title: A phase II trial of dasatinib in patients with metastatic castration-resistant prostate cancer treated previously with chemotherapy.
abstract: There is a need for efficacious therapies for metastatic castration-resistant prostate cancer (mCRPC) after disease progression on docetaxel. The SRC tyrosine kinase and its related family members may be important drivers of prostate cancer and can be inhibited by dasatinib. mCRPC patients, after one previous chemotherapy, started dasatinib at 70 mg twice daily, amended to 100 mg daily. The primary endpoint was the disease control (DC) rate, defined as complete response (CR), partial response (PR), or stable disease (SD) in prostate specific antigen (PSA), RECIST, bone scan, and FACT-P score. Up to 41 patients were to be accrued (two-stage design, 21+20) to rule out a null-hypothesized effect of 5 versus 20% (α=0.05, β=0.1). Secondary endpoints included progression-free survival, toxicity, and pharmacokinetic and pharmacodynamic correlatives. Of 38 patients, 27 were evaluable for response or toxicity. The median duration of therapy was 55 days (6-284). Five patients showed DC after 8 weeks of therapy (18.5% DC, 95% CI: 6.3-38.1%). One PR (3.7% response rate, 95% CI: 0.1-19.0%) was observed in a patient treated for 284 days. Twelve patients (43%) discontinued treatment for toxicity. Dasatinib induced a decrease in phytohemagglutinin-stimulated CSF2, CD40L, GZMB, and IL-2 mRNAs in blood cells, indicating target engagement. Decreases in plasma IL-6 and bone alkaline phosphatase, and in urinary N-telopeptide, were associated with DC. Dasatinib has definite but limited activity in advanced mCRPC, and was poorly tolerated. The observation of a patient with prolonged, objective, clinically significant benefit warrants molecular profiling to select the appropriate patient population.
authors: Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA 91010, USA. ptwardowski@coh.org
authors: Przemyslaw W
authors: PW
authors: Twardowski
authors: Jan H
authors: JH
authors: Beumer
authors: C S
authors: CS
authors: Chen
authors: Andrew S
authors: AS
authors: Kraft
authors: Gurkamal S
authors: GS
authors: Chatta
authors: Masato
authors: M
authors: Mitsuhashi
authors: Wei
authors: W
authors: Ye
authors: Susan M
authors: SM
authors: Christner
authors: Michael B
authors: MB
authors: Lilly
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000069439:Dasatinib; D018572:Disease-Free Survival; D006801:Humans; D008297:Male; D008875:Middle Aged; D009919:Orchiectomy; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D013739:Testosterone / Q000097:blood; D013844:Thiazoles / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D013739:Testosterone; D017430:Prostate-Specific Antigen; D000069439:Dasatinib
references: Oncogene. 2005 Apr 28;24(19):3110-20
references: 15735682
references: J Clin Oncol. 2009 Apr 20;27(12):2022-9
references: 19289629
references: Int J Biol Sci. 2012;8(9):1248-53
references: 23136553
references: Lancet. 2010 Oct 2;376(9747):1147-54
references: 20888992
references: Clin Cancer Res. 2011 Nov 1;17(21):6897-904
references: 21903773
references: Blood. 2011 Apr 7;117(14):3733-6
references: 21346253
references: N Engl J Med. 2004 Oct 7;351(15):1502-12
references: 15470213
references: N Engl J Med. 2010 Jul 29;363(5):411-22
references: 20818862
references: Anticancer Drugs. 2009 Mar;20(3):179-84
references: 19396016
references: Curr Pharm Des. 2003;9(25):2043-59
references: 14529415
references: Semin Hematol. 2005 Oct;42(4 Suppl 4):S3-8
references: 16344099
references: Cancer Res. 2004 Oct 1;64(19):7156-68
references: 15466214
references: Cancer Res. 2005 Oct 15;65(20):9185-9
references: 16230377
references: J Immunol Methods. 2010 Dec 15;363(1):95-100
references: 20951704
references: Clin Cancer Res. 2011 Nov 1;17(21):6905-13
references: 22028489
references: Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13283-8
references: 17684099
references: N Engl J Med. 2011 May 26;364(21):1995-2005
references: 21612468
references: BJU Int. 2002 Feb;89(3):230-40
references: 11856103
references: Clin Cancer Res. 2006 Sep 15;12(18):5578-86
references: 17000695
references: J Clin Oncol. 1999 Nov;17(11):3461-7
references: 10550143
references: Blood. 2009 May 28;113(22):5401-11
references: 19349618
references: Am J Hematol. 2010 Mar;85(3):164-70
references: 20131302
references: J Clin Oncol. 2008 Mar 1;26(7):1148-59
references: 18309951
references: J Clin Pharmacol. 2008 Nov;48(11):1254-69
references: 18779376
references: J Immunol. 2000 Aug 1;165(3):1210-9
references: 10903718
references: Biochim Biophys Acta. 2002 Jun 21;1602(2):114-30
references: 12020799
references: Clin Cancer Res. 2009 Dec 1;15(23):7421-8
references: 19920114
references: Leuk Lymphoma. 2008 Apr;49(4):615-9
references: 18398720