Abstract 4929: A PK/PD study of Delta-4 abiraterone metabolite in metastatic castration-resistant prostate cancer patients
Authors: Blanchet Benoit , Carton Edith , Alyamani Mohammad , Golmard Lisa , Huillard Olivier , Thomas Audrey , Vidal Michel , Goldwasser Francois , Sharifi Nima , Alexandre Jerome 
Published: August 2018

Background : Abiraterone (ABI), a steroidal CYP17A1 inhibitor, blocks the DHT synthesis from adrenal precursor steroids in castration resistant prostate cancer (mCRPC) patients. ABI is converted by 3β-hydroxysteroid dehydrogenase (HSD3B) into D4-abiraterone (D4-ABI). In a previous preclinical study, D4-ABI was shown to block multiple steroidogenic enzymes and antagonize the androgen receptor. Besides, it appeared more active than ABI itself (Li Z et al. Nature 2015). However, the contribution of D4-ABI to the clinical antitumoral activity of abiraterone acetate in men with mCRPC remains unknown.

Methods : From 12/2012 to 10/2014, 61 consecutive mCRPC patients were treated with ABI (1000 mg, once daily) concomitantly with 10 mg of prednisone (Carton et al Eur J Cancer 2017). The study population represents a subgroup of these patients for whom trough plasma ABI and D4-ABI concentrations were assayed using liquid chromatography with fluorescence detection and LC/MS/MS, respectively. The trough plasma concentration of ABI and D4-ABI was assayed one (M1), two (M2) and three (M3) months after treatment initiation. ABI and D4-ABI Cmin were defined as the mean of trough concentrations measured during the first 3 months of treatment. This prospective analysis was in compliance with the Declaration of Helsinki and approved by the local medical ethical board (N°9166). All patients gave their written informed consent to participate in the study.

Results : Thirty-six mCRPC patients were included. Mean plasma ABI and D4-ABI Cmin were 12.6 ± 6.8 ng/mL (coefficient of variation, CV= 54.0%) and 1.6 ± 1.3 ng/mL (CV= 81.3%), respectively. Intra-individual variability for ABI and D4-ABI Cmin was 23.8% and 60.7%, respectively. The mean metabolic ratio (D4-ABI / ABI) was of 0.18 ± 0.25 (CV=140.4%). In regards with in vitro data previously reported for IC50% of ABI and D4-ABI, we estimated that total plasma Cmin enabled to achieve these IC50% in 30 patients (83.3%) and only 2 patients (5.6%), respectively. The univariate Cox proportional-hazard regression model showed that higher D4-ABI Cmin was associated with shorter OS (Hazard ratio, HR 1.54; CI95% 1.06-2.22; p=0.022) but not with PFS. As previously reported, patients with ABI Cmin &gt;8.3 ng/mL exhibited a longer PFS than patients underexposed (322 vs 237 days, p=0.05). The HR associated with the metabolic D4-ABI / ABI ratio for PFS and OS were 7.80 (CI 95% 1.63-37.38; p = 0.010) and 12.52 (CI 95% 1.95-80.47, p = 0.0078), respectively. 

Conclusion : It is unlikely that pharmacologic activity of D4-ABI contributes significantly to abiraterone acetate clinical activity for a daily dosing of 1,000 mg. The poor prognosis of higher D4-ABI Cmin / ABI Cmin ratio could be further in relation with a high activity of HSD3B1 enzyme which drive castration resistance by enhancing the DHT synthesis from non-gonadal precursors.

Citation Format: Benoit Blanchet, Edith Carton, Mohammad Alyamani, Lisa Golmard, Olivier Huillard, Audrey Thomas, Michel Vidal, Francois Goldwasser, Nima Sharifi, Jerome Alexandre. A PK/PD study of Delta-4 abiraterone metabolite in metastatic castration-resistant prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4929.