2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Prognostic, Predictive, and Surrogate Factors
for Individualizing Treatment for Men with
Castration-Resistant Prostate Cancer
By Rhonda L. Bitting, MD, and Andrew J. Armstrong, MD, MSc
Overview: With thesurge in therapeutic options for castrationresistant
prostate cancer (CRPC) comes increasingly complicated
treatment decision making, highlighting the need for
biomarkers that can identify appropriate patients for specific
WITH THE increasing number of U.S. Food and Drug
Administration (FDA) approvals of new systemic
agents for men with metastatic CRPC over the past 2 years,
the optimal treatment strategy and sequence of therapies
are evolving quickly. With novel immunotherapies, hormonal
therapies, bone-targeted radioisotopes, bone microenvironment–targeted
agents, and chemotherapies emerging
in both the predocetaxel and postdocetaxel space, it becomes
imperative to develop rational combinations and sequences
of these agents, as well as to identify groups of men that are
most likely to benefit from a particular treatment. Thus,
there is an increasing need for biomarkers to help guide
clinical decision making, especially considering the number
of emerging agents currently in development and the high
cost of these therapies. Here we discuss the role, context of
use, and the limitations of existing biomarkers in CRPC. We
also examine approaches for the evaluation of novel biomarkers
in clinical trials depending on the clinical or research
context of use.
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.” 1 Biomarkers are
intended to guide the treatment of patients, and they can be
prognostic, predictive, pharmacodynamic, correlative, and/or
surrogate in nature. A prognostic biomarker reflects a patient’s
disease outcome independent of therapy (natural
history), whereas a predictive biomarker identifies the likelihood
of benefit from a specific therapy. 2 A number of
prognostic biomarkers have been reported in CRPC (Table
1); however, there are no validated predictive biomarkers in
this disease. Although predictive biomarkers exist in oncology
(e.g., HER2 overexpression in breast cancer predicts for
benefit with anti-HER2 agents, BRAF mutations predict for
improved outcomes with BRAF inhibitors in melanoma,
anaplastic lymphoma kinase [ALK] fusions predict for benefit
to ALK tyrosine kinase inhibitors in lung adenocarcinoma),
prostate cancer has lagged behind in the clinical
application of predictive biomarkers in drug development.
These predictive biomarkers offer the hope of individualized
approaches to therapy, breaking down a generally heterogeneous
disease into more homogeneous molecularly defined
subsets of patients in order to maximize benefit and minimize
harm.
In addition, surrogate biomarkers of overall survival (OS)
remain uncertain in CRPC, in which measures such as
progression-free survival (PFS), radiographic or pain responses,
and prostate-specific antigen (PSA) declines have
generally fallen short of a generalizable surrogate. A surrogate
biomarker is a biomarker that can substitute for a
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treatments and accurately assess disease response. Here we
discuss existing and potential prognostic, predictive, and
surrogate biomarkers in CRPC.
clinically important endpoint such as OS but must meet
several statistical criteria (such as Prentice’s criteria) and be
validated across multiple trials examining agents with a
range of mechanisms and clinical contexts. 3 Ongoing work
in CRPC to identify optimal surrogate biomarkers, particularly
in the fields of circulating tumor cell (CTC) characterization
and optimal classifications of radiographic
progression in CRPC, holds some promise in providing early
evidence of activity for novel therapies and thus accelerated
drug approvals and delivery of active agents into the clinic.
However, much work is to be done on this front.
Certain biomarkers are entirely used for determining
drug mechanism or metabolism (pharmacogenomic or pharmacogenetic)
and will not be further discussed in this
review. These biomarkers are essential, however, in identifying
pathophysiology and drug mechanism and in suggesting
predictive and surrogate measures of clinical efficacy,
and they are typically explored in the initial characterization,
validation, and qualification of a biomarker. As biomarkers
emerge in clinical settings, these predictive or
surrogate factors can potentially guide treatment decision
making (e.g., when to start a therapy, who to offer a therapy
to, when to stop a treatment and declare failure or response),
underscoring the need for a rigorous approach to the development
of predictive and surrogate biomarkers in parallel
with drug development in CRPC.
Prognostic Biomarkers in CRPC
The sections below provide advantages, limitations, and
evidence for use of common serologic and urinary biomarkers
in CRPC. Imaging response, pain, and quality-of-life
changes are not addressed here, though Table 1 provides a
comprehensive list of prognostic biomarkers in CRPC.
PSA
Serum PSA often reflects the disease burden in men with
CRPC and has been included in prognostic models as an
independent risk factor for disease-related mortality. 4
Changes in PSA over time during treatment may be informative
regarding a patient’s response to therapy; however,
this response is variable depending on the mechanism of
action of the therapy. For example, treatment with the
immunotherapy sipuleucel-T improves survival without
From the Duke Cancer Institute and the Duke Prostate Center, Durham, NC.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Andrew Armstrong, MD, MSc, Duke University Medical
Center 102002, Durham, NC 27710; email: andrew.armstrong@duke.edu..
© 2012 by American Society of Clinical Oncology.
1092-9118/10/1-10