Abstract 5965
Background
The androgen receptor (AR) pathway drives most metastatic castration-resistant prostate cancers (mCRPC) even in late stages of the disease. Anti-androgen resistance mechanisms include AR gene amplification, C-terminal ligand-binding domain (LBD) mutations and expression of constitutively-active truncated AR splice variants lacking the LBD (eg. AR-V7). Selective inhibition of the N-terminal domain (NTD) of the AR can inhibit its’ transcriptional activity even in the presence of LBD-driven resistance. A Phase I clinical trial of the first-generation AR NTD inhibitor, EPI-506, demonstrated minor PSA declines in mCRPC patients. EPI-7386 is a more potent and stable NTD inhibitor (Anitens) that is advancing to clinical trials. The compounds’ characteristics and the initial clinical study plans including potential biomarkers will be reviewed.
Methods
Chemical structure activity relationships were developed to increase molecule potency using a wide variety of CRPC models in vivo and in vitro. Similarly, the stability and selectivity of the molecule were characterized with screening and functional assays. Biomarkers were also explored.
Results
EPI-7386 demonstrated a 20 fold improvement in AR-driven cellular potency compared to EPI-002, while being highly stable in human and animal hepatocytes. In vitro proliferation assays demonstrated on-target activity across a panel of prostante cancer cell lines, with activity in AR-V7-driven cellular models. EPI-7386 was able to control tumor growth and induce tumor regressions in several CRPC xenografts, including enzalutamide resistant models. In addition, the combination of enzalutamide with EPI-7386 demonstrated a more robust and more homogeneuous antitumor response. Pharmacodynamic markers specific to NTD inhibitors will be presented.
Conclusions
The next generation aniten compound EPI-7386 is more active and more metabolically stable than EPI-002. It demonstrated potential as single agent in overcoming anti-androgen clinical resistance as well as in combination therapy in earlier stages of the disease. The clinical strategy supporting the development of this new generation of Aniten will be discussed.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
ESSA Pharmaceuticals.
Funding
ESSA Pharmaceuticals.
Disclosure
R. Le Moigne: Full / Part-time employment: ESSA pharma. C.A. Banuelos: Shareholder / Stockholder / Stock options: ESSA pharma. N.R. Mawji: Shareholder / Stockholder / Stock options: ESSA pharma. R.J. Andersen: Research grant / Funding (institution), Shareholder / Stockholder / Stock options, Officer / Board of Directors: ESSA pharma. A. Cesano: Advisory / Consultancy: ESSA pharma; Full / Part-time employment: Nanostring. M.D. Sadar: Speaker Bureau / Expert testimony, Leadership role, Research grant / Funding (institution), Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Officer / Board of Directors: ESSA pharma; Speaker Bureau / Expert testimony: Pfizer. H. Zhou: Shareholder / Stockholder / Stock options, Full / Part-time employment: ESSA pharma. P. Virsik: Shareholder / Stockholder / Stock options, Full / Part-time employment: ESSA pharma. All other authors have declared no conflicts of interest.
Resources from the same session
4228 - Clinical Evaluation of Drug-Eluting Bead Transcatheter Arterial Chemoembolization(D-TACE) versus Conventional TACE in Treatment of unresectable Hepatocellular Carcinoma
Presenter: Yi Chen
Session: Poster Display session 1
Resources:
Abstract
3930 - Safety profile of tepotinib in patients with advanced solid tumors: pooled analysis of phase I and II data
Presenter: Thomas Decaens
Session: Poster Display session 1
Resources:
Abstract
5373 - Drug-drug interaction profile of tepotinib with CYP3A and P-gp substrates
Presenter: Juergen Heuer
Session: Poster Display session 1
Resources:
Abstract
5455 - Bioavailability of tepotinib: impact of omeprazole and food
Presenter: Juergen Heuer
Session: Poster Display session 1
Resources:
Abstract
2618 - Tislelizumab Exposure-Response Analyses of Efficacy and Safety in Patients with Advanced Tumors
Presenter: Chi-Yuan Wu
Session: Poster Display session 1
Resources:
Abstract
2563 - Population Pharmacokinetics of Tislelizumab in Patients with Advanced Tumors
Presenter: Chi-Yuan Wu
Session: Poster Display session 1
Resources:
Abstract
2021 - The Addition of Metformin to Systemic Anticancer Therapy
Presenter: Jung Han Kim
Session: Poster Display session 1
Resources:
Abstract
5243 - Growth modulation index (GMI) as a comparative measure of clinical activity of larotrectinib versus prior systemic treatments in adult and pediatric TRK fusion cancer patients
Presenter: Antoine Italiano
Session: Poster Display session 1
Resources:
Abstract
598 - Analysis of the overall survival and main surrogates used for FDA approvals in solid and hematological malignancies.
Presenter: Maria Kleniewska-Wieczor
Session: Poster Display session 1
Resources:
Abstract
5381 - Comparison of intratumoral docetaxel exposure in cancer patients between nanoparticle entrapped docetaxel (CPC634) and conventional docetaxel (Cd): the CriTax study
Presenter: Ruben Van Eerden
Session: Poster Display session 1
Resources:
Abstract