Journal
CANCER CHEMOTHERAPY AND PHARMACOLOGY
Volume 90, Issue 6, Pages 511-521Publisher
SPRINGER
DOI: 10.1007/s00280-022-04488-2
Keywords
Ipatasertib; AKT inhibitor; Metastatic castration-resistant prostate cancer; IPATential150; Exposure-response
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Funding
- Genentech Inc., a member of the Roche group
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This study evaluated the efficacy and safety of ipatasertib, a selective AKT kinase inhibitor, in patients with metastatic castration-resistant prostate cancer. The results showed a significant correlation between ipatasertib exposure and improved survival, as well as an increased risk of adverse events with ipatasertib treatment and/or increased exposure. Despite variability in exposure, patients receiving ipatasertib treatment may continue to benefit from this therapy.
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.
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