2021
DOI: 10.3390/cancers13122939
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Evaluation of Darolutamide (ODM201) Efficiency on Androgen Receptor Mutants Reported to Date in Prostate Cancer Patients

Abstract: Resistance to drug treatments is common in prostate cancer (PCa), and the gain-of-function mutations in human androgen receptor (AR) represent one of the most dominant drivers of progression to resistance to AR pathway inhibitors (ARPI). Previously, we evaluated the in vitro response of 24 AR mutations, identified in men with castration-resistant PCa, to five AR antagonists. In the current work, we evaluated 44 additional PCa-associated AR mutants, reported in the literature, and thus expanded the study of the… Show more

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Cited by 17 publications
(17 citation statements)
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“…In 68 AR mutants, darolutamide showed a complete inhibitory effect on AR mutants in 67, even if the concentration of AR mutants increased, there was no partial activation. Bicalutamide led to partial or complete activation to 63% mutants, and eight mutants were completely or partially activated by enzalutamide (171). The research preliminarily confirmed the broad-spectrum inhibitory effect of darolutamide on AR and its mutants.…”
Section: New Mechanismssupporting
confidence: 55%
“…In 68 AR mutants, darolutamide showed a complete inhibitory effect on AR mutants in 67, even if the concentration of AR mutants increased, there was no partial activation. Bicalutamide led to partial or complete activation to 63% mutants, and eight mutants were completely or partially activated by enzalutamide (171). The research preliminarily confirmed the broad-spectrum inhibitory effect of darolutamide on AR and its mutants.…”
Section: New Mechanismssupporting
confidence: 55%
“…In addition, darolutamide is a full antagonist to the W741L and T877A mutations, which mediate bicalutamide resistance, and to F876L mutations, which mediate enzalutamide and apalutamide resistance. In an in vitro study assessing response of ARAs to 68 AR mutations in men with CRPC, darolutamide retained efficacy in all gain-of-function AR-FL mutations except A587V [48]. In contrast, enzalutamide caused full or partial activation of 8 mutant types.…”
Section: Activating Mutations In Ar 321 Ar Point Mutationsmentioning
confidence: 96%
“…Enzalutamide, Apalutamide (A587V, F876L, F877L, G684A, K631T, L595M, Q920R, R630Q, T576A, T878A) [46,47] Darolutamide (A587V) [48] Darolutamide (F876L, F877L, W742L, T787A, W741L, T878A, L702H, H875Y) [48] Galaterone (F877L, T878A) [49] TRC253 (F877L) [50,51]. ARV-110 [52,53] ARCC-4 [54] * Clinical benefit/resistance proven in clinical trials.…”
Section: Acquired Castration Resistancementioning
confidence: 99%
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“…Unfortunately, despite initial response to the current therapy, all patients eventually will develop from castration-resistant prostate cancer (CRPC) to drug-resistant CRPC through androgen-dependent or androgen-independent mechanisms. Androgen-dependent mechanisms include a rise in AR splice variants [ 5 , 6 ], AR overexpression [ 7 ], intratumoral or alternative androgen biosynthesis [ 8 ], and AR mutations [ 9 ], while androgen-independent mechanisms are mediated through the activation of DNA repair pathways [ 10 ], PI3K/AKT/mTOR pathways [ 11 , 12 ], BRAF-MAPK [ 13 ], Wnt signaling pathways [ 14 , 15 ], glucocorticoid receptor pathways [ 16 ], and neuroendocrine differentiation [ 17 ]. Multiple clinical trials are exploring therapeutic strategies to overcome these resistance mechanisms, including those utilizing immunotherapies that work in conjunction with the patient’s immune system.…”
Section: Introductionmentioning
confidence: 99%