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 70mg twice daily, amended to 100mg 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.

Augmentation of the anticancer activity of CYT997 in human prostate cancer by inhibiting Src activity

“…Dasatinib inhibits multiple tyrosine kinases including SRC kinases, which are implemented to promote androgen independence in metastatic castration-resistant prostate cancer (mCRPC) that makes malignant cells unresponsive to therapies [32, 33]. Some of the common chemo drugs used to treat prostate cancer are MTAs.…”

Anoikis and EMT: Lethal "Liaisons" during Cancer Progression

“…125 The Src inhibitor, Dasatinib, clinically approved for patients with chronic myelogenous leukemia, demonstrated a limited therapeutic response in patients with metastatic CRPC. 126 A single patient, however, exhibited a significant therapeutic response, indirectly supporting further molecular profiling to target selective patient populations. 126 The clinical evidence, in terms of the combination of such an anoikis-inducing agent with Docetaxel chemotherapy, failed to provide an additional therapeutic benefit in metastatic CRPC.…”

“…126 A single patient, however, exhibited a significant therapeutic response, indirectly supporting further molecular profiling to target selective patient populations. 126 The clinical evidence, in terms of the combination of such an anoikis-inducing agent with Docetaxel chemotherapy, failed to provide an additional therapeutic benefit in metastatic CRPC. 127 Bosutinib, another Src inhibitor, in combination with ABT-263, a Bcl-2 inhibitor, effectively induces anoikis in lung adenocarcinoma and in advanced leukemia resistant to kinase inhibitors.…”

A randomized phase II study of cediranib alone versus cediranib in combination with dasatinib in docetaxel resistant, castration resistant prostate cancer patients

“…This provides evidence of a potential effect of dasatinib in CRPC, particularly in those lacking androgen receptor activity. However, despite promising preclinical data, clinical results of Src inhibitors in CRPC have been disappointing, with limited antitumor activity observed in a phase II study of single agent dasatinib in chemotherapy-resistant patients [54], and a large randomized phase III trial (READY), in which the addition of dasatinib to docetaxel-based chemotherapy did not improve overall survival [55]. Our data are consistent with previous findings and suggest that other unknown mechanisms, such as pathways activation or signaling cross-talk, may drive the growth of tumor cell and play a role in the bone remodeling processes [70].…”