Olaparib does not cause clinically relevant QT/QT c interval prolongation in patients with advanced solid tumours: results from two phase I studies

Background Some therapeutic agents in oncology can be causally associated with specific cardiovascular events including QT/QT c interval prolongation. We investigated the effect of multiple dosing of the oral poly (ADP-ribose)-polymerase (PARP) inhibitor, olaparib (tablet formulation) on QT/QT c interval. Methods Two phase I, open-label, three-part studies (NCT01921140 [study 4] and NCT01900028 [study 7]) were conducted in adults with refractory/resistant advanced solid tumours. In both studies, parts A and B assessed the QT/QT c interval effects of single-dose oral olaparib 100 (study 4) or 300 (study 7) mg and multiple-dose olaparib 300 mg bid for 5 days, respectively, while part C evaluated continued access to olaparib for additional safety analyses. An ANCOVA model tested the primary objective of multiple-dose effects of olaparib on QT interval corrected using Fridericia’s formula (QT c F). Results Data from 119 and 109 patients were pooled from parts A and B, respectively, for QT/QT c analysis. At pre-dose and up to 12 h post-dose, the upper limits of the 90 % confidence intervals (CIs) for the difference in QT c F least squares means after olaparib multiple dosing versus control (day −1) were <10 ms, suggesting a lack of clinically relevant effect on cardiac repolarization. A slight shortening of QT c F was observed at most time points versus control. QT c F results for the individual studies and single-dose olaparib paralleled the primary multiple-dose pooled analysis, with upper limits of the 90 % CIs < 10 ms. Conclusion Olaparib tablets administered as multiple or single doses had no clinically significant effect on QT/QT c interval.