Exposure-Response-based Product-Profile-driven Clinical Utility Index for Ipatasertib Dose Selection in Prostate Cancer.

The aims of this work were to characterize ipatasertib exposure-response (E-R) relationships in a phase II study and to quantitatively assess benefit-risk using a clinical utility index (CUI) approach to support ipatasertib phase III dose selection in patients with metastatic castration-resistant prostate cancer (mCRPC). Logistic regression and Cox proportional-hazards models characterized E-R relationships for safety and efficacy endpoints, respectively. Exposure metrics with and without considering dose interruptions/reductions (modifications) were tested in the E-R models. Despite a steeper E-R relationship when accounting for dose modifications, similar dose-response projections were generated. The CUI analysis assessed important attributes, weights, and clinically-meaningful cutoff/tradeoff values based on pre-defined minimal, target, and optimistic Product Profiles (PP). Ipatasertib 400 mg daily, showing the highest probability of achieving the minimal PP and better benefit-risk balance than other doses (200 - 500 mg daily), was selected for further development in mCRPC. This article is protected by copyright. All rights reserved.