Dataset Information

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 (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.

SUBMITTER: Kotani N

PROVIDER: S-EPMC9637074 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Publications

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

Kotani Naoki N Wilkins Justin J JJ Wade Janet R JR Dang Steve S Sutaria Dhruvitkumar S DS Yoshida Kenta K Sundrani Sameer S Ding Hao H Garcia Josep J Hinton Heather H Sane Rucha R Chanu Pascal P

Cancer chemotherapy and pharmacology 20221028 6

<h4>Purpose</h4>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).<h4>Methods</h4>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 subjec ...[more]

PMID: 36305957

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Project description:BackgroundEnzalutamide is a novel antiandrogen with proven efficacy in metastatic castration-resistant prostate cancer (mCRPC).ObjectiveTo evaluate enzalutamide's effects on cancer and on androgens in blood and bone marrow, and associate these with clinical observations.Design, setting, and participantsIn this prospective phase 2 study, 60 patients with bone mCRPC received enzalutamide 160mg orally daily and had transilial bone marrow biopsies before treatment and at 8 wk of treatment.Outcome measurements and statistical analysisAndrogen signaling components (androgen receptor [AR], AR splice variant 7 (ARV7), v-ets avian erythroblastosis virus E26 oncogene homolog [ERG], cytochrome P450, family 17, subfamily A, polypeptide 1 [CYP17]) and molecules implicated in mCRPC progression (phospho-Met, phospho-Src, glucocorticoid receptor, Ki67) were assessed by immunohistochemistry; testosterone, cortisol, and androstenedione concentrations were assessed by liquid chromatography-tandem mass spectrometry; AR copy number was assessed by real-time polymerase chain reaction. Descriptive statistics were applied.Results and limitationsMedian time to treatment discontinuation was 22 wk (95% confidence interval, 19.9-29.6). Twenty-two (37%) patients exhibited primary resistance to enzalutamide, discontinuing treatment within 4 mo. Maximal prostate-specific antigen (PSA) decline ≥ 50% and ≥ 90% occurred in 27 (45%) and 13 (22%) patients, respectively. Following 8 wk of treatment, bone marrow and circulating testosterone levels increased. Pretreatment tumor nuclear AR overexpression (> 75%) and CYP17 (> 10%) expression were associated with benefit (p = 0.018). AR subcellular localization shift from the nucleus was confirmed in eight paired samples (with PSA decline) of 23 evaluable paired samples. Presence of an ARV7 variant was associated with primary resistance to enzalutamide (p = 0.018). Limited patient numbers warrant further validation.ConclusionsThe observed subcellular shift of AR from the nucleus and increased testosterone concentration provide the first evidence in humans that enzalutamide suppresses AR signaling while inducing an adaptive feedback. Persistent androgen signaling in mCRPC was predictive of benefit and ARV7 was associated with primary resistance.Patient summaryWe report a first bone biopsy study in metastatic prostate cancer in humans that searched for predictors of outcome of enzalutamide therapy. Benefit is linked to a pretreatment androgen-signaling signature.Trial registrationClinicalTrials.gov identifier NCT01091103.

Project description:ImportanceAbiraterone acetate and enzalutamide are recommended as preferred treatments for metastatic castration-resistant prostate cancer (mCRPC), but differences in their relative efficacy are unclear due to a lack of head-to-head clinical trials. Clear guidance is needed for making informed mCRPC therapeutic choices.ObjectiveTo compare clinical outcomes in patients with mCRPC treated with abiraterone acetate or enzalutamide.Design, setting, and participantsThis retrospective, multicenter cohort study included patients with mCRPC in the US Department of Veterans Affairs health care system who initiated treatment with abiraterone acetate or enzalutamide between January 1, 2014, and October 30, 2022.ExposuresAbiraterone acetate or enzalutamide.Main outcomes and measuresThe study used inverse probability of treatment weighting to balance baseline characteristics between patients initiating abiraterone acetate or enzalutamide and evaluated restricted mean survival time (RMST) differences in overall survival (OS), prostate cancer-specific survival (PCS), time to next treatment switching or death (TTS), and time to prostate-specific antigen (PSA) response (TTR) at different time points after treatment initiation.ResultsThe study included 5779 patients (median age, 74.42 years [IQR, 68.94-82.14 years]). Median follow-up was between 38 and 60 months. Patients initiating enzalutamide on average had longer OS than those initiating abiraterone acetate, with RMSTs of 24.29 months (95% CI, 23.58-24.99 months) and 23.38 months (95% CI, 22.85-23.92 months), respectively, and a difference in RMST of 0.90 months (95% CI, 0.02-1.79 months) at 4 years. Similarly, TTS and TTR were improved in patients initiating enzalutamide, with an RMST at 4 years of 1.95 months (95% CI, 0.92-2.99 months) longer for TTS and 3.57 months (95% CI, 1.76-5.38 months) shorter for TTR. For PCS, the RMST at 2 years was 0.48 months (95% CI, 0.01-0.95 months) longer. An examination of subgroups identified that enzalutamide initiation was associated with longer RMST in OS among patients without prior docetaxel treatment (1.14 months; 95% CI, 0.19-2.10 months) and in those with PSA doubling time of 3 months or longer (2.23 months; 95% CI, 0.81-3.66 months) but not among patients with prior docetaxel (-0.25 months; 95% CI, -2.59 to 2.09 months) or with PSA doubling time of less than 3 months (0.05 months; 95% CI, -1.05 to 1.15 months).Conclusions and relevanceIn this cohort study of patients with mCRPC, initiation of enzalutamide was associated with small but statistically significant improvements in OS, PCS, TTS, and TTR compared with initiation of abiraterone acetate. The improvements were more prominent in short-term outcomes, including TTS and TTR, and in patient subgroups without prior docetaxel or with PSA doubling time longer than 3 months.

Dataset Information

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

Purpose

Methods

Results

Conclusions

Publications

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

Similar Datasets

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