Moving Towards Precision Urologic Oncology: Targeting Enzalutamide-resistant Prostate Cancer and Mutated Forms of the Androgen Receptor Using the Novel Inhibitor Darolutamide (ODM-201).

Abstract

Darolutamide (ODM-201) is a novel androgen receptor (AR) antagonist with a chemical structure distinctly different from currently approved AR antagonists that targets both wild-type and mutated ligand binding domain variants to inhibit AR nuclear translocation. Here, we evaluate the activity of darolutamide in enzalutamide-resistant castration resistant prostate cancer (CRPC) as well as in AR mutants detected in patients after treatment with enzalutamide, abiraterone, or bicalutamide. Darolutamide significantly inhibited cell growth and AR transcriptional activity in enzalutamide-resistant MR49F cells in vitro, and led to decreased tumor volume and serum prostate-specific antigen levels in vivo, prolonging survival in mice bearing enzalutamide-resistant MR49F xenografts. Moreover, darolutamide inhibited the transcriptional activity of AR mutants identified in the plasma of CRPC patients progressing on traditional therapies. In particular, darolutamide significantly inhibited the transcriptional activity of the F877L, H875Y/T878A, F877L/T878A, and the previously unreported T878G AR mutants, that transform enzalutamide into a partial agonist. In silico cheminformatics computer modeling provided atomic level insights confirming darolutamide antagonist effect in F877L and T878G AR mutants. In conclusion, our results provide a rationale for further clinical evaluation of darolutamide in enzalutamide-resistant CRPC, in particular in combination with circulating tumor DNA assays that detect AR mutants sensitive to darolutamide, in a precision oncology setting.

PATIENT SUMMARY:

In this study we evaluated the novel drug darolutamide in preclinical models of prostate cancer. We found that darolutamide delays growth of enzalutamide-resistant prostate cancer, in particular in cells with mutated forms of the androgen receptor after previous treatment. Our data supports further evaluation of darolutamide in clinical trials.

• Authors: Hendrik Borgmann, Nada Lallous, Deniz Ozistanbullu, Eliana Beraldi, Naman Paul, Kush Dalal, Ladan Fazli, Axel Haferkamp, Pascale Lejeune, Artem Cherkasov, Martin E Gleave
• Journal: European urology (Eur Urol) Vol. 73 Issue 1 Pg. 4-8 (01 2018) ISSN: 1873-7560 [Electronic] Switzerland
• PMID: 28851578 (Publication Type: Journal Article)
• Copyright: Copyright © 2017. Published by Elsevier B.V.

Chemical References

• AR protein, human
• Androgen Receptor Antagonists
• Benzamides
• Nitriles
• Pyrazoles
• Receptors, Androgen
• darolutamide
• Phenylthiohydantoin
• enzalutamide

Topics

• Androgen Receptor Antagonists (chemistry, pharmacology)
• Animals
• Benzamides
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Resistance, Neoplasm (genetics)
• Humans
• Male
• Mice
• Models, Molecular
• Molecular Targeted Therapy
• Mutation
• Nitriles
• Phenylthiohydantoin (analogs & derivatives, pharmacology)
• Prostatic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Protein Conformation
• Pyrazoles (chemistry, pharmacology)
• Receptors, Androgen (chemistry, drug effects, genetics, metabolism)
• Signal Transduction (drug effects)
• Structure-Activity Relationship
• Time Factors
• Transcription, Genetic (drug effects)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays