Elsevier

European Urology

Volume 61, Issue 3, March 2012, Pages 549-559
European Urology

Review – Prostate Cancer
Biomarkers in the Management and Treatment of Men with Metastatic Castration-Resistant Prostate Cancer

https://doi.org/10.1016/j.eururo.2011.11.009Get rights and content

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.

Introduction

In 2010–2011, four systemic therapies demonstrated improved overall survival (OS) in men with metastatic castration-resistant prostate cancer (CRPC) and have become part of the therapeutic arsenal. These include the androgen synthesis inhibitor abiraterone acetate (AA) [1], the immunotherapeutic sipuleucel-T [2], and the taxoid cabazitaxel [3]. In addition, the receptor activator of nuclear factor κ-B ligand (RANKL) inhibitor denosumab demonstrated a delay in the onset of skeletal-related events (SREs) in this setting [4], and the radioisotope radium 223 (233Ra) has demonstrated a survival improvement in men with symptomatic bone metastatic CRPC [5]. Given this rapidly changing landscape [6], the expense of these treatment options, and the number of novel agents in development [7], major priorities for both clinical practice and research include the evaluation of biomarkers able to guide therapeutic decision making. In this review, we provide a framework for understanding and using existing biomarkers in CRPC in clinical practice and discuss methods for evaluating novel biomarkers in research settings to maximize clinical benefit.

A biomarker is defined as a “characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” [8]. Thus a biomarker can be a blood test, a response to a validated questionnaire, or radiographic measurements, and it is intended to guide patient management. Biomarkers can be prognostic, predictive, or surrogate in nature, or they can serve multiple roles. A prognostic biomarker provides evidence about a patient's eventual outcomes from a disease independent of a given therapy, whereas a predictive biomarker estimates the likelihood of response/benefit to a specific therapy in a specific context [9]. In metastatic CRPC, a host of prognostic factors have been reported (Table 1), but qualified predictive biomarkers have not been reported. An example of a predictive biomarker in oncology is overexpression of the HER2 oncogene in breast cancer, which is adversely prognostic and also predicts benefit with trastuzumab [10]. A surrogate biomarker goes further and is able to substitute as an intermediate for a clinically meaningful end point such as OS [11]. To fulfill criteria for surrogacy in oncology, a biomarker must satisfy several key statistical criteria described in detail elsewhere [11], [12], [13], [14] and must also be validated across multiple trials of a variety of mechanistically distinct agents [11], [12]. However, for a biomarker to become clinically useful, it must also directly inform and/or alter a medical decision and the treatment algorithm based on its result. Although prognostic markers can be helpful, predictive and surrogate biomarkers carry a greater degree of importance given their direct relationship with treatment decision making. In this paper, we review a selection of validated biomarkers in CRPC and discuss their utility in both the clinical and research settings.

Section snippets

Evidence acquisition

We conducted a literature search using PubMed and American Society of Clinical Oncology or European Society for Medical Oncology abstracts through September 2011 using the search terms for a given biomarker or therapy and prostate cancer with a focus on castration-resistant metastatic disease. Papers were synthesized by one of the authors (AJA), with input from the other authors as to inclusion or exclusion of relevant publications, and all the authors approved the final manuscript.

Evidence synthesis

The following sections focus on the evidence, rationale, advantages, limitations, and recommendations for use and evaluation of blood and urine biomarkers in CRPC rather than the broader landscape of imaging tests and qualitative outcome measures such as pain responses or quality-of-life changes, which are addressed elsewhere [15], [16]. Table 1 provides a synthesized list of currently validated prognostic and predictive biomarkers, and Table 2 provides a broad list of potential surrogate

Conclusions

The clinical utility of biomarkers in men with CRPC is context dependent, meaning that usefulness depends on the clinical/translational question (prognosis, prediction, surrogacy, treatment resistance, pharmacodynamic) and how a biomarker will have an impact on clinical decision making for a given systemic therapy. Currently all biomarkers in clinical use have prognostic implications when measured prior to starting therapy, but they have not yet been credentialed as predictive or surrogate

References (83)

  • R.H. Christenson

    Biochemical markers of bone metabolism: an overview

    Clin Biochem

    (1997)
  • K. Jung et al.

    Bone turnover markers as predictors of mortality risk in prostate cancer patients with bone metastases following treatment with zoledronic acid

    Eur Urol

    (2011)
  • S. Nilsson et al.

    Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study

    Lancet Oncol

    (2007)
  • A.J. Armstrong et al.

    The development of risk groups in men with metastatic castration-resistant prostate cancer based on risk factors for PSA decline and survival

    Eur J Cancer

    (2010)
  • J.S. de Bono et al.

    Abiraterone and increased survival in metastatic prostate cancer

    N Engl J Med

    (2011)
  • P.W. Kantoff et al.

    Sipuleucel-T immunotherapy for castration-resistant prostate cancer

    N Engl J Med

    (2010)
  • E.S. Antonarakis et al.

    Evolving standards in the treatment of docetaxel-refractory castration-resistant prostate cancer

    Prostate Cancer Prostatic Dis

    (2011)
  • E.S. Antonarakis et al.

    Emerging therapeutic approaches in the management of metastatic castration-resistant prostate cancer

    Prostate Cancer Prostatic Dis

    (2011)
  • Biomarkers and surrogate endpoints: preferred definitions and conceptual framework Clin Pharmacol Ther...
  • J.E. Dancey et al.

    Guidelines for the development and incorporation of biomarker studies in early clinical trials of novel agents

    Clin Cancer Res

    (2010)
  • D.J. Slamon et al.

    Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2

    N Engl J Med

    (2001)
  • R.L. Prentice

    Surrogate endpoints in clinical trials: definition and operational criteria

    Stat Med

    (1989)
  • M. Buyse et al.

    The validation of surrogate endpoints in meta-analyses of randomized experiments

    Biostatistics

    (2000)
  • L.S. Freedman et al.

    Statistical validation of intermediate endpoints for chronic diseases

    Stat Med

    (1992)
  • M. Buyse et al.

    Biomarkers and surrogate end points—the challenge of statistical validation

    Nat Rev Clin Oncol

    (2010)
  • H.I. Scher et al.

    Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group

    J Clin Oncol

    (2008)
  • H.I. Scher et al.

    End points and outcomes in castration-resistant prostate cancer: from clinical trials to clinical practice

    J Clin Oncol

    (2011)
  • R.T. Vollmer et al.

    The dynamics of prostate specific antigen in hormone refractory prostate carcinoma: an analysis of cancer and leukemia group B study 9181 of megestrol acetate

    Cancer

    (1998)
  • A.J. Armstrong et al.

    A contemporary prognostic nomogram for men with hormone-refractory metastatic prostate cancer: a TAX327 study analysis

    Clin Cancer Res

    (2007)
  • S. Halabi et al.

    Prognostic model for predicting survival in men with hormone-refractory metastatic prostate cancer

    J Clin Oncol

    (2003)
  • A.J. Armstrong et al.

    Prostate-specific antigen and pain surrogacy analysis in metastatic hormone-refractory prostate cancer

    J Clin Oncol

    (2007)
  • D.P. Petrylak et al.

    Evaluation of prostate-specific antigen declines for surrogacy in patients treated on SWOG 99-16

    J Natl Cancer Inst

    (2006)
  • H.I. Scher et al.

    Post-therapy serum prostate-specific antigen level and survival in patients with androgen-independent prostate cancer

    J Natl Cancer Inst

    (1999)
  • W.D. Stein et al.

    Tumor regression and growth rates determined in five intramural NCI prostate cancer trials: the growth rate constant as an indicator of therapeutic efficacy

    Clin Cancer Res

    (2011)
  • S. Halabi et al.

    Progression-free survival as a predictor of overall survival in men with castrate-resistant prostate cancer

    J Clin Oncol

    (2009)
  • M. Hussain et al.

    Prostate-specific antigen progression predicts overall survival in patients with metastatic prostate cancer: data from Southwest Oncology Group Trials 9346 (Intergroup Study 0162) and 9916

    J Clin Oncol

    (2009)
  • H.I. Scher et al.

    Eligibility and outcomes reporting guidelines for clinical trials for patients in the state of a rising prostate-specific antigen: recommendations from the Prostate-Specific Antigen Working Group

    J Clin Oncol

    (2004)
  • H.I. Scher et al.

    The association between measures of progression and survival in castrate-metastatic prostate cancer

    Clin Cancer Res

    (2007)
  • M.R. Smith et al.

    Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer

    J Clin Oncol

    (2005)
  • M.R. Smith et al.

    Disease and host characteristics as predictors of time to first bone metastasis and death in men with progressive castration-resistant nonmetastatic prostate cancer

    Cancer

    (2011)
  • E. Banu et al.

    Serum PSA half-life as a predictor of survival for hormone-refractory prostate cancer patients: modelization using a standardized set of response criteria

    Prostate

    (2007)
  • Cited by (154)

    • New generation biomarkers for the detection of prostate cancer

      2022, Biosensors and Bioelectronics: X
      Citation Excerpt :

      Throughout recent years, the fundamental restriction of PSA-based discoveries was an evident absence of biopsy reports affirming negative results in ˃ 75% of men and even PSA levels in the scope of 4.0–10.0 ng/mL (Barry, 2001). Examination of ordinarily utilized PSA biomarkers beats the limits of prostate biopsy and works on precise testing (Armstrong et al., 2012). A PSA-based conclusion can't separate PCa from other prostatic side effects (De Marzo et al., 2007).

    View all citing articles on Scopus
    View full text