Lessons learned from the metastatic castration-resistant prostate cancer phase I trial of EPI-506, a first-generation androgen receptor N-terminal domain inhibitor.

Abstract

257 Background: Aniten compounds bind to the N-terminal domain (NTD) of the androgen receptor (AR) and inhibit AR dependent transcription. EPI-506, the pro-drug of EPI-002, was the first AR NTD inhibitor tested in a Phase 1 study in men with metastatic castration-resistant prostate cancer (mCRPC). The drug was well-tolerated but required high doses. At doses >1280 mg, EPI-506 treatment resulted in PSA declines; however, these were minor and of short duration, reflecting EPI-506’s low potency and short half-life. To understand EPI-506’s metabolic vulnerabilities, patient plasma samples were analyzed to identify metabolites. Methods: PSA serum levels were assessed after a month of dosing. Patient plasma samples were analyzed and pharmacokinetic (PK) parameters calculated. Three plasma samples from patients (one 80 and two 3,600 mg doses), were pooled across timepoints and metabolites were analyzed. EPI-506 metabolism was assessed in in vitro ADME assays and metabolite activity was measured. Results: EPI-002 patient plasma profiles exhibited dose-proportional Cmax and AUC following once or twice-daily EPI-506 administration. PSA declines (range of 8-29%) were observed, especially at higher doses (≥ 1,280 mg). A total of 19 metabolites were identified. Metabolite M19, a glycerol-moiety oxidant, was the major drug-related component. Other metabolic pathways included O-glucuronidation, sulfation, carboxylic acid formation, and oxidative chlorine loss. The major metabolites were tested in an AR driven reporter assay and were shown to be inactive. Interestingly, in vitro ADME assays predicted glucuronidation and sulfation but not cytochrome dependent metabolism. Conclusions: EPI-506 was tested in a phase 1 trial and showed minor PSA declines. The drug was well-tolerated but was highly metabolized. Patient plasma samples identified 19 metabolites. Newer molecules have been synthesized to address EPI-002’s metabolic liabilities and demonstrate > 20-fold improved potency and higher stability. These next generation Anitens are currently being characterized for IND filing. Clinical trial information: NCT02606123.

The Androgen Receptor in Prostate Cancer: Effect of Structure, Ligands and Spliced Variants on Therapy

“…In vivo, it prevents tumor growth in AR-expressing xenograft models with limited toxicities [ 108 ].The most potent stereoisomer, EPI-002, was developed into a prodrug, EPI-506, which was the first AR NTD inhibitor tested in a Phase 1 study in men with CRPC. The drug was well-tolerated but required high doses (>1280 mg) to achieve minor and transient PSA declines, reflecting EPI-506′s low potency and short half-life [ 110 , 111 ]. A newer molecule, EPI-7386, synthesized from EPI-002 demonstrates >20-fold improved potency and higher stability [ 112 ] ( Figure 6 ).…”

Development of an Androgen Receptor Inhibitor Targeting the N-Terminal Domain of Androgen Receptor for Treatment of Castration Resistant Prostate Cancer

“…Work by Sadar and Andersen demonstrated that despite the disorder, small molecule NTD inhibitors can be developed against this challenging target [ 9 , 10 , 11 ]. From these compounds, EPI-506 progressed into clinical trials for metastatic CRPC but was terminated due to poor pharmacokinetics that necessitated a very high pill burden [ 12 ]. However, even with low levels of circulating EPI-506, there was partial pharmacodynamic efficacy with a 4–29% decrease in PSA, an AR regulated gene.…”

Anti-Androgen Receptor Therapies in Prostate Cancer: A Brief Update and Perspective

“…Although the older EPI compounds did not affect AR protein levels (the full length and AV variants), the new analog EPI-7170 suppressed AR-V7 expression in CRPC cells ( 138 ). EPI-002 (commercial name Ralaniten) is one of the four EPI-001 stereoisomers, and its pro-drug EPI-506 (Ralaniten acetate) was failed in a phase-I clinical trial due to excessive pill burden and poor oral bioavailability ( 139 , 140 ). The newest analog, EPI-7386, showed 20-fold higher anti-androgenic potency than Ralaniten ( 141 ), and it is being tested in clinical trials in combination with Enzalutamide (NCT05075577/NCT04421222).…”