Olaparib plus abiraterone as first-line therapy in men with metastatic castration-resistant prostate cancer: Pharmacokinetics data from the PROpel trial.

Abstract

5050 Background: PROpel (NCT03732820) is a double-blind, Phase III trial of abiraterone + olaparib vs abiraterone + placebo as first-line treatment in patients with metastatic castration-resistant prostate cancer (mCRPC). Here we report results from the pharmacokinetics (PK) analysis of patients in PROpel. Methods: Patients were randomized 1:1 to receive abiraterone (1000 mg qd) plus prednisone/prednisolone with either olaparib (full monotherapy dose: 300 mg bid) or placebo. Eligible patients were biomarker unselected with confirmed prostate adenocarcinoma and castration-resistant metastatic disease. They had not received prior chemotherapy or next-generation hormonal agents (NHAs) for mCRPC. PK sampling was performed in a subset of patients. Concentrations of olaparib and abiraterone, and its active metabolite Δ4-abiraterone, were measured at steady state predose, at 30 min, 2 h, 3 h, 5 h, and 8 h postdose. The data underwent noncompartmental analysis to evaluate the effect of olaparib on abiraterone PK. The PK of olaparib in the presence of abiraterone was also compared with olaparib PK from other monotherapy studies to evaluate the effect of abiraterone on olaparib PK. Results: The PK analysis included 66 patients from the olaparib + abiraterone arm and 58 patients from the placebo + abiraterone arm. Olaparib absorption was rapid, with median tmax,ss of 2 h. Absorption of abiraterone was rapid in both treatment groups, with median tmax,ss observed between 2.00 and 2.04 h. The steady state exposure of olaparib in the presence of abiraterone, based on AUCss, Cmax,ss and Cmin,ss, was similar to observations for patients receiving olaparib 300 mg bid monotherapy in other Phase III studies, with values of 39.3 μg⋅h/mL, 6.3 μg/mL, and 1.0 μg/mL, respectively. Steady state exposures for abiraterone were similar between the two treatment arms (abiraterone + placebo: AUC(0–8) = 339.5 ng⋅h/mL, Cmax,ss = 105.4 ng/mL, Cmin,ss = 8.5 ng/mL; abiraterone + olaparib: AUC(0–8) = 393.7 ng⋅h/mL, Cmax,ss = 112.6 ng/mL, Cmin,ss = 7.7 ng/mL), and PK data for the abiraterone + olaparib arm were similar to those reported in the literature for abiraterone monotherapy. Conclusions: Combination treatment of olaparib ( full monotherapy dose: 300 mg bid) and abiraterone (1000 mg qd) in patients with mCRPC had no clinically significant effect on the PK profiles of either drug. The steady state exposures for abiraterone were similar between the two treatment arms, indicating that co-administration with olaparib 300 mg bid has no effect on the PK of abiraterone. In line with previous Phase II trial data, results from PROpel confirmed that there were no relevant PK based drug–drug-interactions between olaparib and abiraterone. Clinical trial information: NCT03732820.