Clinical Development of Darolutamide: A Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer

Fizazi, Karim; Smith, Matthew R.; Tombal, Bertrand

doi:10.1016/j.clgc.2018.07.017

Cited by 66 publications

(45 citation statements)

References 40 publications

(83 reference statements)

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“…Darolutamide is a novel oral AR antagonist which has recently completed a pivotal Phase 3 clinical study to determine its efficacy in nonmetastatic castration-resistant prostate cancer. 10,11 It has a unique chemical structure, exists as two pharmacologically active diastereomers, (S,R)-and (S,S)darolutamide, 12 and forms keto-darolutamide as main metabolite in patients. 13,14 Darolutamide strongly impairs androgen binding to the AR and androgen-induced nuclear translocation.…”

Section: Introductionmentioning

confidence: 99%

Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models

Sugawara

Baumgart

Nevedomskaya

et al. 2019

Intl Journal of Cancer

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Darolutamide is a novel androgen receptor (AR) antagonist with a distinct chemical structure compared to other AR antagonists and currently in clinical Phase 3 trials for prostate cancer. Using cell‐based transactivation assays, we demonstrate that darolutamide, its diastereomers and its main metabolite keto‐darolutamide are strong, competitive antagonists for AR wild type, and also for several mutants identified in prostate cancer patients for which other AR antagonists show reduced antagonism or even agonism. Darolutamide, its two diastereomers and main metabolite are also strong antagonists in assays measuring AR N/C interaction and homodimerization. Molecular modeling suggests that the flexibility of darolutamide allows accommodation in the W742C/L mutated AR ligand‐binding pocket while for enzalutamide the loss of the important hydrophobic interaction with W742 leads to reduced AR interaction. This correlates with an antagonistic pattern profile of coregulator recruitment for darolutamide. In vitro efficacy studies performed with androgen‐dependent prostate cancer cell lines show that darolutamide strongly reduces cell viability and potently inhibits spheroid formation. Also, a marked down‐regulation of androgen target genes paralleled by decreased AR binding to gene regulatory regions is seen. In vivo studies reveal that oral dosing of darolutamide markedly reduces growth of the LAPC‐4 cell line‐derived xenograft and of the KuCaP‐1 patient‐derived xenograft. Altogether, these results substantiate a unique antagonistic profile of darolutamide and support further development as a prostate cancer drug.

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Section: Introductionmentioning

confidence: 99%

Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models

Sugawara

Baumgart

Nevedomskaya

et al. 2019

Intl Journal of Cancer

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“…AR mutant data for training was collected as described by Lallous et al [ 6 ] in which single and multiple amino acid substitutions of the AR were expressed in PC3 cells. Responses to seven different anti-androgens (bicalutamide [ 18 ], enzalutamide [ 19 , 20 ], hydroxyflutamide [ 21 ], Apalutamide [ 22 ], darolutamide [ 23 ], and 2 in-house developed AR inhibitors, VPC-13566 and VPC-13789) were measured in a luciferase-reporter assay. Chemical structures of experimental antiandrogens can be seen in Supplementary Figure S1 .…”

Section: Results and Discussionmentioning

confidence: 99%

Deep Learning Modeling of Androgen Receptor Responses to Prostate Cancer Therapies

Snow

Lallous

Ester

et al. 2020

IJMS

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Gain-of-function mutations in human androgen receptor (AR) are among the major causes of drug resistance in prostate cancer (PCa). Identifying mutations that cause resistant phenotype is of critical importance for guiding treatment protocols, as well as for designing drugs that do not elicit adverse responses. However, experimental characterization of these mutations is time consuming and costly; thus, predictive models are needed to anticipate resistant mutations and to guide the drug discovery process. In this work, we leverage experimental data collected on 68 AR mutants, either observed in the clinic or described in the literature, to train a deep neural network (DNN) that predicts the response of these mutants to currently used and experimental anti-androgens and testosterone. We demonstrate that the use of this DNN, with general 2D descriptors, provides a more accurate prediction of the biological outcome (inhibition, activation, no-response, mixed-response) in AR mutant-drug pairs compared to other machine learning approaches. Finally, the developed approach was used to make predictions of AR mutant response to the latest AR inhibitor darolutamide, which were then validated by in-vitro experiments.

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“…Furthermore, two phase III clinical studies, the ARAMIS and ARASENS trials, were performed [33,34]. The first one examined the safety and efficacy of darolutamide in 1509 men with nmCRPC.…”

Section: Clinical Trialsmentioning

confidence: 99%

Renal and Cardiovascular Toxicities by New Systemic Treatments for Prostate Cancer

Saltalamacchia

Frascaroli

Bernardo

et al. 2020

Cancers

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Prostate cancer (PC) is the most common male cancer in Western Countries. In recent years, the treatment of relapsed or metastatic disease had benefited by the introduction of a variety of new different drugs. In consideration of the relative long survival of PC patients, side effects of these drugs must be considered and monitored. In this review, we analyzed the newly developed therapies for PC treatment, describing the mechanism of action, the metabolism and latest clinical trials that led to the approval of these drugs in clinical practice. We then evaluated the cardiovascular and renal side effects from pivotal phase III and II studies and meta-analyses. Cardiovascular side effects are the most frequent, in particular hypertension, while renal toxicity is rarer and not well described in literature. Therefore, there is a need to better define the effects of these therapies, in order to personalize patient treatment on the basis of their comorbidities and preferences, in addition to their symptoms and disease load.

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Clinical Development of Darolutamide: A Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer

Cited by 66 publications

References 40 publications

Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models

Darolutamide is a potent androgen receptor antagonist with strong efficacy in prostate cancer models

Deep Learning Modeling of Androgen Receptor Responses to Prostate Cancer Therapies

Renal and Cardiovascular Toxicities by New Systemic Treatments for Prostate Cancer

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