Promising Results with Dasatinib Added to Docetaxel for Treating Castration-resistant Prostate Cancer

Abstract & Commentary

By William B. Ershler, MD

Synopsis: The tyrosine kinase inhibitor dasatinib was added to docetaxel in the treatment of advanced castration-resistant prostate cancer in a Phase 1-2 trial. The combination was shown to be generally well-tolerated and to result in markers of reduced bone turnover in the great majority of patients and in durable PSA responses in approximately 50%. The findings justify proceeding to Phase 3 clinical trial.

Source: Araujo JC, et al. Dasatinib combied with docetaxel for castration-resistant prostate cancer. Results from a Phase 1-2 study. Cancer 2012;118:63-71.

Treatment of castration-resistant prostate cancer remains challenging primarily because of the relentless progression of metastatic disease within bone and visceral tissue. Chemotherapy, such as with docetaxel, has provided limited benefit, and current research has focused on targets that are involved in disease progression. In vitro and animal model research has indicated certain tyrosine kinases are important in the generation of mediators that influence prostate cancer growth, invasion, and metastases.1,2 Furthermore, tyrosine kinase inhibitors have been shown to modulate the production of these mediators and restrain tumor growth in these models.3-6 Thus, a rationale for the study of tyrosine kinase inhibitors in the setting of progressive prostate cancer has been established.

In the current report, Araujo and colleagues conducted a Phase 1-2 trial combining docetaxel with dasatinib, an oral SRC inhibitor to determine the potential efficacy of targeting both the tumor and bone microenvironment in patients with castration-resistant prostate cancer. The Phase 1 part of the trial involved escalating doses of dasatinib (from 50 mg once daily to 120 mg once daily) and docetaxel (60 to 75 mg/m2) every 21 days in to a total of 15 patients. In Phase 2, 30 additional patients received dasatinib 100 mg once daily/docetaxel 75 mg/m2 every 21 days. Efficacy endpoints included changes in prostate-specific antigen (PSA), measurable disease, bone scans, and markers of bone metabolism. Safety and pharmacokinetics were also studied.

Combination dasatinib and docetaxel therapy was generally well tolerated. Thirteen of 46 patients (28%) had a grade 3-4 toxicity. Pharmacokinetic analysis indicated no drug-drug interactions, and in the Phase 1 study, a maximum tolerated dose was not identified. Durable 50% PSA declines occurred in 26 of 46 patients (57%). Of 30 patients with measurable disease, 18 (60%) had a partial response. Fourteen patients (30%) had disappearance of a lesion on bone scan. In bone marker assessments, 33 of 38 (87%) and 26 of 34 (76%) had decreases in urinary N-telopeptide or bone-specific alkaline phosphatase levels, respectively. Twenty-eight patients (61%) received single-agent dasatinib after docetaxel discontinuation and had stabilization of disease for an additional 1 to 12 months.

Commentary

Chemotherapy for castrate-resistant prostate cancer provides some, but limited, improvement in overall survival and is associated with toxicity.7-9 However, therapy targeted at mediators of disease progression, particularly in bone, hold some promise. Dasatinib is a potent inhibitor of SRC-family kinases and is one such targeted therapy that is being explored in this regard, either as a single agent,10,11 or in combination with docetaxel, as in the current report.

In this study dasatinib and docetaxel combination therapy was shown to be well-tolerated and to have encouraging efficacy.

The relatively high objective response rate and favorable toxicity profile are sufficient justification to proceed to randomized studies of docetaxel and dasatinib in castration-resistant prostate cancer. Based on this study, it is quite likely that the combination will prove superior to docetaxel alone, but a number of questions related to the comparative tolerability and safety, the appropriate time to start, and how long the combined or dasatinib treatment alone should continue will need to be addressed.

References

1. Chen N, et al. A secreted isoform of ErbB3 promotes osteonectin expression in bone and enhances the invasiveness of prostate cancer cells. Cancer Res 2007;67:6544-6548.

2. Kimura T, et al. Targeting of bone-derived insulin-like growth factor-II by a human neutralizing antibody suppresses the growth of prostate cancer cells in a human bone environment. Clin Cancer Res 2010;16:121-129.

3. Koreckij T, et al. Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis. Br J Cancer 2009;101:263-268.

4. Nam S, et al. Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells. Cancer Res 2005;65:9185-9189.

5. Park SI, et al. Targeting SRC family kinases inhibits growth and lymph node metastases of prostate cancer in an orthotopic nude mouse model. Cancer Res 2008;68:3323-3333.

6. Recchia I, et al. Pyrrolopyrimidine c-Src inhibitors reduce growth, adhesion, motility and invasion of prostate cancer cells in vitro. Eur J Cancer 2003;39:1927-1935.

7. Berthold DR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: Updated survival in the TAX 327 study. J Clin Oncol 2008;26:242-245.

8. Petrylak DP, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351:1513-1520.

9. Tannock IF, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351:1502-1512.

10. Yu EY, et al. Once-daily dasatinib: Expansion of phase II study evaluating safety and efficacy of dasatinib in patients with metastatic castration-resistant prostate cancer. Urology 2011;77:1166-1171.

11. Yu EY, et al. Phase II study of dasatinib in patients with metastatic castration-resistant prostate cancer. Clin Cancer Res 2009;15:7421-7428.