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.
Written by:
Twardowski PW, Beumer JH, Chen CS, Kraft AS, Chatta GS, Mitsuhashi M, Ye W, Christner SM, Lilly MB. Are you the author?
Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte; Loma Linda University Cancer Center, Division of Hematology/Oncology, Loma Linda; Hitachi Chemical Research Center; Chao Family Comprehensive Cancer Center, Division of Hematology/Oncology, University of California, Irvine, California; Department of Pharmaceutical Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; Medical University of South Carolina Hollings Cancer Center, Division of Hematology/Oncology, Charleston, South Carolina, USA.
Reference: Anticancer Drugs. 2013 May 6. Epub ahead of print.
doi: 10.1097/CAD.0b013e328361feb0
PubMed Abstract
PMID: 23652277
