Taxane mechanisms of action: potential implications for treatment sequencing in metastatic castration-resistant prostate cancer

Abstract

Context: In the past few years, there has been a rapid increase in the number of therapies available to treat metastatic castration-resistant prostate cancer (mCRPC). Currently, approved treatments consist of the taxane class of cytotoxic drugs and androgen-targeted therapies. The challenge for clinicians is to decide the best sequence in which to give these therapies to provide the greatest benefit to their patients.

Objective: To review recent research into the mechanism of action of taxanes in prostate cancer (PCa) cells and the clinical evidence for an interaction between taxanes and androgen-targeted therapies. The implications of these findings for clinical practice are discussed.

Evidence acquisition: A nonsystematic review of the relevant medical literature between 2004 and the present, in combination with clinical trial data reported at oncology meetings during 2012, was undertaken. Our perspective, focussing on the potential implications for sequencing of therapies for mCRPC, is provided.

Evidence synthesis: Taxanes are shown to interact with androgen signalling in PCa cells at both the cytoplasmic level (via microtubules) and the nuclear level, affecting transcriptional regulators of androgen-responsive gene expression. Data from clinical trials suggest that androgen deprivation can potentially decrease the efficacy of taxanes in treating PCa.

Conclusions: These findings have important implications for clinical practice, and there is an urgent need for strong clinical data to support a recommendation for an optimal sequence of therapies.

Keywords: Abiraterone; Cabazitaxel; Castration-resistant prostate cancer; Docetaxel; Enzalutamide; Therapy sequence.