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

Abstract

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 (AUCSS). 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 AUCSS and improved survival was found in patients with PTEN-loss tumors (hazard ratio [HR]: 0.92 per 1000 ng h/mL AUCSS, 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 AUCSS in the intention-to-treat population. Incidences of some adverse events (AEs) had statistically significant association with ipatasertib AUCSS (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.