Dasatinib combined with docetaxel for castration-resistant prostate cancer: results from a phase 1-2 study

Abstract

Background: To determine the potential efficacy of targeting both the tumor and bone microenvironment in patients with castration-resistant prostate cancer (PC), the authors conducted a phase 1-2 trial combining docetaxel with dasatinib, an oral SRC inhibitor.

Methods: In phase 1, 16 men received dasatinib 50 to 120 mg once daily and docetaxel 60 to 75 mg/m(2) every 21 days. In phase 2, 30 additional men received dasatinib 100 mg once daily/docetaxel 75 mg/m(2) 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.

Results: Combination dasatinib and docetaxel therapy was generally well tolerated. Thirteen of 46 patients (28%) had a grade 3-4 toxicity. Drug-drug interactions and a maximum tolerated dose were 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.

Conclusions: The high objective response rate and favorable toxicity profile are promising and justify randomized studies of docetaxel and dasatinib in castration-resistant PC. Parallel declines in levels of PSA and bone markers are consistent with cotargeting of epithelial and bone compartments of the cancer. Treatment with single-agent dasatinib following docetaxel cessation warrants further study. Cancer 2012;. © 2011 American Cancer Society.

Trial registration: ClinicalTrials.gov NCT00439270.

Conflict of interest statement

Conflicts of Interest:

GCT is an employee of and owns stocks in Bristol-Myers Squibb. PP and SA are employees of Bristol-Myers Squibb. AJA has received research funding from and acted in a consultant/advisory role for Bristol-Myers Squibb, has received research funding and honoraria from sanofi-aventis, and received research funding from ImClone and Medivation. CJL has acted in a consultant/advisory role for and received research funding and honoraria from Bristol-Myers Squibb. JCA, PM, ELB, EP, ML, and GEG have no conflicts of interest to disclose.

Copyright © 2011 American Cancer Society.

Figures

Figure 1

Mean plasma concentrations (+ standard deviations) of dasatinib and docetaxel administered alone or in combination.

Figure 2

Waterfall plots showing maximal percentage changes from baseline in individual patients. (A) PSA. (B) Tumor size. (C) uNTX. (D) BAP. In Figures (C) and (D), patients who were receiving ongoing bisphosphonate therapy are shown by white bars.

Figure 2

Waterfall plots showing maximal percentage changes from baseline in individual patients. (A) PSA. (B) Tumor size. (C) uNTX. (D) BAP. In Figures (C) and (D), patients who were receiving ongoing bisphosphonate therapy are shown by white bars.

Figure 2

Waterfall plots showing maximal percentage changes from baseline in individual patients. (A) PSA. (B) Tumor size. (C) uNTX. (D) BAP. In Figures (C) and (D), patients who were receiving ongoing bisphosphonate therapy are shown by white bars.

Figure 2

Waterfall plots showing maximal percentage changes from baseline in individual patients. (A) PSA. (B) Tumor size. (C) uNTX. (D) BAP. In Figures (C) and (D), patients who were receiving ongoing bisphosphonate therapy are shown by white bars.