A clinically relevant decrease in abiraterone exposure associated with carbamazepine use in a patient with castration‐resistant metastatic prostate cancer

Benoist, Guillemette E.; Doelen, Maarten J. van der; Heine, Rob ter; Erp, Nielka P. van; Mehra, Niven

doi:10.1111/bcp.13532

Cited by 6 publications

(3 citation statements)

References 17 publications

(22 reference statements)

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“…Our results suggest that enzalutamide induces abiraterone metabolism, similar to other CYP3A4 inducers. 20,23 Although this drug-drug interaction may have limited the efficacy of the combination, toxicities were still significantly higher, suggesting that further dose escalation of abiraterone may not be well tolerated or acceptable, and only a dedicated dose-escalation trial of higher doses of abiraterone given with enzalutamide could address this.…”

Section: Discussionmentioning

confidence: 99%

Randomized Phase III Study of Enzalutamide Compared With Enzalutamide Plus Abiraterone for Metastatic Castration-Resistant Prostate Cancer (Alliance A031201 Trial)

Morris

Heller

Hillman

et al. 2023

JCO

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PURPOSE Enzalutamide and abiraterone both target androgen receptor signaling but via different mechanisms. The mechanism of action of one drug may counteract the resistance pathways of the other. We sought to determine whether the addition of abiraterone acetate and prednisone (AAP) to enzalutamide prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the first-line setting. PATIENTS AND METHODS Men with untreated mCRPC were randomly assigned (1:1) to receive first-line enzalutamide with or without AAP. The primary end point was OS. Toxicity, prostate-specific antigen declines, pharmacokinetics, and radiographic progression-free survival (rPFS) were also examined. Data were analyzed using an intent-to-treat approach. The Kaplan-Meier estimate and the stratified log-rank statistic were used to compare OS between treatments. RESULTS In total, 1,311 patients were randomly assigned: 657 to enzalutamide and 654 to enzalutamide plus AAP. OS was not statistically different between the two arms (median, 32.7 [95% CI, 30.5 to 35.4] months for enzalutamide v 34.2 [95% CI, 31.4 to 37.3] months for enzalutamide and AAP; hazard ratio [HR], 0.89; one-sided P = .03; boundary nominal significance level = .02). rPFS was longer in the combination arm (median rPFS, 21.3 [95% CI, 19.4 to 22.9] months for enzalutamide v 24.3 [95% CI, 22.3 to 26.7] months for enzalutamide and AAP; HR, 0.86; two-sided P = .02). However, pharmacokinetic clearance of abiraterone was 2.2- to 2.9-fold higher when administered with enzalutamide, compared with clearance values for abiraterone alone. CONCLUSION The addition of AAP to enzalutamide for first-line treatment of mCRPC was not associated with a statistically significant benefit in OS. Drug-drug interactions between the two agents resulting in increased abiraterone clearance may partly account for this result, although these interactions did not prevent the combination regimen from having more nonhematologic toxicity.

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Section: Discussionmentioning

confidence: 99%

Randomized Phase III Study of Enzalutamide Compared With Enzalutamide Plus Abiraterone for Metastatic Castration-Resistant Prostate Cancer (Alliance A031201 Trial)

Morris

Heller

Hillman

et al. 2023

JCO

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“…Few clinical studies have been conducted on the interaction between individual drugs and AA. One study ( Benoist et al, 2018 ) strongly recommended to replace carbamazepine (DS = −5) during AA treatment. In addition, among the other drugs with negative DS, insulin (−3) and spironolactone (−1) have also been shown to impair the efficacy of AA treatment ( Serrano Domingo et al, 2021 ; Vicente-Valor et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…Statins can increase the efficacy of AA treatment ( Harshman et al, 2017 ; Gordon et al, 2018 ; Wilson et al, 2022 ). Carbamazepine has an inverse effect, decreases the exposure to AA ( Benoist et al, 2018 ). Indomethacin reduces prostate cancer cell growth and improves the response to AA ( Liu et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

A new method to quantify the effect of co-medication on the efficacy of abiraterone in metastatic castration-resistant prostate cancer patients

Fekete,

Bársony,

Biró

et al. 2023

Front. Pharmacol.

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Background and Objective: Patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA) have co-morbidities treated with different drugs. The aim was to quantify the potential effect of co-medications on AA treatment duration (TD) and overall survival (OS).Methods: A new parameter, called “individual drug score” (IDS) was calculated by summing the “drug score”-s (DS) of all co-medications for each patient. The DS was determined by quantifying the effect of a given co-drug on enzymes involved in steroidogenesis and metabolism of AA. The correlation between log (IDS) and TD was tested by non-linear curve fit. Kaplan-Meier method and multivariate Cox regression was used for analysis of TD and OS.Results: The IDS and TD of AA+prednisolone showed a dose-response correlation (n = 166). Patients with high IDS had significantly longer TD and OS (p <0.001). In multivariate analysis IDS proved to be an independent marker of TD and OS. The same analysis was performed in a separate group of 81 patients receiving AA+dexamethasone treatment. The previously observed relationships were observed again between IDS and TD or OS. After combining the AA+prednisolone and AA+dexamethasone groups, analysis of the IDS composition showed that patients in the high IDS group not only used more drugs (p <0.001), but their drugs also had a higher mean DS (p = 0.001).Conclusion: The more co-drugs with high DS, the longer the duration of AA treatment and OS, emphasizing the need for careful co-medication planning in patients with mCRPC treated with AA. It is recommended that, where possible, co-medication should be modified to minimize the number of drugs with negative DS and increase the number of drugs with high DS. Our new model can presumably be adapted to other drugs and other cancer types (or other diseases).

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Impact of trough abiraterone level on adverse events in patients with prostate cancer treated with abiraterone acetate

Takahashi

Narita

Shiota

et al. 2022

Eur J Clin Pharmacol

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A clinically relevant decrease in abiraterone exposure associated with carbamazepine use in a patient with castration‐resistant metastatic prostate cancer

Cited by 6 publications

References 17 publications

Randomized Phase III Study of Enzalutamide Compared With Enzalutamide Plus Abiraterone for Metastatic Castration-Resistant Prostate Cancer (Alliance A031201 Trial)

Randomized Phase III Study of Enzalutamide Compared With Enzalutamide Plus Abiraterone for Metastatic Castration-Resistant Prostate Cancer (Alliance A031201 Trial)

A new method to quantify the effect of co-medication on the efficacy of abiraterone in metastatic castration-resistant prostate cancer patients

Impact of trough abiraterone level on adverse events in patients with prostate cancer treated with abiraterone acetate

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