Clinical Development of Darolutamide: A Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer. 2018

Karim Fizazi, and Matthew R Smith, and Bertrand Tombal
Institut Gustave Roussy, Department of Cancer Medicine, University of Paris Sud, Villejuif, France. Electronic address: Karim.fizazi@gustaveroussy.fr.

Prostate cancer (PC) is the second most common cancer in men and is the fifth leading cause of cancer-related deaths among men. Androgen receptor (AR) signaling plays a key role in PC tumor growth and progression, with androgens stimulating PC proliferation and survival. Castration-resistant PC (CRPC) is characterized by increasing levels of prostate-specific antigen or radiographic progression despite androgen-deprivation therapy (ADT). In most patients, castration resistance results from aberrations in AR or the AR signaling pathway. Up to one-third of patients with localized high-risk PC will have disease progression on local therapy and develop CRPC. This review summarizes the key clinical data, including ongoing trials, for hormonal therapies in CRPC and provides an overview of the clinical development of darolutamide, a novel, nonsteroidal AR antagonist currently in phase III development for the treatment of nonmetastatic CRPC and metastatic hormone-sensitive PC. In phase I/II trials, darolutamide has demonstrated a favorable safety profile, antitumor activity, and significant decreases in prostate-specific antigen in patients with metastatic CRPC. In the phase III ARAMIS (NCT02200614; A Multinational, Randomized, Double-Blind, Placebo-Controlled, Phase III Efficacy and Safety Study of Darolutamide [ODM-201] in Men With High-Risk Non-metastatic Castration-Resistant Prostate Cancer) study, metastasis-free survival is being evaluated in men with nonmetastatic CRPC who will receive ADT in combination with darolutamide or placebo. The ARASENS (NCT02799602; A Randomized, Double-Blind, Placebo Controlled Phase III Study of Darolutamide [ODM-201] Versus Placebo in Addition to Standard Androgen Deprivation Therapy and Docetaxel in Patients With Metastatic Hormone Sensitive Prostate Cancer) study is a placebo-controlled trial assessing whether the addition of darolutamide to ADT and docetaxel significantly prolongs overall survival in men with metastatic hormone-sensitive PC.

UI MeSH Term Description Entries
D008297 Male Males
D011720 Pyrazoles Azoles of two nitrogens at the 1,2 positions, next to each other, in contrast with IMIDAZOLES in which they are at the 1,3 positions.
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D015337 Multicenter Studies as Topic Works about controlled studies which are planned and carried out by several cooperating institutions to assess certain variables and outcomes in specific patient populations, for example, a multicenter study of congenital anomalies in children. Multicenter Trials,Multicentre Studies as Topic,Multicentre Trials,Multicenter Trial,Multicentre Trial,Trial, Multicenter,Trial, Multicentre,Trials, Multicenter,Trials, Multicentre
D016032 Randomized Controlled Trials as Topic Works about clinical trials that involve at least one test treatment and one control treatment, concurrent enrollment and follow-up of the test- and control-treated groups, and in which the treatments to be administered are selected by a random process, such as the use of a random-numbers table. Clinical Trials, Randomized,Controlled Clinical Trials, Randomized,Trials, Randomized Clinical
D016896 Treatment Outcome Evaluation undertaken to assess the results or consequences of management and procedures used in combating disease in order to determine the efficacy, effectiveness, safety, and practicability of these interventions in individual cases or series. Rehabilitation Outcome,Treatment Effectiveness,Clinical Effectiveness,Clinical Efficacy,Patient-Relevant Outcome,Treatment Efficacy,Effectiveness, Clinical,Effectiveness, Treatment,Efficacy, Clinical,Efficacy, Treatment,Outcome, Patient-Relevant,Outcome, Rehabilitation,Outcome, Treatment,Outcomes, Patient-Relevant,Patient Relevant Outcome,Patient-Relevant Outcomes
D017326 Clinical Trials, Phase III as Topic Works about comparative studies to verify the effectiveness of diagnostic, therapeutic, or prophylactic drugs, devices, or techniques determined in phase II studies. During these trials, patients are monitored closely by physicians to identify any adverse reactions from long-term use. These studies are performed on groups of patients large enough to identify clinically significant responses and usually last about three years. This concept includes phase III studies conducted in both the U.S. and in other countries. Clinical Trials, Phase 3 as Topic,Drug Evaluation, FDA Phase 3 as Topic,Drug Evaluation, FDA Phase III as Topic,Evaluation Studies, FDA Phase 3 as Topic,Evaluation Studies, FDA Phase III as Topic
D059002 Androgen Receptor Antagonists Compounds that bind to and inhibit the activation of ANDROGEN RECEPTORS. Androgen Receptor Antagonist,Antagonist, Androgen Receptor,Antagonists, Androgen Receptor,Receptor Antagonist, Androgen,Receptor Antagonists, Androgen
D064129 Prostatic Neoplasms, Castration-Resistant Tumors or cancer of the PROSTATE which can grow in the presence of low or residual amount of androgen hormones such as TESTOSTERONE. Androgen-Independent Prostatic Cancer,Androgen-Independent Prostatic Neoplasms,Androgen-Insensitive Prostatic Cancer,Androgen-Insensitive Prostatic Neoplasms,Androgen-Resistant Prostatic Cancer,Androgen-Resistant Prostatic Neoplasms,Castration-Resistant Prostatic Cancer,Castration-Resistant Prostatic Neoplasms,Hormone Refractory Prostatic Cancer,Hormone Refractory Prostatic Neoplasms,Prostatic Cancer, Androgen-Independent,Prostatic Cancer, Androgen-Insensitive,Prostatic Cancer, Androgen-Resistant,Prostatic Cancer, Castration-Resistant,Prostatic Cancer, Hormone Refractory,Prostatic Neoplasms, Androgen-Independent,Prostatic Neoplasms, Androgen-Insensitive,Prostatic Neoplasms, Androgen-Resistant,Prostatic Neoplasms, Hormone Refractory,Androgen Independent Prostatic Cancer,Androgen Independent Prostatic Neoplasms,Androgen Insensitive Prostatic Cancer,Androgen Insensitive Prostatic Neoplasms,Androgen Resistant Prostatic Cancer,Androgen Resistant Prostatic Neoplasms,Androgen-Independent Prostatic Cancers,Androgen-Independent Prostatic Neoplasm,Androgen-Insensitive Prostatic Cancers,Androgen-Insensitive Prostatic Neoplasm,Androgen-Resistant Prostatic Cancers,Androgen-Resistant Prostatic Neoplasm,Cancer, Androgen-Independent Prostatic,Cancer, Androgen-Insensitive Prostatic,Cancer, Androgen-Resistant Prostatic,Cancer, Castration-Resistant Prostatic,Cancers, Androgen-Independent Prostatic,Cancers, Androgen-Insensitive Prostatic,Cancers, Androgen-Resistant Prostatic,Cancers, Castration-Resistant Prostatic,Castration Resistant Prostatic Cancer,Castration Resistant Prostatic Neoplasms,Castration-Resistant Prostatic Cancers,Castration-Resistant Prostatic Neoplasm,Neoplasm, Androgen-Independent Prostatic,Neoplasm, Androgen-Insensitive Prostatic,Neoplasm, Androgen-Resistant Prostatic,Neoplasm, Castration-Resistant Prostatic,Neoplasms, Androgen-Independent Prostatic,Neoplasms, Androgen-Insensitive Prostatic,Neoplasms, Androgen-Resistant Prostatic,Neoplasms, Castration-Resistant Prostatic,Prostatic Cancer, Androgen Independent,Prostatic Cancer, Androgen Insensitive,Prostatic Cancer, Androgen Resistant,Prostatic Cancer, Castration Resistant,Prostatic Cancers, Androgen-Independent,Prostatic Cancers, Androgen-Insensitive,Prostatic Cancers, Androgen-Resistant,Prostatic Cancers, Castration-Resistant,Prostatic Neoplasm, Androgen-Independent,Prostatic Neoplasm, Androgen-Insensitive,Prostatic Neoplasm, Androgen-Resistant,Prostatic Neoplasm, Castration-Resistant,Prostatic Neoplasms, Androgen Independent,Prostatic Neoplasms, Androgen Insensitive,Prostatic Neoplasms, Androgen Resistant,Prostatic Neoplasms, Castration Resistant

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