Background: Olaparib, a small molecule inhibitor of poly (ADP-ribose) polymerase (PARP), may improve GBM outcomes by enhancing cytotoxic effects of ionising radiation and TMZ. Clinical development of PARP inhibitors has been restricted by exacerbation of hematological toxicity. We investigated tumor pharmacokinetics (PK) of olaparib and safety and tolerability of its combination with TMZ. Methods: Dose escalation explored different schedules of olaparib (tablet formulation) with 42 day cycles of daily low dose TMZ. A dose expansion cohort evaluated the maximum tolerated schedule. PK analysis was performed on tumor and blood samples from patients undergoing neurosurgical resection, who received 4 olaparib doses pre-operatively. 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. 13 evaluable patients received expansion dose schedule (median age 54(21-67); 9 male, 4 female). Olaparib was detected in 73 of 74 tumor core specimens from 27 patients; mean conc. 588nM (97-1374nM), and in 27 of 28 tumor margin specimens from 10 patients; mean conc. 500nM (97-1237nM). Margin: core ratios ranged from 0.2–3.9(mean 1.2); tumor: plasma ratios ranged from 0.01 to 0.9 (mean 0.25). Olaparib dosing on days 1-5 was hindered by myelosuppression. Expansion cohort dose was defined as TMZ 75 mg/m²daily plus olaparib 150 mg (OD) days 1-3 weekly. Of 13 evaluable patients receiving expansion dose-schedule, 9 completed cycle 1, 2 completed cycle 2 and 2 completed cycle 3. Currently 45% of the evaluable patients remain progression-free at 6 months, with 2 still on treatment (full data set May2017). Of 35 evaluable patients, 24 experienced AE Grade ≥3 (see Table). Conclusions: Olaparib penetrates both core and margins of recurrent GBM despite failing to penetrate the intact brain barrier in pre-clinical heathy rodent models. Combination with extended low dose TMZ is safe and well tolerated, yielding encouraging 6 month progression-free survival rates. Clinical trial information: NCT01390571