Moving towards Precision Urologic Oncology: Targeting Enzalutamide-Resistant Prostate Cancer and Mutated Forms of the Androgen Receptor Using the Novel Inhibitor Darolutamide
This week we profile a recent publication in European Eurology from the laboratory of
Dr. Martin Gleave (pictured) at the Vancouver Prostate Centre
What is the significance of the findings in this publication?
The manuscript describes our results of evaluating activity of darolutamide in enzalutamide-resistant castration-resistant prostate cancer (CRPC) as well as in androgen receptor (AR) mutants detected in patients after treatment with enzalutamide, abiraterone, or bicalutamide. We found that darolutamide potently inhibits enzalutamide-resistant CRPC both in vitro and in vivo. Moreover, darolutamide supppressed the transcriptional activity of AR mutants identified in the plasma of CRPC patients progressing on traditional therapies. We applied in silico cheminformatics computer modeling to provide atomic level insights into the mode of action of darolutamide in AR mutants. Our paper contains data on the first head-to-head comparison (in vitro) of darolutamide and enzalutamide. These results provide a rationale for further clinical evaluation of darolutamide in enzalutamide-resistant CRPC, in particular in combination with circulating tumour DNA assays that detect AR mutants sensitive to darolutamide, in a precision oncology setting.
We feel that this is timely and relevant new data particularly in the context of evolving treatment landscape in CRPC and emerging roles for ctDNA in segmenting the disease and guiding optimal sequencing of AR pathway inhibitors.