A Phase 2 Trial of Abiraterone Followed by Randomization to Addition of Dasatinib or Sunitinib in Men With Metastatic Castration-Resistant Prostate Cancer.
Abiraterone Acetate
/ therapeutic use
Androstenes
Antineoplastic Combined Chemotherapy Protocols
/ adverse effects
Dasatinib
/ adverse effects
Humans
Male
Prednisone
/ therapeutic use
Prostatic Neoplasms, Castration-Resistant
/ drug therapy
Random Allocation
Sunitinib
/ therapeutic use
Treatment Outcome
Tumor Microenvironment
Androgen-signaling inhibition
Neoangiogenesis
Src pathway
Targeted agents
Tumor microenvironment
Journal
Clinical genitourinary cancer
ISSN: 1938-0682
Titre abrégé: Clin Genitourin Cancer
Pays: United States
ID NLM: 101260955
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
13
12
2019
revised:
19
05
2020
accepted:
19
05
2020
pubmed:
18
7
2020
medline:
19
8
2021
entrez:
18
7
2020
Statut:
ppublish
Résumé
Resistance to novel androgen signaling inhibition and metastatic castration-resistant prostate cancer (mCRPC) progression is likely dependent on tumor microenvironment interactions. The Src pathway and neoangiogenesis have been implicated in prostate cancer progression. We studied the effect of adding the targeted agents dasatinib and sunitinib to abiraterone acetate (AA) in men with mCRPC. In this open-label randomized phase 2 study, mCRPC patients received AA. At resistance to AA, they were randomized 1:1 to combination with dasatinib or sunitinib. At second progression, patients crossed over. The primary end point was time to treatment failure (TTF), defined as time to progression or death. Secondary end points included overall survival and safety. From March 2011 to February 2015, a total of 179 patients were enrolled and 132 subsequently randomized. Median TTF was 5.7 months in the dasatinib group and 5.5 months in the sunitinib group. There was no difference between the two groups in terms of TTF (hazard ratio, 0.85; 95% confidence interval, 0.59-1.22). Median overall survival from study entry was 26.3 months in the dasatinib group and 27.7 months in the sunitinib group (hazard ratio, 1.02; 95% confidence interval, 0.71-1.47). Grade 3 or higher adverse events related to study medication were more frequent with sunitinib (n = 44, 46%) compared to dasatinib (n = 26, 24%). At data cutoff, 7 patients were experiencing a continuous response to AA, with a median duration of treatment of 5.7 years. There is no difference in overall survival and TTF between dasatinib and sunitinib combined with abiraterone in the treatment of patients with bone mCRPC.
Sections du résumé
BACKGROUND
Resistance to novel androgen signaling inhibition and metastatic castration-resistant prostate cancer (mCRPC) progression is likely dependent on tumor microenvironment interactions. The Src pathway and neoangiogenesis have been implicated in prostate cancer progression. We studied the effect of adding the targeted agents dasatinib and sunitinib to abiraterone acetate (AA) in men with mCRPC.
PATIENTS AND METHODS
In this open-label randomized phase 2 study, mCRPC patients received AA. At resistance to AA, they were randomized 1:1 to combination with dasatinib or sunitinib. At second progression, patients crossed over. The primary end point was time to treatment failure (TTF), defined as time to progression or death. Secondary end points included overall survival and safety.
RESULTS
From March 2011 to February 2015, a total of 179 patients were enrolled and 132 subsequently randomized. Median TTF was 5.7 months in the dasatinib group and 5.5 months in the sunitinib group. There was no difference between the two groups in terms of TTF (hazard ratio, 0.85; 95% confidence interval, 0.59-1.22). Median overall survival from study entry was 26.3 months in the dasatinib group and 27.7 months in the sunitinib group (hazard ratio, 1.02; 95% confidence interval, 0.71-1.47). Grade 3 or higher adverse events related to study medication were more frequent with sunitinib (n = 44, 46%) compared to dasatinib (n = 26, 24%). At data cutoff, 7 patients were experiencing a continuous response to AA, with a median duration of treatment of 5.7 years.
CONCLUSION
There is no difference in overall survival and TTF between dasatinib and sunitinib combined with abiraterone in the treatment of patients with bone mCRPC.
Identifiants
pubmed: 32675015
pii: S1558-7673(20)30121-X
doi: 10.1016/j.clgc.2020.05.013
pmc: PMC10014037
mid: NIHMS1599466
pii:
doi:
Substances chimiques
Androstenes
0
Abiraterone Acetate
EM5OCB9YJ6
abiraterone
G819A456D0
Dasatinib
RBZ1571X5H
Sunitinib
V99T50803M
Prednisone
VB0R961HZT
Types de publication
Clinical Trial, Phase II
Journal Article
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
22-31.e5Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NIGMS NIH HHS
ID : U54 GM104942
Pays : United States
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Références
Ann Oncol. 2012 Mar;23(3):688-694
pubmed: 21821830
Eur J Cancer. 2009 Jan;45(2):228-47
pubmed: 19097774
J Clin Oncol. 2004 May 1;22(9):1655-63
pubmed: 15117988
Urology. 1999 Sep;54(3):567-72
pubmed: 10475375
Anticancer Drugs. 2013 Aug;24(7):743-53
pubmed: 23652277
Br J Cancer. 2009 Jul 21;101(2):263-8
pubmed: 19603032
Clin Cancer Res. 2009 May 15;15(10):3540-9
pubmed: 19447874
Ann Oncol. 2010 Feb;21(2):319-324
pubmed: 19633050
N Engl J Med. 2011 Feb 10;364(6):501-13
pubmed: 21306237
Cancer Discov. 2013 Aug;3(8):849-61
pubmed: 23811619
Cancer Treat Rev. 2017 Jun;57:16-27
pubmed: 28527407
Clin Cancer Res. 2010 Feb 15;16(4):1100-7
pubmed: 20145177
Lancet Oncol. 2015 Feb;16(2):152-60
pubmed: 25601341
Clin Genitourin Cancer. 2019 Aug;17(4):241-247.e1
pubmed: 31227432
Lancet. 2006 Oct 14;368(9544):1329-38
pubmed: 17046465
Eur Urol. 2018 Jul;74(1):17-23
pubmed: 28939004
N Engl J Med. 2014 Jul 31;371(5):424-33
pubmed: 24881730
Urology. 2011 May;77(5):1166-71
pubmed: 21539969
Eur Urol. 2014 Nov;66(5):815-25
pubmed: 24647231
N Engl J Med. 2017 Jul 27;377(4):338-351
pubmed: 28578639
Lancet Oncol. 2019 May;20(5):686-700
pubmed: 30987939
Lancet Oncol. 2013 Dec;14(13):1307-16
pubmed: 24211163
Cancer. 2012 Jan 1;118(1):63-71
pubmed: 21976132
N Engl J Med. 2007 Jan 11;356(2):115-24
pubmed: 17215529
Invest New Drugs. 2014 Oct;32(5):1005-16
pubmed: 24788563
Ann Oncol. 2009 May;20(5):913-20
pubmed: 19403935
Ann Oncol. 2007 Nov;18(11):1765-73
pubmed: 17426060
Eur Urol. 2017 Feb;71(2):151-154
pubmed: 27477525
Clinics (Sao Paulo). 2006 Oct;61(5):401-8
pubmed: 17072437
J Clin Oncol. 2008 Mar 1;26(7):1148-59
pubmed: 18309951
Lancet Oncol. 2012 Oct;13(10):983-92
pubmed: 22995653
N Engl J Med. 2010 Jun 17;362(24):2260-70
pubmed: 20525995
BMC Cancer. 2019 Jan 14;19(1):60
pubmed: 30642291
J Clin Oncol. 2014 Jan 10;32(2):76-82
pubmed: 24323035
Invest New Drugs. 2016 Dec;34(6):771-776
pubmed: 27565809
Clin Cancer Res. 2009 Dec 1;15(23):7421-8
pubmed: 19920114
Oncotarget. 2017 Feb 7;8(6):10324-10347
pubmed: 28055971
J Med Chem. 2004 Dec 30;47(27):6658-61
pubmed: 15615512
Cancer Res. 2006 Oct 1;66(19):9566-75
pubmed: 17018613
Cancer Res. 2008 May 1;68(9):3323-33
pubmed: 18451159