Pharmacokinetic (PK) effects and safety of olaparib in combination with tamoxifen, anastrozole, or letrozole: Phase I study.

2562 Background: The PARP inhibitorolaparib (Lynparza) is being evaluated in combination with other anticancer agents. We investigated the steady-state (ss) PK effects and safety of olaparib (tablet) co-administered with the anti-hormonal agents tamoxifen, anastrozole, or letrozole. Methods: An open-label, nonrandomized study was conducted in 79 eligible patients with advanced solid tumors. During three consecutive treatment periods, patients received: (1) olaparib 300 mg twice daily (bd) for 5 days, followed by a 4-day washout period; (2) either tamoxifen 60 mg once daily (qd) for 4 days (loading dose) then 20 mg qd to day 26 (n=30), or anastrozole 1 mg qd to day 19 (n=23), or letrozole 2.5 mg qd to day 38 (n=26); (3) same as treatment period 2 concomitantly with olaparib 300 mg bd for 5 days. Blood samples for PK analysis were taken at ss. Safety was monitored throughout. Results: Olaparib AUC0-t and Cmax decreased by 27% and 20%, respectively, when co-administered with tamoxifen. Anastrozole and letrozole had no relevant impact on ss exposure to olaparib. Olaparib had minimal effects on ss exposure to tamoxifen, anastrozole or letrozole. Most AEs were of mild or moderate severity and as expected in this patient population. Conclusions: Exposure to olaparib decreased slightly when given with tamoxifen; tamoxifen exposure increased slightly when given with olaparib. These effects were considered unlikely to be clinically significant and no dose adjustments for either drugare required. There were no drug interactions between olaparib and letrozole or anastrozole. Safety data were consistent with the known safety profiles of study drugs. Clinical trial information: NCT02093351.Comparison Reference boundary* Cmax GLS mean ratio AUC0-t GLS mean ratio Point estimate 90% CI Point estimate 90% CI T + O vs O 0.7–1.43 0.80 0.71–0.90 0.73 0.63–0.84 A + O vs O 0.7–1.43 0.94 0.84–1.04 0.89 0.76–1.05 L + O vs O 0.7–1.43 1.09 0.99–1.21 1.15 1.07–1.25 T + O vs T 0.7–1.43 1.13 1.06–1.22 1.16 1.11–1.21 A + O vs A 0.8–1.25 0.90 0.84–0.97 0.86 0.80–0.93 L + O vs L 0.8–1.25 0.94 0.91–0.98 0.95 0.91–0.99 *90% CIs falling within this boundary indicate lack of interaction. Abbreviations: O, olaparib; T, tamoxifen; A, anastrozole; L, letrozole; GLS, geometric least squares.