EPI-506 (ralaniten acetate), a novel androgen receptor (AR) N-terminal domain (NTD) inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC): Phase 1 update on safety, tolerability, pharmacokinetics and efficacy

Background: EPI-506 (ralaniten acetate) is being studied in a Phase 1/2 study as a first-in-class transcription inhibitor of the AR NTD. Methods: Open-label, single-arm, Phase 1/2 study evaluating EPI-506 administered orally. The Phase 1 is a modified 3 + 3 design to establish safety, tolerability, pharmacokinetics (PK), maximum-tolerated-dose (MTD) and the recommended phase 2 dose (RP2D) of EPI-506. Anti-tumor activity is evaluated by PSA and imaging. Inclusion criteria include: mCRPC with progression after > =1 line of hormonal therapy or chemotherapy, failure to treatment with enzalutamide and/or abiraterone. Results: Twenty-one patients (pts) have been enrolled in the dose escalation phase over 6 dose levels (80 - 2,400 mg). Median age was 72 (range 58-87). Prior treatments included enzalutamide only (N = 9), abiraterone only (N = 3) or both (N = 9). Eight pts also had prior chemotherapy. Twelve pts discontinued due to disease progression and 2 pts due to adverse events (AEs): Grade 4 elevated amylase (probably related; at 640mg) and Grade 4 gastrointestinal bleeding (unrelated). Median exposure was 87 days at cut-off (range 21-418). Most frequently reported treatment emergent AEs were diarrhea (N = 8), nausea (N = 6), and pain in extremities (N = 5). One possibly related Grade 3 AE (AST elevation) was observed at 1280 mg. PK data demonstrate a dose-proportional profile for Cmax and AUC together with a positive food effect above 640 mg. Three of 21 evaluable pts demonstrated PSA declines ranging from 4 – 29%, and one pt with unchanged PSA at doses >1,280 mg. Three pts have had prolonged treatment (median of 286 days; range 219 – not reached), after intrapatient dose escalation. The study is currently enrolling pts with a total dose of 3,600 mg in both a QD and a BID dosing schedule. Conclusions: EPI-506 is well-tolerated with an acceptable safety profile. PK indicates dose-proportionality. PSA declines and stable disease have been observed at higher dose cohorts in this ongoing study. This study is the first to evaluate targeting the AR NTD, a region critical for transcriptional function of all known AR species. Clinical trial identification: NCT02606123 Legal entity responsible for the study: ESSA Pharmaceuticals Funding: ESSA Pharmaceuticals Disclosure: U. Vaishampayan, M.S. Gordon, D.C. Smith: ESSA Pharmaceuticals Corp. (Research funding) R.B. Montgomery, K.N. Chi: ESSA Pharmaceuticals Corp. (Scientific advisory board; Honoraria received; Research funding). K. Barber, F. Perabo, N. Thapar, C. Chandhasin: ESSA Pharmaceuticals Corp. (Employed, Ownership interest). A. de Haas-Amatsaleh: ESSA Pharmaceuticals Corp. (Consultant).