2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

INDIVIDUALIZING TREATMENT FOR MEN WITH CRPC
changing PSA levels, whereas a 30% or greater PSA decline
within 3 months of treatment initiation with the cytotoxic
agent docetaxel correlates with a survival benefit in retrospective
analyses. 5-7 However, there is no percentage of PSA
decline that consistently correlates with survival across
trials of a range of drug mechanisms, and therefore PSA
decline is not a surrogate for survival in itself and should not
be a primary endpoint for systemic therapy trials in CRPC
or for regulatory approval. Prospective evaluation is needed
for PSA declines in certain contexts where the correlation
appears strongest, particularly for hormonal therapies. 8
Likewise, PSA progression during therapy conveys a poor
prognosis but is not a surrogate for survival. 9,10 Early but
transient rises in PSA occur in up to 20% of men during
chemotherapy but do not affect survival. 11 PSA declines can
often lag or be slow to occur. Therefore, the Prostate Cancer
Working Group (PCWG2) recommends that PSA change not
be used in isolation to define disease progression or to stop
therapy, particularly during the first several months of
systemic therapy. Regular PSA evaluation is recommended
in clinical trials, however, so that it can be studied independently
but in the context of other disease-related outcomes. 8
Reporting of PSA changes in the form of descriptive water-
KEY POINTS
● The utility of a biomarker depends on the clinical
question and its context of use.
● Prostate-specific antigen (PSA), circulating tumor
cell (CTC) count, markers of bone turnover, lactate
dehydrogenase, and hemoglobin are traditional biomarkers
that are correlated with overall survival in
castration-resistant prostate cancer (CRPC) but are
not predictive of benefit from specific therapies in
CRPC.
● Predictive biomarkers of sensitivity to systemic therapies
in CRPC are needed and are likely to be based
on the mechanism of action of a given agent (i.e.,
androgen receptor activity and MDV3100, microtubule
mutations and docetaxel sensitivity, androgen
precursor levels and abiraterone sensitivity, phosphatase
and tensin homolog loss or phosphoinositide
3-kinase (PI3K) pathway activation and PI3K pathway
inhibitors) and may be determined from tumor
tissue or blood-/plasma-/urine-based assays such as
CTCs or cell-free tumor DNA.
● Improvements in PSA, CTC count, pain, radiographic
tumor burden, and/or quality of life and delays in
progression are associated with improved prognosis
post-treatment, and work is ongoing to determine the
association of these improvements with overall survival
in patients with CRPC in a range of contexts.
● Although there are no current validated surrogates
for overall survival in CRPC, it is imperative that
we incorporate intermediate endpoints and biomarkers
into clinical trial design to develop potential
surrogates of activity in order to accelerate drug
development.
Table 1. Prognostic Factors in CRPC a
Baseline Prognostic Factors Post-Treatment Prognostic Factors Predictive Factors
Performance status PSA decline None validated
Visceral metastatic disease Pain improvement See Table 3
Anemia Quality-of-life improvement
Alkaline phosphatase and
other bone turnover
markers (e.g., TRAP)
Change in CTC count to � 5
PSA PSA PFS
PSA kinetics Radiographic response PFS
Type of progression (bone,
measurable disease, PSA
only)
Induction of immunity to tumor
antigens (sipuleucel-T)
CTC count Skeletal-related event
development
LDH Development of anemia
Albumin LDH changes
Pain Type of progression
Number of disease sites Alkaline phosphatase
improvements
Age
VEGF levels
Interleukin-6 levels
Chromogranin-A
C-reactive protein
Bone turnover markers
Gleason sum in primary
Urinary N-telopeptide
Abbreviations: CRPC, castration-resistant prostate cancer; CTC, circulating
tumor cell; LDH, lactate dehydrogenase; PFS, progression-free survival; PSA,
prostate-specific antigen; TRAP, tartrate-resistant acid phosphatase; VEGF,
vascular endothelial growth factor.
a Adapted from Armstrong and colleagues. 35
fall plots provides a visual clue to the effect of a systemic
agent on PSA. However, many agents in prostate cancer
have demonstrated benefit without notable early PSA
changes, particularly immunotherapies. 5
PSA doubling time (PSADT) is prognostic for OS in
CRPC. 4 In nonmetastatic CRPC, both the absolute PSA and
the PSADT can identify men at high risk for early disease
progression. In metastatic but asymptomatic CRPC, rapid
PSA kinetics may suggest the need for more aggressive
therapy, whereas reduction in PSADT with chemotherapy is
suggestive of a better prognosis. 4,6 However, PSADT may
also change over time without intervention, and changes in
PSA kinetics have not been demonstrated to be surrogates of
OS broadly, so these findings must be interpreted cautiously.
12
In neuroendocrine or small cell prostate cancer, very little
or no PSA is produced, and therefore PSA changes do not
correlate with disease status. Chromogranin A levels are
prognostic but not predictive in these cases, and thus other
biomarkers such as CTCs will be needed in this emerging
and virulent subset of CRPC. 13
CTCs
To establish distant metastases, invasive cancer cells
likely circulate in the bloodstream and home in on their
target of choice, which in CRPC is often bone. CellSearch
(Veridex LLC of Raritan, NJ) is the only FDA-cleared
technology for the detection of CTCs in patients with cancer.
Using this technology, CTCs are defined as nucleated cells at
least 4 microns in diameter, immunomagnetically captured
from the bloodstream using antibodies against epithelial cell
293