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.

中文翻译：

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朝着精密泌尿外科肿瘤学迈进：使用新型抑制剂Darolutamide（ODM-201）靶向抗Enzalutamide的前列腺癌和雄激素受体的突变形式。

darolutamide（ODM-201）是一种新型雄激素受体（AR）拮抗剂，其化学结构与目前批准的AR拮抗剂截然不同，后者以野生型和突变的配体结合域变体为靶标，以抑制AR核易位。在这里，我们评估了在耐enzalutamide的去势抵抗性前列腺癌（CRPC）中以及在使用enzalutamide，abiraterone或bicalutamide治疗的患者中检测到的AR突变体中的darolutamide的活性。达洛鲁胺在体外显着抑制耐enzalutamide的MR49F细胞中的细胞生长和AR转录活性，并导致体内肿瘤体积和血清前列腺特异性抗原水平降低，从而延长了耐enzalutamide MR49F异种移植物的小鼠的存活期。而且，达洛鲁胺抑制了在传统疗法上进展的CRPC患者血浆中鉴定的AR突变体的转录活性。特别地，达洛鲁胺显着抑制F877L，H875Y / T878A，F877L / T878A和先前未报道的T878G AR突变体的转录活性，这些突变体将enzalutamide转化为部分激动剂。在计算机化学信息学中，计算机建模提供了原子水平的见解，从而证实了达洛鲁胺拮抗剂在F877L和T878G AR突变体中的作用。总之，我们的结果为进一步的临床评估提供了理论依据，特别是在精确的肿瘤学背景下，结合环苯甲酰胺类肿瘤的循环DNA检测方法，进一步评估了对达洛鲁胺耐药的CRPC中的darolutamide的临床疗效，该循环DNA检测可检测对darolutamide敏感的AR突变体。

病人总结

在这项研究中，我们在前列腺癌的临床前模型中评估了新药达洛鲁胺。我们发现达洛鲁胺延迟了耐enzalutamide耐药性前列腺癌的生长，特别是在先前治疗后雄激素受体突变形式的细胞中。我们的数据支持在临床试验中进一步评估darolutamide。