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.

Conflict of interest statement

Conflicts of interest

There are no conflicts of interest.

Figures

Fig. 1

Confirmed partial prostate specific antigen (PSA) response during therapy.

Fig. 2

Computed tomography scans showing partial response of lung metastases by RECIST in the same patient with a prostate specific antigen response.

Fig. 3

Waterfall plot of changes in prostate specific antigen (PSA) levels among patients with or without disease control on day 56.

Fig. 4

PFS according to the PCWG2 criteria in patients with DC or who failed to achieve DC. PCWG2, Prostate Cancer Working Group 2.

Fig. 5

(a–c) Relationship between disease control and biochemical parameters in patients evaluable for response. (a) Plasma bone alkaline phosphatase; (b) urinary N-telopeptide; and (c) plasma IL-6.

Fig. 6

Ex-vivo inhibition of cytokine mRNA expression in PHA-stimulated whole blood. Blood from a normal volunteer was treated ex vivo with the indicated concentrations of dasatinib, and then stimulated with PHA for 2 h. mRNAs were then extracted and analyzed (CSF2, IL-2, CD40L). Each point represents the mean (±SD) of triplicate determinations from a representative experiment. Fold increase was calculated by 2ΔCt [19]. PHA, phytohemagglutinin.

Fig. 7

(a–d) Time course of cytokine mRNA suppression following institution of dasatinib therapy. Whole blood was obtained serially within 6 h of the daily dose of dasatinib, and then stimulated ex vivo with PHA×4 h, followed by cytokine mRNA assessment. (a) CD40L, (b)GZMB, (c) CSF2, (d) IL-2. P-values are for comparisons between day 0 and later days. For each sample, the cytokine mRNA measurements were normalized to that sample’s level of ACTB mRNA (=1).

Fig. 8

(a–d) A dose–response relationship between cytokine mRNA expression and plasma dasatinib level. Whole blood was obtained within 6 h of dasatinib administration, and then assayed for both cytokine mRNA expression [(a) CD40L, (b) CSF2, (c) GZMB, (d) IL-2], and dasatinib level. The range of dasatinib levels was divided into quartiles.

Fig. 9

Estimation of IC50 values for dasatinib in inhibiting cytokine mRNA expression (IL-2) in vivo. Blood samples were obtained from patients taking dasatinib, and then analyzed for plasma dasatinib level and IL-2 mRNA expression. For each sample, the cytokine mRNA measurements were normalized to that sample’s level of ACTB mRNA (=1). CI, confidence interval.