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
5103 - CANOPY phase 3 program: Three studies evaluating canakinumab in patients with non-small cell lung cancer (NSCLC)
Presenter: Luis Paz-Ares
Session: Poster Display session 1
Resources:
Abstract
3666 - The Elderly Patient Individualized Chemotherapy (EPIC) trial, a study for an aged population of non-small cell lung cancer.
Presenter: Francesco Passiglia
Session: Poster Display session 1
Resources:
Abstract
4799 - KEYNOTE-495/KeyImPaCT: A Randomized, Biomarker-Directed, Phase 2 Trial of Pembrolizumab-Based Therapy for Non–Small Cell Lung Cancer (NSCLC)
Presenter: Martin Gutierrez
Session: Poster Display session 1
Resources:
Abstract
6035 - Safety, tolerability and activity of autologous T cells with enhanced T-cell receptors specific to NY ESO 1/LAGE 1a (GSK3377794) alone, or in combination with pembrolizumab, in advanced non small cell lung cancer: A Phase 1b/2a randomised pilot study
Presenter: Karen Reckamp
Session: Poster Display session 1
Resources:
Abstract
2176 - IFCT-1701 DICIPLE: a randomized phase 3 trial comparing continuation Nivolumab-Ipilimumab doublet immunotherapy until progression versus observation in patients with PDL1-positive stage IV Non-Small Cell Lung Cancer (NSCLC) after Nivolumab-Ipilimumab induction treatment
Presenter: Gerard Zalcman
Session: Poster Display session 1
Resources:
Abstract
2352 - ATALANTE-1 randomized phase 3 trial, OSE-2101 versus standard treatment as second or third line in HLA-A2 positive advanced non-small cell lung cancer (NSCLC) patients
Presenter: Enriqueta Felip
Session: Poster Display session 1
Resources:
Abstract
2451 - Phase Ib dose-escalation/expansion study of BI 836880, a VEGF/Ang2-blocking nanobody®, in combination with BI 754091, an anti-PD-1 antibody, in patients with advanced solid tumours
Presenter: Nicolas Girard
Session: Poster Display session 1
Resources:
Abstract
4285 - Radiosurgery followed by Tumor Treating Fields (TTFields) for brain metastases (1-10) from NSCLC in the phase 3 METIS trial
Presenter: Minesh Mehta
Session: Poster Display session 1
Resources:
Abstract
4909 - Nivolumab plus ipilimumab (NI) versus chemotherapy plus nivolumab (CN) in squamous cell lung cancer (SqCLC): the SQUINT trial
Presenter: Lorenza Landi
Session: Poster Display session 1
Resources:
Abstract
4125 - DUBLIN-3, a Stage IIIb/IV NSCLC Phase (Ph)3 Trial Comparing the Plinabulin (P)/Docetaxel(D) Combination with D Alone
Presenter: Ramon Mohanlal
Session: Poster Display session 1
Resources:
Abstract