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Poster display session: Breast cancer - early stage, locally advanced & metastatic, CNS tumours, Developmental therapeutics, Genitourinary tumours - prostate & non-prostate, Palliative care, Psycho-oncology, Public health policy, Sarcoma, Supportive care

1459 - Pharmacokinetic/Pharmacodynamic relationship of Enzalutamide and its active metabolite N-desmethyl Enzalutamide in metastatic castration-resistant prostate cancer patients

Date

22 Oct 2018

Session

Poster display session: Breast cancer - early stage, locally advanced & metastatic, CNS tumours, Developmental therapeutics, Genitourinary tumours - prostate & non-prostate, Palliative care, Psycho-oncology, Public health policy, Sarcoma, Supportive care

Topics

Cytotoxic Therapy

Tumour Site

Prostate Cancer

Presenters

Marie-Liesse Joulia

Citation

Annals of Oncology (2018) 29 (suppl_8): viii271-viii302. 10.1093/annonc/mdy284

Authors

M. Joulia1, E. Carton Vienet Legue1, M. Allard2, O. Huillard3, M. Peyromaure4, M. Zerbib4, M. Vidal2, F. Goldwasser1, J. Alexandre1, B. Blanchet2

Author affiliations

  • 1 Medical Oncology, Hôpital Cochin, 75014 - Paris/FR
  • 2 Clinical Pharmacology, Hôpital Cochin, 75014 - Paris/FR
  • 3 Medical Oncology, Hôpital Cochin, 75679 - Paris/FR
  • 4 Urology, Hôpital Cochin, 75014 - Paris/FR
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Resources

Abstract 1459

Background

Enzalutamide (ENZA) is an oral androgen receptor inhibitor approved for the treatment of metastatic Castration-Resistant Prostate Cancer (mCRPC). ENZA is extensively metabolized by CYP 3A4 into N-desmethyl enzalutamide (NDE). Based on in vitro assays, NDE has been identified as pharmacologically active metabolite. We aimed to explore the relationship between ENZA, NDE plasma concentration and progression-free survival (PFS) in mCRPC.

Methods

Trough plasma concentrations of ENZA and NDE were measured at steady-state one month after treatment start, using liquid chromatography. Trough ENZA and NDE plasma concentrations were dichotomized into 2 groups (high and low) according to their median value. Progression was defined as clinical progression, PSA increase or imaging progression according to the prostate working group criteria 3 or death. A survival analysis was used to explore relationship between PFS and plasma drug exposure.

Results

From January 2015 to May 2017, 18 mCRPC patients treated with ENZA (median age 77.5 years, Interquartile range (IQR) 67.2-82.7) were prospectively included. Median follow-up was 10.6 months (ms) (IQR 5.1-21.3 ms). Median trough plasma concentration of ENZA and NDE were 10.5 ± 3.7 µg/mL (Coefficient of variation (CV) = 33.8%; IQR 8.2-13.2) and 8.1 ± 4.2 µg/mL (CV = 52.7%; IQR 5,4-10,1), respectively. Pearson correlation coefficient value was 0,3 (p = 0.21). Eleven patients (61%) achieved a PSA response. Median PFS in the whole cohort was 11.2 ms (IQR 3.4-12.4). High trough plasma concentration of ENZA was associated with a shorter PFS (9 ms vs 22.6 ms respectively in the high and the low group) (Hazard Ratio (HR) 0.2; 95% CI 0.04-0.57; p = 0.005). Conversely, a high trough plasma concentration of NDE was associated with a longer PFS: 12,8 ms vs 7.2 ms respectively in the high and low group (HR 3.04; 95% CI 1.19-48.45; p = 0.03).

Conclusions

Overall, these results suggest that NDE could be more pharmacologically active than ENZA in vivo. Plasma monitoring of ENZA and NDE could lead to early identification of patients who will not benefit from ENZA as well as to optimize their treatment choice.

Clinical trial identification

Legal entity responsible for the study

Department of Medical Oncology, Cochin Hospital, Paris Descartes University, Pr Goldwasser.

Funding

Has not received any funding.

Editorial Acknowledgement

Disclosure

O. Huillard: Consultant/advisor: Astellas Pharma, Sanofi, Janssen Oncology, Bristol-Myers Squibb; Travel, accommodations reimburse: Roche/Genentech, Astellas Pharma, Pfizer; Sanofi. F. Goldwasser: Consultant/advisor: Fresenius Kabi, Baxter. J. Alexandre: Consultant/advisor: Novartis, Roche; Honoraria: Novartis, AstraZeneca, Roche, Ipsen; Research funding: Jansen; Travel, accommodations reimburse: Jansen. All other authors have declared no conflicts of interest.

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