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Masofaniten (EPI-7386) in Patients with Metastatic Castration-Resistant Prostate Cancer

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A Phase 1/2 Study of EPI-7386 in Combination With Enzalutamide Compared With Enzalutamide Alone in Subjects With Metastatic Castration-Resistant Prostate Cancer

  • Condition: Prostate Cancer
  • Study ID: NCT05075577
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Publications
Articles and Abstracts
  • Combination of masofaniten plus enzalutamide continues to be well tolerated with deep and durable reductions in PSA in patients with mCRPC
  • Phase 2 dose expansion currently underway at the RP2CDs of masofaniten 600 mg BID in combination with enzalutamide 160 mg QD
  • Across all dosing cohorts, 81% of patients achieved PSA90, 69% of patients achieved PSA90 in less than 90 days, and 63% of patients achieved PSA <0.2ng/mL. While the data are still maturing, median time to PSA progression is currently at 16.6 months.

Background The androgen receptor (AR) is activated by androgen binding to the ligand binding domain (LBD) which induces the dimerization and nuclear translocation of the AR. Current AR-targeted therapies work directly or indirectly through the LBD of the AR either by competing with androgen binding to the LBD (lutamide) or by inhibiting the androgen production (centrally or through CYP17 inhibition).

View poster as PDF

Androgen receptor (AR) signaling is the most important driver of prostate cancer initiation, development, and progression, even into the castration-resistant state.  Androgen deprivation therapy (ADT) is the original “targeted therapy” in oncology.  The next generation androgen- and AR-targeted agents, such as abiraterone acetate, enzalutamide, apalutamide and darolutamide further prove the concept that AR signaling remains critical in even later disease states.  There are various mechanisms of resistance that continue to be inclusive of AR; this ranges from AR amplification, AR mutation, and potentially AR spliced variants.

Conference Coverage
Conference Highlights Written by Physician-Scientist
Presented by Christos Kyriakopoulos, MD

Christos Kyriakopoulos presented the phase 1 results and phase 2 study design of a phase 1/2 trial evaluating the combination of oral EPI-7386 (masofaniten) plus enzalutamide versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC).  EPI-7386 is an aniten, a class of compounds that inhibit androgen receptor activity by binding to the N-terminal domain, irrespective of resistance abrogation in the ligand binding domain that render androgen receptor pathway inhibitors (ARPIs) ineffective.

Presented by Andrew L. Laccetti, MD, MS
(UroToday.com) The 2023 ESMO annual meeting included a session on prostate cancer, featuring a presentation by Dr. Andrew Laccetti discussing the results of the phase 1/2 trial of oral EPI-7386 in combination with enzalutamide compared to enzalutamide alone in metastatic castration-resistant prostate cancer (mCRPC). The androgen receptor is activated by androgen binding to the ligand binding domain which induces the dimerization and nuclear translocation of the androgen receptor. Current androgen receptor targeted therapies work directly or indirectly through the ligand binding domain of the androgen receptor either by competing with androgen binding to the ligand binding domain or by inhibiting the androgen production (centrally through CYP17 inhibition). EPI-7386 is a next generation antiandrogen designed to inhibit androgen receptor activity by binding the N-terminal domain
Presented by Russell Kent Pachynski, MD
(UroToday.com) The need for additional effective therapies for metastatic castration resistant prostate cancer (mCRPC) is omnipresent, particularly as therapies previously used in later lines or only in CRPC are now being deployed in earlier disease states. Among well-established mechanisms of resistance are alterations in the androgen receptor (AR), including mutations and copy number changes, which effect its activity and ligand independent signaling. EPI-7386 is an aniten, a class of compounds which can inhibitor AR activity by binding to the N-terminal domain (NTD) irrespective of resistance abrogation in the ligand binding domain that may otherwise make AR signaling inhibitors ineffective, as supported by preclinical data. Trial of this agent in a first-in-human study in heavily pre-treated patients with mCRPC was undertaken (NCT04221222), and preliminary data are reported here.
Presented by Andrew Laccetti, MD, MS
(UroToday.com) Alterations in the Androgen Receptor (AR) remain a common locus for castration resistance in prostate cancer (CRPC), and impact response to AR-targeted novel hormonal therapies, including enzalutamide. Dr. Laccetti and colleagues present preliminary safety and efficacy data on the combination of enzalutamide with a next generation antigen EPI-7386 in chemotherapy-exposed patients with CRPC prior to exposure to any AR pathway inhibitor.
Presented by Andrew Laccetti, MD, MS
Reno, Nevada (UroToday.com) -- ESSA Pharma Inc., a clinical-stage pharmaceutical company focused on developing novel therapies for the treatment of prostate cancer, announced that further analyses of initial clinical data from two Phase 1 studies of EPI-7386 in patients with metastatic castration-resistant prostate cancer ("mCRPC") will be presented at the 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium ("ASCO GU"), taking place February 16-19, 2023, in San Francisco, California and online. EPI-7386 is a first-in-class N-terminal domain androgen receptor ("AR") inhibitor that suppresses androgen activity through a novel mechanism of action. The two poster presentations are available on the ASCO GU Digital Program and the "Publications" section of the Company's website at www.essapharma.com.