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

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RESEARCH PRODUCT

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

Deniz Ozistanbullu Eliana Beraldi Pascale Lejeune Ladan Fazli Martin E. Gleave Artem Cherkasov Axel Haferkamp Naman Paul Kush Dalal Nada Lallous Hendrik Borgmann

subject

0301 basic medicine Male Models Molecular Time Factors Transcription Genetic Protein Conformation Prostate cancer chemistry.chemical_compound Mice 0302 clinical medicine Molecular Targeted Therapy Tumor Burden Darolutamide Receptors Androgen 030220 oncology & carcinogenesis Benzamides medicine.drug Signal Transduction medicine.medical_specialty Bicalutamide Urology Partial agonist 03 medical and health sciences Structure-Activity Relationship In vivo Internal medicine Cell Line Tumor Nitriles Phenylthiohydantoin medicine Androgen Receptor Antagonists Enzalutamide Animals Humans Cell Proliferation Dose-Response Relationship Drug Cell growth business.industry Prostatic Neoplasms medicine.disease Xenograft Model Antitumor Assays Androgen receptor 030104 developmental biology Endocrinology chemistry Drug Resistance Neoplasm Mutation Cancer research Pyrazoles business

description

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.

year	journal	country	edition	language
2017-05-25	European urology

10.1016/j.eururo.2017.08.012 https://pubmed.ncbi.nlm.nih.gov/28890248