Background: The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (O) has radio and chemosensitizing properties in GBM models. Clinical development of PARP inhibitor combinations has been restricted by exacerbation of hematological toxicity and acute radiation toxicity. We studied pharmacokinetics (PK), safety and toxicity of O with RT and/or TMZ in three phase I studies. Methods: OPARATIC determined PK of O (AZ tablet formulation) in core and margins of recurrent GBM and maximum tolerated dose (MTD) of O with 42 day cycles of daily TMZ. PARADIGM determined recommended phase II dose (RP2D) of O with 40 Gy 15 fractions of radiotherapy in newly diagnosed patients aged > 70. PARADIGM-2 comprises two phase I studies of O+RT (60 Gy 30#, MGMT unmethylated) or O+RT+TMZ (MGMT methylated) in newly diagnosed patients aged < 70. Results: OPARATIC: 48 patients recruited; 27 underwent surgery, 36 receiving O/TMZ were evaluable. O detected in 71/75 tumor core specimens (27 patients); mean conc. 588nM (97-1374nM), and 27/28 tumor margin specimens (10 patients); mean conc. 500nM (97-1237 nM). Myelosuppression necessitated intermittent O dosing. MTD defined as O 150 mg (OD) days 1-3 weekly plus TMZ 75 mg/m2 daily. For 36 evaluable patients receiving 0/TMZ, progression-free survival at 6 months was 39%. PARADIGM: 16 patients (median age 72) treated in four O dose cohorts. One DLT (agitation grade 3) recorded (cohort 3, 100 mg BID). RP2D of O +40Gy 5# in elderly GBM was 200 mg BID daily. Median overall survival 10.3 months (80% CI: 6.3 – 11.7 months) at 12.9 months median follow up. PARADIGM-2: 29 patients screened, 14 commenced study treatment. Three MGMT unmethylated patients completed cohort 1 (50 mg QID) with no DLTs and 4 recruited to cohort 2 (100 mg QID) with no DLTs to date. Seven MGMT methylated patients recruited to cohort 1 (100 mg x1 per week); 1 DLT reported to date (low platelets). Conclusions: O penetrates core and margins of recurrent GBM. Combination with TMZ requires intermittent dosing but is safe and well tolerated. Combination with radiotherapy is extremely well tolerated and randomized phase II evaluation is underway. Clinical trial information: NCT01390571