Background: The metabolism of olaparib (Lynparza) is mediated predominantly by CYP3A4/5 enzymes. Two Phase Istudies are reported here investigating pharmacokinetic interactions between olaparib (tablet formulation) and itraconazole, a potent CYP3A4 inhibitor (Study 1, NCT01900028), and rifampin, a potent CYP3A4 inducer (Study 2, NCT01929603). Methods: In Study 1, 59 eligible patients (pts) received a single oral dose of olaparib 100 mg on Day 1 and olaparib 100 mg plus itraconazole 200 mg on Day 9; itraconazole 200 mg was administered once daily (qd) on Days 5–11. In Study 2, 22 pts received a single oral dose of olaparib 300 mg on Day 1 and single oral dose olaparib 300 mg plus rifampin 600 mg on Day 14; rifampin 600 mg qd was administered on Days 5–17. Results: Co-administration with itraconazole in Study 1 resulted in a significant increase in mean C_max (treatment ratio 1.42; 90% CI: 1.33, 1.52) and mean AUC (treatment ratio 2.70; CI: 2.44, 2.97) compared with olaparib alone. Olaparib absorption was slightly slower in the presence of itraconazole (median [range] t_max, 1.50 [0.5–12] hours) vs olaparib alone (1.03 [0.5–8.25] hours). In Study 2, a significant decrease in olaparib bioavailability was observed when co-administered with rifampin (decrease of 71% in C_max [treatment ratio: 0.29; 90% CI: 0.24, 0.33] and 87% in AUC [0.13; 90% CI: 0.11, 0.16]) vs olaparib alone. Median t_max, was reduced in the presence of rifampin (0.78 [0.27–5.95] hours compared with 1.49 [0.57–3.05] hours for olaparib alone). In both studies, the majority of adverse events were of mild or moderate severity; safety data were consistent with the known safety profile of olaparib. Conclusions: It is recommended that potent CYP3A enzyme inhibitors (eg. itraconazole, telithromycin, clarithromycin, ketoconazole, voriconazole, nefazodone, posaconazole, ritinovir, lopinavir, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or inducers (eg. phenytoin, rifampin, carbamazepine, St John’s Wort) be avoided during olaparib treatment. Clinical trial information: NCT01929603