Biomarkers in the management and treatment of men with metastatic castration-resistant prostate cancer

Abstract

Context: We have recently witnessed a rapid increase in the number of effective systemic agents for men with metastatic castration-resistant prostate cancer (CRPC), including novel hormonal therapies (abiraterone acetate and MDV3100), immunotherapies (sipuleucel-T), chemotherapies (cabazitaxel), and bone microenvironment targeting agents (denosumab, radium 223). Given the increasing complexity of treatment decisions for this disease, major research and clinical priorities are (1) finding biomarkers that enable an understanding of the natural history and complex biology of this heterogeneous malignancy, (2) defining predictive biomarkers that identify men most likely to benefit from a given therapy, and (3) identifying biomarkers of early response or progression to optimize outcomes.

Objective: In this review, we discuss existing and potential biomarkers in CRPC and how they may currently inform prognosis, aid in treatment selection (predictive value), and relate to survival outcomes (surrogacy).

Evidence acquisition: PubMed-based literature searches and abstracts through September 2011 provided the basis for this literature review as well as expert opinion.

Evidence synthesis: We address blood and urine-based biomarkers such as prostate-specific antigen, lactate dehydrogenase, total and bone alkaline phosphatase and other bone turnover markers, hemoglobin, and circulating tumor cells in the context of prognosis, prediction, and patient selection for therapy. Given the inherent problems associated with defining progression-free survival in CRPC, the importance of biomarker development and the needed steps are highlighted. We place the discussion of biomarkers within the context of the design/intent of a trial and mechanism of action of a given systemic therapy. We discuss novel biomarker development and the pathway for surrogate or predictive biomarkers to become credentialed as useful tests that inform therapeutic decisions.

Conclusions: A greater understanding of biomarkers in CRPC permits a more personalized approach to care that maximizes benefit and minimizes harm and can inform clinical trials tailored to men most likely to derive benefit.

Fig. 1

The problem of defining progression-free survival (PFS) in castration-resistant prostate cancer (CRPC): the relationship with overall survival (OS) is nonlinear. Plot of the hazard ratios (HRs) for PFS on the x-axis versus OS on the y-axis in large reported phase 3 trials of men with metastatic CRPC that included information on both OS and PFS (typically prostate-specific antigen [PSA] PFS for the majority except Cougar 302, which reported radiographic PFS HR). Note that although differences in PFS definitions existed in these trials, these largely used older definitions did not account for bone scan or PSA flare and often included PSA as part of the progression criteria. The exception to this was the Cougar 301 trial that used the updated Prostate Cancer Working Group PFS criteria. A 1:1 relationship between PFS and OS would fall along the line drawn, which is seen for abiraterone, docetaxel, and cabazitaxel (note this is not a regression line). Immunotherapies (Prostvac, sipuleucel-T) fall below the line, whereas antiangiogenic therapies and satraplatin produced results above the line, indicating discordances between PFS and OS.