A phase II trial of dasatinib in patients with metastatic castration-resistant prostate cancer treated previously with chemotherapy

Przemyslaw W. Twardowski, Jan H. Beumer, C. S. Chen, Andrew S. Kraft, Gurkamal S. Chatta, Masato Mitsuhashi, Wei Ye, Susan M. Christner, Michael B. Lilly

Research output: Contribution to journalArticle

29 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)743-753
Number of pages11
JournalAnti-cancer drugs
Volume24
Issue number7
DOIs
StatePublished - Aug 1 2013
Externally publishedYes

Keywords

  • SRC inhibition
  • dasatinib
  • prostate cancer

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Cancer Research

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  • Cite this

    Twardowski, P. W., Beumer, J. H., Chen, C. S., Kraft, A. S., Chatta, G. S., Mitsuhashi, M., Ye, W., Christner, S. M., & Lilly, M. B. (2013). A phase II trial of dasatinib in patients with metastatic castration-resistant prostate cancer treated previously with chemotherapy. Anti-cancer drugs, 24(7), 743-753. https://doi.org/10.1097/CAD.0b013e328361feb0