Novel NTD Inhibitor EPI-7386 Plus Enzalutamide Under Evaluation in mCRPC

Mar 31, 2021

The first-in-class N-terminal domain androgen receptor inhibitor EPI-7386 is being examined in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer as part of a phase 1/2 trial.

The first-in-class N-terminal domain (NTD) androgen receptor (AR) inhibitor EPI-7386 is being examined in combination with enzalutamide (Xtandi) in patients with metastatic castration-resistant prostate cancer (mCRPC) as part of a phase 1/2 trial, according to an announcement from ESSA Pharma Inc.1

The study is the product of a clinical collaboration forged between ESSA Pharma Inc., a clinical-stage pharmaceutical company focused on developing novel therapies for the treatment of patients with prostate cancer and manufacturer of EPI-7386, and Astellas Pharma Inc. As part of the terms of their supply agreement, ESSA Pharma Inc. will sponsor the trial and retain all rights to EPI-7386, while Astellas Pharma Inc. will supply enzalutamide for the research.

The clinical trial will specifically examine the combination in patients with mCRPC who have not received prior treatment with second-generation antiandrogen therapies; it is slated to begin enrollment in 2021.

"We are delighted to collaborate with Astellas to explore the potential clinical role of EPI-7386 in combination with Astellas' enzalutamide in patients with mCRPC, who have progressed on androgen deprivation therapy," David R. Parkinson, MD, chief executive officer of ESSA Pharma Inc., stated in a press release. "Combining our 2 therapies will simultaneously target both ends of the AR. In preclinical models, we have seen that combining EPI-7386 with current antiandrogens can lead to deeper and broader inhibition of androgen biology. We look forward to investigating the combination of these therapies and their potential role together in the treatment of [patients with] prostate cancer."

Most patients with mCRPC experience progression with a rising prostate-specific antigen, underlying a persistent dependence on the AR pathway.2 Although standard-of-care options target the AR axis, resistance eventually develops to antiandrogens and this can involve mechanisms such as AR gene amplification, ligand-binding domain (LBD) mutations, and expression of constitutively active AR splice variants that are missing the LBD. Inhibition of the NTD of the AR can hinder its transcriptional activity, even in the presence of resistance driven by LBD. 

Investigators evaluated the potency of EPI-7386 through the use of reporter cellular models or viability assays several cell lines that either expressed AR or did not. Investigators determined pharmacodynamic markers of activity in AR full length or AR-V7–driven models through the use of quantitative polymerase chain reaction or RNA sequencing. Using screening and functional assays, investigators learned more about the stability and selectivity of the molecule.

Results from the research indicated that EPI-7386 has an IC50 of 421 nM in LNCaP reporter assays, which is a range that is comparable to most LBD inhibitors; however, this agent differs from known agents in that its antitumor activity was maintained in CRPC models that expressed AR-V7. As anticipated, no activity with the agent was reported in non-AR–driven models. The agent was able to successfully inhibit the expression of AR full length driven genes like PSA, FKBP5, and STEAP4, while also modulating the expression of genes driven by AR V7. The investigative agent was also found to have impressive in vivo activity in several models, including a CRC patient-derived xenograft that was enzalutamide resistant.

Additionally, RNA sequencing revealed that the agent had on-target activity, although it had a transcriptomic profile that differed from that of enzalutamide. Investigators surmised that this finding meant that the combination of both LBD inhibition and NTD AR inhibition could potentially result in more robust hindrance of the AR pathway. The enhanced activity of the combination was confirmed in vivo when investigators utilized a CRPC model VCaP.

“The second-generation aniten compound EPI-7386 is more active and metabolically stable than EPI-506,” the investigators had concluded. “It has a favorable safety profile and ADME profile, with predicted long half-life in humans, supporting [a] once-daily dose. In vivo, EPI-7386 demonstrated potential as a single agent in overcoming antiandrogen clinical resistance as well as in combination therapy.”

In September 2020, the FDA granted fast track designation to EPI-7386 for the treatment of adult patients with mCRPC who are resistant to standard-of-care options. This investigational, highly-selective, oral small molecule inhibitor is currently under investigation in a first-in-human phase 1 trial (NCT04421222).3 Here, investigators set out to examine the safety of the agent and to determine a dose that can be administered without intolerable adverse effects. Investigators also seek to characterize the pharmacokinetic, biological, and antitumor effects of EPI-7386.4


  1. ESSA Pharma announces clinical collaboration with Astellas to evaluate the combination of EPI-7386 and enzalutamide for patients with metastatic castration-resistant prostate cancer. News release. ESSA Pharma Inc. February 25, 2021. Accessed March 15, 2021. 
  2. Hong NH. Le Moigne R, Banuelos CA, et al. Pre-clinical development of the second-generation N-terminal domain androgen receptor inhibitor, EPI-7386, for the treatment of prostate cancer. Cancer Res. 2020;80(16). doi:10.1158/1538-7445.AM2020-1953
  3. ESSA Pharma announces fast track designation granted by the FDA to EPI-7386 for the treatment of metastatic castration-resistant prostate cancer. News release. ESSA Pharma Inc. September 14, 2020. Accessed March 15, 2021. 
  4. Oral EPI-7386 in patients with metastatic castration-resistant prostate cancer (EPI-7386). Updated July 29, 2020. Accessed March 15, 2021. 
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