Management of Metastatic Castration-resistant Prostate Cancer

European Oncology & Haematology, 2011;7(4):251-256


The management of men with metastatic castration-resistant prostate cancer (CRPC) has taken several leaps forwards in the last two years, with the demonstration of improved overall survival with three novel agents (sipuleucel-T, cabazitaxel and abiraterone acetate) and a significant delay in skeletal-related events observed with denosumab. The pipeline of systemic therapies in prostate cancer remains strong, as multiple agents with a diverse array of mechanisms of action are demonstrating preliminary signs of clinical benefit, leading to more definitive Phase III confirmatory trials. In this review, we will discuss the evolving landscape of treatment options for men with CRPC, with a particular focus on currently approved and emerging treatment options for these patients. Knowledge of these evolving standards will help to optimise delivery of care and long-term outcomes in men with advanced CRPC.
Keywords: Castration-resistant prostate cancer, novel therapies, drug development, sipuleucel-T, cabazitaxel, abiraterone, denosumab, orteronel, MDV3100, ipilimumab
Disclosure: Emmanuel S Antonarakis has served as an advisor/consultant for Sanofi-Aventis.
Received: August 12, 2011 Accepted October 19, 2011 Citation European Oncology & Haematology, 2011;7(4):251-256
Correspondence: Emmanuel S Antonarakis, Prostate Cancer Research Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, CRB1-1M45, Baltimore, MD 21231-1000, US. E:

While much of the recent focus on prostate cancer relates to the over-diagnosis and over-treatment of this disease, each year almost 100,000 men in Europe and more than 30,000 men in the US still die of advanced prostate cancer, making it the second most common cause of cancer-related deaths.1 Androgen deprivation therapy is the most effective systemic treatment for recurrent prostate cancer; however, the vast majority of these patients will eventually develop resistance to hormonal approaches (see Table 1) necessitating other forms of therapy. Although several chemotherapeutic strategies have been employed to treat castration-resistant prostate cancer (CRPC), it was not until 2004 that one such approach was shown to be life-prolonging. In that year, two Phase III clinical trials reported a survival advantage with the use of docetaxel chemotherapy in men with metastatic CRPC,2,3 resulting in the US Food and Drug Administration (FDA) approval of this agent. However, while docetaxel is both palliative and life-prolonging, it is not the ultimate answer for patients with CRPC, as virtually all men develop eventual resistance to this chemotherapy agent or are unable to tolerate its toxicities long term.
Until 2010, there were no additional treatment options conferring a survival benefit for patients with CRPC, although mitoxantrone was often employed in these patients for its palliative effects on bone pain.4 This situation changed in 2010 when an autologous immunotherapy product, sipuleucel-T, was FDA approved for the treatment of minimally symptomatic or asymptomatic metastatic CRPC, based on the results of a randomised Phase III trial comparing this agent against a placebo. In that same year, a randomised Phase III trial demonstrated a survival advantage for a novel taxane, cabazitaxel, over mitoxantrone in men with metastatic CRPC that had progressed after prior docetaxel therapy. Based on those results, cabazitaxel was approved by the FDA for the second-line treatment of metastatic CRPC. Several months later, an oral agent with the ability to suppress extra-gonadal androgen synthesis, abiraterone, was also reported to improve survival in a Phase III study when evaluated against placebo in men with docetaxel-pre-treated metastatic CRPC, resulting in the FDA approval of this agent for patients that have previously received docetaxel (see Figure 1). In addition to these life-prolonging therapies, novel bone-targeting approaches are also being developed to address skeletal complications resulting from bone metastases. To this end, an osteoclast-inhibiting agent, denosumab, was FDA approved in 2010 for the prevention of skeletal-related events (SREs) in men with castration-resistant bone metastases after showing superiority against the previously approved bisphosphonate zoledronic acid (see Figure 1).
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Keywords: Castration-resistant prostate cancer, novel therapies, drug development, sipuleucel-T, cabazitaxel, abiraterone, denosumab, orteronel, MDV3100, ipilimumab