2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

INDIVIDUALIZING TREATMENT FOR MEN WITH CRPC
Table 2. Post-treatment Prognostic and Potential Surrogate Endpoints in CRPC a
Biomarker References Pros Cons
PSA decline 6, 7 Easily measurable Not validated for use with novel agents
Widely available PSA flares may occur
Time � 3 mo Threshold of response unclear
Evidence to support use with cytotoxic therapy Not useful with immunotherapy
Subgroups of CRPC do not make PSA
CTCs 15, 18, 19 Change before PSA Not present in all CRPC using CellSearch
Tumor-specific Expensive
Strongly prognostic Requires specialized lab
Surrogacy use under evaluation Requires processing within 72 h
May reflect current disease phenotype New CTC definitions and technologies require validation
Bone turnover markers 30 Reflects tumor-stromal interaction Normal in patients without bony metastases
Widely available May be normal if bony metastases
Prognostic Clinical relevance of partial changes unclear
Quality-of-life or pain improvement 6, 36 Direct patient measure Qualitative, requires validated scales
Subjective and variable
May be multifactorial
Inherent biases
Radiographic changes (RECIST 1.1, PCWG2) 8, 16, 34 Well-defined criteria for response Not useful if nonmetastatic disease
Not always measurable (i.e., bone lesions)
Only modestly prognostic
Bone scan flare may occur
Some agents (i.e., immunotherapy) may have benefit
without affecting imaging
PFS (PCWG2) 9, 10 May capture clinical benefit Exact definition is critical
Can measure effect of cytostatic agents Not validated as a surrogate for OS
Censorship prevents current surrogate analyses
Abbreviations: CRPC, castration-resistant prostate cancer; CTC, circulating tumor cell; h, hours; mo, months; OS, overall survival; PFS, progression-free survival;
PSA, prostate-specific antigen.
a Adapted from Armstrong and colleagues. 35
however, it is an indirect measurement that detects not only
the cancer but also unassociated inflammation and degeneration.
In fact, effective therapies sometimes cause what
appear to be enlarging bony lesions but actually represent
healing bone surrounding cancerous bone, known as the
flare phenomenon or osteoblastic reactions. 34 To account for
this, bone scan progression per PCWG2 criteria requires the
confirmation of bony lesions on a subsequent scan. 8 Overall,
however, there is only a modest correlation between bone
scan changes and survival in CRPC to date. 9
The time from the initiation of therapy or study entry to
the documentation of disease progression is known as
progression-free survival. Because PFS is generally measurable
sooner than OS, has more independent events than OS,
and is not confounded by subsequent therapeutic interventions,
PFS is a convenient endpoint for use in clinical
trials. 17 The major limitation of the PFS endpoint is that
disease progression can be suggested by PSA alone, radiographic
changes based on lesion size or the presence of new
lesions, and/or symptomatology, and the clinical significance
of each varies. The PCWG2 criteria for disease progression
provides a consensus on the definition, but the relevance of
this outcome depends on the mechanism of action of the
therapy. 8 Immunotherapy, for example, prolongs OS without
affecting PFS, therefore, the use of PFS as a surrogate
for survival must be considered in the context of the therapy
in question and drug mechanism. 5 Given the poor correlation
of PFS and OS across phase III trials in CRPC, we are
faced with a conundrum of how to approve drugs based only
on PFS benefit without knowing the full effect of a novel
agent on OS. 4 Table 2 provides a list of potential surrogate
biomarkers in CRPC as well as a brief summary of advantages
and disadvantages for each.
Predictive Biomarkers in CRPC
As described above, there are a number of prognostic
biomarkers in CRPC. However, there is a paucity of biomarkers
under consideration for predictive use, and only
CTCs are being evaluated in clinical trials for surrogacy use.
In an era where costs of medical therapies are skyrocketing
Table 3. Predictive Biomarkers under Consideration a
Biomarker Potential CRPC Application
CTC count Potential surrogate for OS with abiraterone,
prognostic predocetaxel, may be mechanismindependent
High urinary N-telopeptide Benefit from denosumab or zoledronic acid
or bone turnover markers
Androgen receptor splice
variants
Levels of androgen
precursors
Predict sensitivity or resistance to anti-androgens
(e.g., MDV3100) or to abiraterone
Predict benefit from androgen synthesis inhibitors
(e.g., abiraterone acetate or TAK700)
c-Met/HGF activity Enrich for benefit from c-met inhibitors (e.g.,
cabozantinib)
PTEN loss in CTCs or
metastases
Enrich for benefit from PI3 kinase pathway
inhibitors
Ras/raf mutations Potential benefit from ras pathway inhibitors (e.g.,
sorafenib, vemurafenib)
Tubulin mutations May predict resistance to microtubule-based
therapies (e.g., docetaxel, cabazitaxel)
DNA repair defects Enrich for benefit from PARP inhibitors
Myc amplification Predict sensitivity to cell-cycle inhibitors
(antiproliferation agents)
Abbreviations: CRPC, castration-resistant prostate cancer; CTC, circulating
tumor cell; HGF, hepatocyte growth factor; OS, overall survival; PARP, poly(adenosine
diphosphate [ADP] ribose) polymerase; PTEN, phosphatase and tensin
homolog.
a Adapted from Armstrong and colleagues. 35
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