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

Autor: Kotani N; Genentech, Inc., South San Francisco, CA, USA. kotani.naoki47@chugai-pharm.co.jp.; Pharmaceutical Science Department, Chugai Pharmaceutical Co., Ltd., 1-1 Nihonbashi-Muromachi 2-Chome, Chuo-ku, Tokyo, 103-8324, Japan. kotani.naoki47@chugai-pharm.co.jp., Wilkins JJ; Occams Coöperatie UA, Amstelveen, The Netherlands., Wade JR; Occams Coöperatie UA, Amstelveen, The Netherlands., Dang S; Genentech, Inc., South San Francisco, CA, USA., Sutaria DS; Genentech, Inc., South San Francisco, CA, USA., Yoshida K; Genentech, Inc., South San Francisco, CA, USA., Sundrani S; Genentech, Inc., South San Francisco, CA, USA.; Department of Bioengineering/Biomedical Computation, Stanford University, Stanford, CA, USA., Ding H; Genentech, Inc., South San Francisco, CA, USA., Garcia J; F. Hoffmann-La Roche AG, Basel, Switzerland., Hinton H; F. Hoffmann-La Roche AG, Basel, Switzerland., Sane R; Genentech, Inc., South San Francisco, CA, USA., Chanu P; Department of Clinical Pharmacology, Genentech/Roche, Lyon, France.
Jazyk: angličtina
Zdroj: Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2022 Dec; Vol. 90 (6), pp. 511-521. Date of Electronic Publication: 2022 Oct 28.
DOI: 10.1007/s00280-022-04488-2
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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