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Genitourinary Cancer

Using Surrogate Biomarkers to Predict Clinical Benefit in Men with Castration-Resistant Prostate Cancer: An Update and Review of the Literature

^aDepartments of Medicine and Surgery, Divisions of Medical Oncology and Urology, Duke Comprehensive Cancer Center and the Duke Prostate Center, Durham, North Carolina, USA; ^bDepartments of Medicine and Molecular Genetics and Microbiology, Duke Comprehensive Cancer Center and the Duke Prostate Center, Duke Institute for Genome Science and Policy, Durham, North Carolina, USA

Key Words. Prostate cancer • Surrogate markers • Prostate-specific antigen • src family kinases

Correspondence: Andrew J. Armstrong, M.D., Sc.M., Departments of Medicine and Surgery, Divisions of Medical Oncology and Urology, Duke Comprehensive Cancer Center and the Duke Prostate Center, DUMC Box 102002, Durham, NC 27710, USA. Telephone: 919-668-8797; Fax: 919-668-7117; e-mail: andrew.armstrong{at}duke.edu

Received March 10, 2009; accepted for publication July 20, 2009; first published online in THE ONCOLOGIST Express on August 14, 2009.

Disclosures: Andrew J. Armstrong: Research funding/contracted research: Bristol-Myers Squibb; Phillip G. Febbo: Research funding/contracted research: Bristol-Myers Squibb.

This article discusses the unlabeled, investigational, or alternative use of dasatinib (Bristol-Myers Squibb) and AZD0530 (AstraZeneca) for prostate cancer.

The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the independent peer reviewers.

Recurrent prostate cancer has a complex molecular etiology and a prolonged disease course. Although initially responsive to androgen ablation, many men eventually become castration resistant, develop skeletal metastases, and are palliatively treated with docetaxel-based chemotherapy, radiation therapy, bisphosphonates, and best supportive care. Given the modest success rates of the current standard of care, clinical trial enrollment is encouraged. Castration-resistant prostate cancer (CRPC) is a heterogeneous disease, both in clinical manifestations and outcomes, requiring an individualized approach to both patient care and trial design. Herein, we review surrogate markers of disease progression and treatment efficacy in advanced prostate cancer in light of recently published guidelines that have redefined eligibility, response criteria, and suitable endpoints in prostate cancer drug development. The guidelines have refined outcome measures to potentially better capture clinical benefit and the ability of novel targeted molecular and biologic agents to impact favorably on this disease. We consider prostate-specific antigen changes, circulating tumor cells, bone scan alterations, markers of bone metabolism (urinary N-telopeptide and bone-specific alkaline phosphatase), pain improvements, and progression-free survival. To illustrate the role and challenges of these potential biomarkers and endpoints in drug development, we discuss a class of novel molecularly targeted agents, the src kinase inhibitors. Given that there are currently no validated surrogate markers of overall survival for assessing early clinical benefit from systemic therapy in metastatic CRPC, incorporation of relevant biomarkers into all phases of clinical development is essential to accelerate drug development in this field.