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Platelet-Derived Growth Factor Receptor Inhibition and Chemotherapy for Castration-Resistant Prostate Cancer with Bone Metastases

Authors' Affiliations: Departments of ¹ Genitourinary Medical Oncology, ² Biostatistics, ³ Pathology, ⁴ Behavioral Sciences, and ⁵ Cancer Biology, and ⁶ Division of Quantitative Sciences, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; ⁷ Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; ⁸ Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; and ⁹ Sarah Cannon Cancer Center, Nashville, Tennessee

Requests for reprints: Paul Mathew, Department of Genitourinary Medical Oncology, Unit 1374, The University of Texas M. D. Anderson Cancer Center, 1155 Herman P. Pressler, Houston, TX 77030. Phone: 713-792-2830; Fax: 713-745-1625; E-mail: pmathew{at}mdanderson.org.

Purpose: To further assess preclinical and early clinical evidence that imatinib mesylate, a platelet-derived growth factor receptor (PDGFR) inhibitor, modulates taxane activity in prostate cancer and bone metastases, a randomized study was conducted.

Experimental Design: Men with progressive castration-resistant prostate cancer with bone metastases (n = 144) were planned for equal randomization to i.v. 30 mg/m² docetaxel on days 1, 8, 15, and 22 every 42 days with 600 mg imatinib daily or placebo, for an improvement in median progression-free survival from 4.5 to 7.5 months (two-sided = 0.05 and ß = 0.20). Secondary end points included differential toxicity and bone turnover markers, tumor phosphorylated PDGFR (p-PDGFR) expression, and modulation of p-PDGFR in peripheral blood leukocytes.

Results: Accrual was halted early because of adverse gastrointestinal events. Among 116 evaluable men (57 docetaxel + imatinib; 59 docetaxel + placebo), respective median times to progression were 4.2 months (95% confidence interval, 3.1-7.5) and 4.2 months (95% confidence interval, 3.0-6.8; P = 0.58, log-rank test). Excess grade 3 toxicities (n = 23) in the docetaxel + imatinib group were principally fatigue and gastrointestinal. Tumor p-PDGFR expression was observed in 12 of 14 (86%) evaluable bone specimens. In peripheral blood leukocytes, p-PDGFR reduction was more likely in docetaxel + imatinib–treated patients compared with docetaxel + placebo (P < 0.0001), as were reductions in urine N-telopeptides (P = 0.004) but not serum bone-specific alkaline phosphatase (P = 0.099).

Conclusions: These clinical and translational results question the value of PDGFR inhibition with taxane chemotherapy in prostate cancer bone metastases and are at variance with the preclinical studies. This discordance requires explanation.

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