Challenges and Opportunities in Hormone-Resistant Prostate Cancer

ContextThe lack of options available for the treatment of hormone-resistant prostate cancer (HRPC) presents a significant challenge to clinicians. In the TAX 327 trial, treatment with docetaxel plus prednisone was demonstrated to improve survival compared with mitoxantrone plus prednisone but was associated with a higher incidence of adverse events, notably haematologic toxicities. Indeed, there is debate about the use of this cytotoxic regimen, particularly for patients with metastatic disease who are asymptomatic or only mildly symptomatic for pain.ObjectiveThere is a need to develop less toxic regimens suitable for such patients and to develop treatment options which offer better efficacy than the currently available agents.Evidence acquisitionA nonsystematic review of the literature was performed in 2008. Databases browsed included PubMed, abstracts from congresses, and PR Newswire.Evidence synthesisA number of studies have been conducted or are underway to investigate the use of docetaxel in combination with a number of new agents, including high-dose calcitriol and the antiangiogenesis agents bevacizumab and aflibercept. Other treatments administered as monotherapy include abiraterone, denosumab, and satraplatin and the cancer vaccines G-VAX and Provenge.One promising novel approach is antagonism of the endothelin A (ETA) receptor, which plays a key role in tumour progression in HRPC. Atrasentan is an endothelin receptor antagonist with selectivity for the ETA receptor and in a phase 2 study was associated with a significantly increased time to progression versus placebo. The atrasentan phase 3 study failed to meet its primary end point, although this may have been related to limitations inherent in the trial design. ZD4054 is a specific ETA receptor antagonist that has shown a promising improvement in overall survival versus placebo in a phase 2 study and was generally well tolerated.ConclusionsThe ENdoTHelin A USE (ENTHUSE) programme, consisting of three large, multicentre phase 3 trials, is now ongoing to study ZD4054 as a monotherapy or in combination with docetaxel in patients with M0 and M1 HRPC.