Treating patients with metastatic castration-resistant prostate cancer: a comprehensive review of available therapies.
Purpose: The availability of newly approved options for treatment of metastatic castration-resistant prostate cancer (mCRPC) is not matched with conclusive data on optimal sequencing strategies and resistance patterns. A comprehensive review of efficacy and safety data for new agents, and current knowledge regarding treatment sequencing, will enable treating physicians to make rational drug selections in patients with mCRPC.
Materials and Methods: We searched MEDLINE® and relevant congresses for data on cabazitaxel, docetaxel, radium-223 dichloride, abiraterone, enzalutamide and sipuleucel-T, focusing on sequencing strategies, resistance mechanisms and biomarkers of response.
Results: Abiraterone and enzalutamide target the androgen axis with different mechanisms of action-abiraterone blocks cytochrome P450 17 (CYP17), inhibiting androgen synthesis, whereas enzalutamide inhibits the androgen receptor (AR), reducing nuclear translocation of the AR complex and subsequent DNA binding. Both agents provide improved overall survival (OS) in mCRPC both in patients with prior docetaxel treatment and in chemotherapy-naive patients. Cabazitaxel provides improved OS in patients with mCRPC with prior docetaxel therapy, while sipuleucel-T provides improved OS in asymptomatic patients and radium-223 provides improved OS in both chemotherapy-naive and chemotherapy-treated patients with symptomatic bone metastases. Selecting the correct treatment for patients with mCRPC is complex, as no head-to-head trials have been conducted, and comparison between existing trials is difficult due to differences in study populations and a lack of validated biomarkers. Factors to consider include prior therapy, symptom burden, type of metastases, performance status, comorbidities, AE profiles and patient preference. Another consideration is treatment sequence, as some agents affect responses to subsequent choices. For example, resistance to abiraterone or enzalutamide may result in limited responses to subsequent androgen-targeted agents. Identification of factors predictive of resistance is an area of ongoing research, with androgen-receptor variants representing a good candidate. Prognostic factors for survival are also likely to be useful and are currently being studied.
Conclusions: New therapies for mCRPC have brought new challenges with regard to treatment selection and sequencing. While hormonal agents provide good therapeutic responses, resistance may be intrinsic without prior drug exposure. Identifying predictors of response and relevant biomarkers will allow therapies to be more precisely tailored to individual patient profiles.