Abstract and Introduction
Androgen deprivation is the mainstay of advanced prostate cancer treatment. Despite initial responses, almost all patients progress to castration-resistant prostate cancer (CRPC). The understanding of the biology of CRPC and the evidence that CRPC still remains driven by androgen receptor signaling led to the discovery of new therapeutic targets. In the last few years, large Phase III trials showed improvements in survival and outcomes and led to the approval of a CYP17 inhibitor (abiraterone), an androgen receptor antagonist (enzalutamide), the taxane cabazitaxel, an α-emitter (radium-223), the bone resorption-targeting drug denosumab and an immunotherapy (sipuleucel-T). This article describes the molecular mechanisms underlying castration resistance, discusses recent and ongoing trials and offers some insights into identifying the best sequence of new drugs.
Androgen deprivation is the mainstay of therapy for advanced prostate cancer, and this treatment leads to prostate-specific antigen (PSA) responses and clinical improvements in more than 90% of patients; however, this treatment is not curative and the majority of patients eventually become castrate resistant. The term 'castration-resistant prostate cancer' (CRPC) identifies a heterogeneous group of both symptomatic and asymptomatic patients with or without clinical metastases. The Prostate Cancer Working Group 2 (PCWG2) recommendations improved clinical trials during the beginning of the 21st century, clearly defining CRPC as prostate cancer progressed despite castrate levels of testosterone (<0.5 ng/ml); this progression may be biochemical, radiological or symptomatic.
In recent years, the introduction of highly effective novel therapies has significantly changed the treatment landscape of metastatic CRPC (mCRPC) patients, with overall survival (OS) increasing from approximately 9–18 months to >30 months, with associated symptomatic benefits. From 2002 onward, a stepwise improvement in the management of mCRPC patients was observed: in 2002, it was shown that treatment with zoledronic acid could reduce skeletal-related event (SRE) incidence; and in 2004, the TAX 327 study demonstrated that docetaxel improves OS and the SWOG 9916 trial demonstrated that docetaxel plus extramustine prolonges OS and progression-free survival (PFS). In 2010, immunotherapy with sipuleucel-T was approved by the US FDA due to treated patients experiencing prolonged survival. In 2011, a novel tubulin-binding taxane, cabazitaxel, demonstrated its efficacy as a second-line chemotherapy and treatment with denosumab significantly prolonged the median time to the first SRE. Between 2011 and 2012, two new hormonal agents, abiraterone acetate and enzalutamide, showed further OS improvements as second-line therapies.[10,11] In 2013, radium-223, an α-emitting radium isotope, became available to clinical practice due to its efficacy in prolonging OS and in delaying the time to the first symptomatic skeletal event (SSE).
This article provides an overview of the evolution of the current treatment landscape for mCRPC and reviews the novel therapeutic agents currently in clinical evaluation.
Future Oncol. 2015;11(1):91-106. © 2015 Future Medicine Ltd.