Characterization of exposure-response relationships of ipatasertib in patients with metastatic castration-resistant prostate cancer in the IPATential150 study
Naoki Kotani, Justin J Wilkins, Janet R Wade, Steve Dang, Dhruvitkumar S Sutaria, Kenta Yoshida, Sameer Sundrani, Hao Ding, Josep Garcia, Heather Hinton, Rucha Sane, Pascal Chanu, Naoki Kotani, Justin J Wilkins, Janet R Wade, Steve Dang, Dhruvitkumar S Sutaria, Kenta Yoshida, Sameer Sundrani, Hao Ding, Josep Garcia, Heather Hinton, Rucha Sane, Pascal Chanu
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).
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References
- Blake JF, Xu R, Bencsik JR, et al. Discovery and preclinical pharmacology of a selective ATP-competitive Akt inhibitor (GDC-0068) for the treatment of human tumors. J Med Chem. 2012;55(18):8110–8127. doi: 10.1021/jm301024w.
- Lin K, Lin J, Wu WI, et al. An ATP-site on-off switch that restricts phosphatase accessibility of Akt. Sci Signal. 2012;5:ra37. doi: 10.1126/scisignal.2002618.
- Robinson D, Van Allen EM, Sawyers CL, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161:1215–1228. doi: 10.1016/j.cell.2015.05.001.
- Yoshimoto M, Cunha IW, Coudry RA, et al. FISH analysis of 107 prostate cancers shows that PTEN genomic deletion is associated with poor clinical outcome. Br J Cancer. 2007;97(5):678–685. doi: 10.1038/sj.bjc.6603924.
- Reid AHM, Attard G, Ambroisine L, et al. Molecular characterisation of ERG, ETV1 and PTEN gene loci identifies patients at low and high risk of death from prostate cancer. Br J Cancer. 2010;102(4):678–684. doi: 10.1038/sj.bjc.6605554.
- Antonarakis ES, Keizman D, Zhang Z, et al. An immunohistochemical signature comprising PTEN, MYC, and Ki67 predicts progression in prostate cancer patients receiving adjuvant docetaxel after prostatectomy. Cancer. 2012;118:6063–6071. doi: 10.1002/cncr.27689.
- Chaux A, Peskoe SB, Gonzalez-Roibon N, et al. Loss of PTEN expression is associated with increased risk of recurrence after prostatectomy for clinically localized prostate cancer. Mod Pathol. 2012;25:1543–1549. doi: 10.1038/modpathol.2012.104.
- Zafarana G, Ishkanian AS, Malloff CA, et al. Copy number alterations of c-MYC and PTEN are prognostic factors for relapse after prostate cancer radiotherapy. Cancer. 2012;118:4053–4062. doi: 10.1002/cncr.26729.
- Cuzick J, Yang ZH, Fisher G, et al. Prognostic value of PTEN loss in men with conservatively managed localised prostate cancer. Br J Cancer. 2013;108:2582–2589. doi: 10.1038/bjc.2013.248.
- Barnett CM, Heinrich MC, Lim J. Genetic profiling to determine risk of relapse free survival in high-risk localized prostate cancer. Clin Cancer Res. 2014;20:1306–1312. doi: 10.1158/1078-0432.CCR-13-1775.
- Ferraldeschi R, Nava Rodrigues D, Riisnaes R, et al. PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate. Eur Urol. 2015;67(4):795–802. doi: 10.1016/j.eururo.2014.10.027.
- Kim SH, Kim SH, Joung JY, et al. Overexpression of ERG and wild-type PTEN are associated with favorable clinical prognosis and low biochemical recurrence in prostate cancer. PLoS One. 2015;10:e0122498. doi: 10.1371/journal.pone.0122498.
- de Bono JS, De Giorgi U, Rodrigues DN, et al. Randomized Phase II Study Evaluating Akt Blockade with Ipatasertib, in Combination with Abiraterone, in Patients with Metastatic Prostate Cancer with and without PTEN Loss. Clin Cancer Res. 2019;25(3):928–936. doi: 10.1158/1078-0432.CCR-18-0981.
- Zhu R, Poland B, Wada R, et al. Exposure-response-based product profile-driven clinical utility index for ipatasertib dose selection in prostate cancer. CPT Pharmacometr Syst Pharmacol. 2019;8(4):240–248. doi: 10.1002/psp4.12394.
- Sweeney C, Bracarda S, Sternberg CN, et al. Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2021;398(10295):131–142. doi: 10.1016/S0140-6736(21)00580-8.
- Yoshida K, Wilkins J, Winkler J, et al. Population pharmacokinetics of ipatasertib and its metabolite in cancer patients. J Clin Pharmacol. 2021 doi: 10.1002/jcph.1942.
- Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer. 2009;45:228–247. doi: 10.1016/j.ejca.2008.10.026.
- Scher HI, Morris MJ, Stadler WM, et al. Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016;34:1402–1418. doi: 10.1200/JCO.2015.64.2702.
- Beal SL, Sheiner LB, Boeckmann AJ, Bauer RJ. NONMEM users’ guides. Ellicott City: ICON Development Solutions; 2016.
- Lindbom L, Ribbing J, Jonsson EN. Perl-speaks-NONMEM (PsN)—a Perl module for NONMEM related programming. Comput Methods Programs Biomed. 2004;75(2):85–94. doi: 10.1016/j.cmpb.2003.11.003.
- Lindbom L, Pihlgren P, Jonsson EN. PsN-Toolkit–a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Programs Biomed. 2005;79(3):241–257. doi: 10.1016/j.cmpb.2005.04.005.
Source: PubMed