Characterization of exposure-response relationships of ipatasertib in patients with metastatic castration-resistant prostate cancer in the IPATential150 study.
Cancer Chemother Pharmacol
; 90(6): 511-521, 2022 Dec.
Article
em En
| MEDLINE
| ID: mdl-36305957
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piperazinas
/
Pirimidinas
/
Neoplasias de Próstata Resistentes à Castração
Tipo de estudo:
Prognostic_studies
Limite:
Humans
/
Male
Idioma:
En
Revista:
Cancer Chemother Pharmacol
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos