalation study of olaparib in combination with temozolomide (TMZ) in patients with relapsed glioblastoma (GBM)


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Anthony Chalmers1,Garth Cruickshank2,Laurence Dunn3,Sara Erridge4,Lisa Godfrey5,Christopher Herbert6,Sarah Jefferies7,Juanita Lopez8,Catherine McBain9,Marc Pittman5,Rebecca Sleigh10,Colin Watts11,Mark Webster-Smith5,Sarah Halford5
1Glasgow Centre for Cancer Research,2University of Birmingham,3University of Glasgow,4University of Edinburgh,5Cancer Research UK,6University Hospitals Bristol NHS Foundation Trust,7Cambridge University Hospitals NHS Trust,8Institute of Cancer Research,9The Christie NHS Foundation Trust,10LGC,11University of Cambridge

Abstract

Background

Olaparib, a small molecule inhibitor of poly(ADP-ribose) polymerase (PARP), may improve GBM outcomes by enhancing the cytotoxic effects of ionising radiation and TMZ. Clinical development of PARP inhibitors in combination with chemotherapy has been restricted by exacerbation of haematological toxicity. We investigated tumour pharmacokinetics (PK) of olaparib and safety and tolerability of its combination with TMZ.

Method

Dose escalation explored different schedules of olaparib with daily low dose TMZ. A dose expansion cohort evaluated the maximum tolerated schedule. Olaparib exposure was measured in tumour core, tumour margin and plasma following four doses prior to neurosurgical resection.

Results

48 patients were recruited (median age 51 (18-68); 29 male, 19 female) of whom 27 underwent surgery and 35 received olaparib/TMZ and were evaluable.

Olaparib was detected in 73 of 74 tumour core specimens from 27 patients. The mean concentration was 588nM (97-1374nM), similar to breast cancer data. Olaparib was also detected in 27 of 28 tumour margin specimens from 10 patients; mean concentration 500nM (97-1237nM), mean margin:core ratio 1.2 (0. 2–3.9). Although plasma exposure was dose-dependent, no correlation between dose and tumour exposure was seen and tumour:plasma ratios ranged from 0.01 to 0.9 (mean 0.25).

Olaparib dosing on days 1-5 was hindered by myelosuppression (≥grade 3 in up to 51% of evaluable patients). The expansion cohort dose was defined as TMZ 75mg/m2 daily plus olaparib 150mg (OD) days 1-3 weekly. In the expansion cohort 9/13 patients completed cycle 1, 2/13 completed cycle 2 and 2/13 completed cycle 3. 39% of evaluable (efficacy) patients remained progression-free at 6 months.

Conclusion

Olaparib penetrates both core and margins of recurrent GBM despite failing to penetrate the intact blood brain barrier. Combination with low dose TMZ is safe and tolerated, yielding encouraging 6 month progression-free survival rates. Intermittent olaparib dosing is required to mitigate haematological toxicity.