Characterization of exposure-response relationships of ipatasertib in patients with metastatic castration-resistant prostate cancer in the IPATential150 study

Abstract

Purpose: The exposure-response relationships for efficacy and safety of ipatasertib, a selective AKT kinase inhibitor, were characterized using data collected from 1101 patients with metastatic castration-resistant prostate cancer in the IPATential150 study (NCT03072238).

Methods: External validation of a previously developed population pharmacokinetic model was performed using the observed pharmacokinetic data from the IPATential150 study. Exposure metrics of ipatasertib for subjects who received ipatasertib 400 mg once-daily orally in this study were generated as model-predicted area under the concentration-time curve at steady state (AUC_SS). The exposure-response relationship with radiographic progression-free survival (rPFS) was evaluated using Cox regression and relationships with safety endpoints were assessed using logistic regression.

Results: A statistically significant correlation between ipatasertib AUC_SS and improved survival was found in patients with PTEN-loss tumors (hazard ratio [HR]: 0.92 per 1000 ng h/mL AUC_SS, 95% confidence interval [CI] 0.87-0.98, p = 0.011). In contrast, an improvement in rPFS was seen in subjects receiving ipatasertib treatment (HR: 0.84, 95% CI 0.71-0.99, p = 0.038) but this effect was not associated with ipatasertib AUC_SS in the intention-to-treat population. Incidences of some adverse events (AEs) had statistically significant association with ipatasertib AUC_SS (serious AEs, AEs leading to discontinuation, and Grade ≥ 2 hyperglycemia), while others were associated with only ipatasertib treatment (AEs leading to dose reduction, Grade ≥ 3 diarrhea, and Grade ≥ 2 rash).

Conclusions: The exposure-efficacy results indicated that patients receiving ipatasertib may continue benefiting from this treatment at the administered dose, despite some variability in exposures, while the exposure-safety results suggested increased risks of AEs with ipatasertib treatment and/or increased ipatasertib exposures.

Keywords: AKT inhibitor; Exposure–response; IPATential150; Ipatasertib; Metastatic castration-resistant prostate cancer.