REVIEWS The changing therapeutic landscape of castration-resistant prostate cancer Timothy A. Yap, Andrea Zivi, Aurelius Omlin and Johann S. de Bono Abstract | Castration-resistant prostate cancer (CRPC) has a poor prognosis and remains a significant therapeutic challenge. Before 2010, only docetaxel-based chemotherapy improved survival in patients with CRPC compared with mitoxantrone. Our improved understanding of the underlying biology of CRPC has heralded a new era in molecular anticancer drug development, with a myriad of novel anticancer drugs for CRPC entering the clinic. These include the novel taxane cabazitaxel, the vaccine sipuleucel‑T, the CYP17 inhibitor abiraterone, the novel androgen-receptor antagonist MDV‑3100 and the radioisotope alpharadin. With these developments, the management of patients with CRPC is changing. In this Review, we discuss these promising therapies along with other novel agents that are demonstrating early signs of activity in CRPC. We propose a treatment pathway for patients with CRPC and consider strategies to optimize the use of these agents, including the incorporation of predictive and intermediate end point biomarkers, such as circulating tumor cells. Yap, T. A. et al. Nat. Rev. Clin. Oncol. 8, 597–610 (2011); published online 9 August 2011; doi:10.1038/nrclinonc.2011.117
Introduction Prostate cancer is the most common malignancy, and the second leading cause of cancer mortality among men.1,2 Approximately 10–20% of patients with prostate cancer present with advanced-stage disease, while others develop disease progression to castration-resistant prostate cancer (CRPC), which has a poor prognosis and is a therapeutic challenge.3,4 Strategies developed to counteract androgendeprivation therapy (ADT) resistance have had only modest clinical benefit.5–8 Indeed, before 2010, only docetaxelbased chemot herapy improved overall survival in patients with CRPC compared with mitoxantrone.9,10 Improved understanding of the biology underlying CRPC has heralded a new era in molecular-targeted anticancer drug development.11 Many novel anticancer drugs are currently in clinical studies, and several promising agents are nearing completion or have recently completed late-phase clinical trials. It is likely that the treatment landscape for patients with CRPC will change inextri cably in the near future. In this Review, we focus on these promising therapies, propose a treatment pathway for patients with CRPC and suggest strategies to optimize the application of these agents. Finally, we detail promising novel targets, against which future agents in CRPC Competing interests T. A. Yap, A. Zivi, A. Omlin and J. S. de Bono declare an association with the following organization: The Institute of Cancer Research. J. S. de Bono also declares associations with the following companies: Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Cougar Biotechnology, Dendreon, Enzon, Exelixis, Genentech, GlaxoSmithKline, Medivation, Merck, Novartis, Pfizer, Roche, Sanofi-Aventis, Supergen, Takeda. See the article online for full details of the relationships.
may potentially be developed, and consider paradigms for modern clinical therapy for CRPC.
Targeting the AR The development of CRPC is characterized by a rise in prostate-specific antigen (PSA) and subsequent prog ression of disease despite castrate blood levels of testo sterone (
