ASCO 2017: Efficacy, safety, tolerability, and pharmacokinetics of EPI-506 (ralaniten acetate), a novel androgen receptor N-terminal domain (NTD) inhibitor, in men with metastatic castration-resistant prostate cancer progressing after enzalutamide and/or

Chicago, IL ( While the introduction of enzalutamide (Enza) and abiraterone (Abi) have revolutionized the management of castration-resistant prostate cancer (CRPC), the influx of drugs targeted the androgen axis has subsequently led to the identification of new resistance mechanisms.1 The androgen-receptor variants (ARV), specifically ARV-7, are variants in which the ligand-binding domain is typically lost, resulting in a constitutively active AR, independent of androgens.

The presence of ARV-7 has been demonstrated to be associated with Enza and Abi resistance, as these agents work on the ligand binding domain or androgen production.

Epi-506 (ralaniten acetate) is a novel agent that targets the N-terminus of the AR, which is preserved in most ARVs. While prior agents (Epi-001) demonstrated good preclinical activity, clinical efficacy was less convincing. This second-generation agent is tested in this ongoing phase 1/2 open-label study.

Study Design: 
Phase 1 is designed to establish the safety, pharmacokinetic (PK) profile, and recommended phase 2 dose of EPI-506. While emphasis is on safety and dosing, clinical efficacy is also evaluated. Inclusion criteria included: mCRPC with progression after ≥1 line of hormonal therapy or chemotherapy and progression on enzalutamide and/or abiraterone. Progression defined by PSA rise. Asymptomatic or minimally symptomatic patients only. 

Twenty-one patients were enrolled and included in the first phase of the study, and 6 different doses of EPI-506 were tested (80, 160, 320, 640, 1280 mg, 2400 mg). All 21 had previously been treated with enza (9), abi (3), or both (9); eight patients have even been treated with prior chemotherapy. Median exposure was approximately 87 days (3 months).

In terms of tolerability, 2 patients discontinued due to adverse events (AEs). Grade 4 toxicity included elevated amylase (related) and GI bleeding (unrelated). Two patients withdrew consent. The most common (>10%) Grade 3-4 adverse events included anemia and neutropenia.

In terms of dosing, pharmacokinetic data demonstrates dose proportionality. As such, they plan on adding two more arms for 1800 mg bid or 3600 mg daily dosing. Human exposures at higher dose levels correlated to exposures ranges that demonstrated tumor regression in preclinical models. The optimal dose has not yet been determined.

Thirteen patients eventually progressed and stopped taking the medication. While the clinical outcome data is lacking, this is just the first phase of the two-phase study. PSA decline and stable disease has been observed at higher doses. All four patients that had PSA decline were taking the 1280 mg dose or higher. 

The side effect profile appears to be tolerable, and phase 2 will likely proceed once the optimal dose is determine. As options for patients who have failed at least one line of therapy for mCRPC is limited, finding a new target with effective therapy is essential.

Presented By: Kim N. Chi, MD, British Columbia Cancer Agency, Vancouver, BC, Canada

Co-Author(s): Ulka N. Vaishampayan, Michael S. Gordon, David C. Smith, Erin Rudsinski, Angela De Haas-Amatsaleh, Neil Thapar, Frank Perabo, Robert B. Montgomery

Institution(s): Karmanos Cancer Institute, Detroit, MI; Pinnacle Oncology Hematology, A Division of Arizona Center for Cancer Care, HonorHealth Research Institute Clinical Trials Program at the Virginia G. Piper Cancer Center, Scottsdale, AZ; University of Michigan, Ann Arbor, MI; Essa Pharmaceuticals Corp., Houston, TX; ESSA Pharmaceuticals, Houston, TX; University of Washington Oncology, Seattle, WA

Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto
Twitter: @tchandra_uromd

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 - Chicago, Illinois, USA

1. Chandrasekar T, Yang JC, Gao AC, Evans CP. Targeting molecular resistance in castration-resistant prostate cancer. BMC Med. 2015 Sep 1;13:206. doi: 10.1186/s12916-015-0457-6. Review.
2. Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, Chen Y, Mohammad TA, Chen Y, Fedor HL, Lotan TL, Zheng Q, De Marzo AM, Isaacs JT, Isaacs WB, Nadal R, Paller CJ, Denmeade SR, Carducci MA, Eisenberger MA, Luo J. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med. 2014 Sep 11;371(11):1028-38. doi: 10.1056/NEJMoa1315815. Epub 2014 Sep 3.