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 (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.

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

Conflict of interest statement

Naoki Kotani is a current employee of Chugai Pharmaceutical Co., Ltd. and was working at Genentech, Inc. at the time of this study. Steve Dang, Dhruvitkumar S. Sutaria, Kenta Yoshida, Hao Ding, Rucha Sane and Pascal Chanu are current employees of either Genentech, Inc. (a member of the Roche group) or Roche and own stock in F. Hoffman-La Roche. Sameer Sundrani was working at Genentech, Inc. at the time of this study. Josep Garcia and Heather Hinton are current employees of F. Hoffmann-La Roche AG and own stock in F. Hoffman-La Roche. Justin J. Wilkins and Janet R. Wade are salaried employees of Occams, which was contracted by Genentech.

© 2022. The Author(s).

Figures

Fig. 1

Distributions of the simulated ipatasertib AUCSS in the IPATential150 study population by AUCSS quartile (left panel) or as overall (right panel). Filled circles represent the simulated exposure of individual patients. Annotations represent medians in each group. Solid bold lines, shaded boxes, and whiskers in the box plots represent the medians, interquartile ranges, and 1.5 times the interquartile range, respectively. AUCSS area under the concentration–time curve at steady state, AUCSSQ AUCSS Quartiles

Fig. 2

Kaplan–Meier plot for rPFS by ipatasertib AUCSS quartile in patients with PTEN-loss tumors only in the IPATential150 study. The ipatasertib AUCSS ranges in each quartile group were 631–2850 ng h/mL for Q1, 2850–3470 ng h/mL for Q2, 3490–4250 ng h/mL for Q3, and 4290–10,500 ng h/mL for Q4. AUCSS area under the concentration–time curve at steady state, rPFS radiographic progression-free survival

Fig. 3

Forest plots for rPFS (point estimates and 95% CIs of HR) including all covariates of interest (A) and after stepwise reduction (i.e., final model; B) in patients with PTEN-loss tumors only in the IPATential150 study. AUCSS area under the concentration–time curve at steady state, CI confidence interval; CSS trough concentration at steady state, HR hazard ratio, rPFS radiographic progression-free survival

Fig. 4

Bootstrapped model predictions (n = 1000) of relationship between ipatasertib exposure and safety endpoints in which ipatasertib exposure was retained in the final exposure–safety model (A SAE, B AE leading to discontinuation, C Grade ≥ 2 hyperglycemia). AE adverse event, AUCSS area under the concentration–time curve at steady state, SAE serious adverse event