Phase I/II Trial of Enzalutamide and Mifepristone, a Glucocorticoid Receptor Antagonist, for Metastatic Castration-Resistant Prostate Cancer.
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
14 04 2022
14 04 2022
Historique:
received:
09
12
2021
revised:
18
01
2022
accepted:
31
01
2022
pubmed:
4
2
2022
medline:
16
4
2022
entrez:
3
2
2022
Statut:
ppublish
Résumé
Although androgen deprivation therapy (ADT) and androgen receptor (AR) signaling inhibitors are effective in metastatic prostate cancer, resistance occurs in most patients. This phase I/II trial assessed the safety, pharmacokinetic impact, and efficacy of the glucocorticoid receptor (GR) antagonist mifepristone in combination with enzalutamide for castration-resistant prostate cancer (CRPC). One hundred and six patients with CRPC were accrued. Phase I subjects were treated with enzalutamide monotherapy at 160 mg per day for 28 days to allow steady-state accumulation. Patients then entered the dose escalation combination portion of the study. In phase II, patients were randomized 1:1 to either receive enzalutamide alone or enzalutamide plus mifepristone. The primary endpoint was PSA progression-free survival (PFS), with radiographic PFS, and PSA response rate (RR) as key secondary endpoints. Circulating tumor cells were collected before randomization for exploratory translational biomarker studies. We determined a 25% dose reduction in enzalutamide, when added to mifepristone, resulted in equivalent drug levels compared with full-dose enzalutamide and was well tolerated. However, the addition of mifepristone to enzalutamide following a 12-week enzalutamide lead-in did not delay time to PSA, radiographic or clinical PFS. The trial was terminated early due to futility. This is the first prospective trial of dual AR-GR antagonism in CRPC. Enzalutamide combined with mifepristone was safe and well tolerated but did not meet its primary endpoint. The development of more specific GR antagonists combined with AR antagonists, potentially studied in an earlier disease state, should be explored.
Identifiants
pubmed: 35110415
pii: 1078-0432.CCR-21-4049
doi: 10.1158/1078-0432.CCR-21-4049
pmc: PMC9012680
mid: NIHMS1778885
doi:
Substances chimiques
Androgen Antagonists
0
Androgen Receptor Antagonists
0
Benzamides
0
Nitriles
0
Receptors, Glucocorticoid
0
Phenylthiohydantoin
2010-15-3
Mifepristone
320T6RNW1F
enzalutamide
93T0T9GKNU
Prostate-Specific Antigen
EC 3.4.21.77
Banques de données
ClinicalTrials.gov
['NCT03674814', 'NCT03437941']
Types de publication
Clinical Trial, Phase I
Clinical Trial, Phase II
Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1549-1559Subventions
Organisme : NCI NIH HHS
ID : L30 CA171032
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA180995
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA014599
Pays : United States
Informations de copyright
©2022 American Association for Cancer Research.
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