NcXHF

HUSSAIN AND DIPAOLA
TABLE 1. U.S. Food and Drug Administration
Approvals for Metastatic Castration-Resistant
Prostate Cancer Since 1996
Survival improvement since 2004
Pain
Skeletal-related events
*Pre- and post-docetaxel.
Docetaxel
Sipuleucel-T
Cabazitaxel
Abiraterone*
Enzalutamide*
Radium 223 dichloride
Mitoxantrone
Strontium
Samarium
Zoledronic acid
Denusomab
KEY POINTS
Several therapies targeting the androgen receptor and
other pathways have improved survival and quality of life
for patients with metastatic prostate cancer.
Many costly therapeutic clinical trial efforts have failed to
improve outcomes.
Prostate cancer is a complex disease. Its biologic
heterogeneity warrants that future clinical trials be
carefully designed to achieve higher levels of clinical
impact by attention to targeting more critical pathways;
integrating improved diagnostics; well-designed and
powered clinical trials using multi-targeted strategies; and
optimized timing of therapy.
TABLE 2. Examples of Disproven Regimens in Phase
III Trials
Miscellaneous targets
Bone
VEGF/Angiogenesis
GVAX
Docetaxel GVAX
Satraplatin
Docetaxel DN101
TAK700
Ipilimumab
Docetaxel dasatinib
Atrasentan
Docetaxel atrasentan
Zibotenan
Docetaxel zibotenan
Docetaxel bevacizumab
Docetaxel aflibercept
Docetaxel lenalidomide
Sunitinib
acizumab, dasatinib, aflibercept, and lenalidomide) were
negative, which raises concerns about the adequacy and
depth of current preclinical, diagnostic, and early clinical
evaluation strategies and highlights the importance of the
disease’s biologic context.
Although these agents with demonstrated effıcacy have
been valuable to date, there is little question that current therapies
have substantial limitations, including the fact that
their effect on survival continues to be very modest (2 to 5
months’ improvements). 7 Clearly, not all patients benefıt.
Furthermore, unlike many other solid tumors, we still use a
one-size-fıts-all treatment approach with no predictive
biomarkers to maximize chance for benefıt and reduce
treatment burden on patients, both physical and monitory.
Furthermore, although some trials were positive,
these predominantly were conducted in an era in which essentially
only one major treatment choice (docetaxel) existed.
Also, many nonchemotherapy trials reported to date
had a placebo control arm, which was a low bar to cross.
Therefore, the true effıcacy of current therapies in the current
clinical context in which patients have undergone multiple
prior treatments is unclear. In fact, several anecdotal and observational
data are emerging on the suboptimal response to
sequential AR pathway targeting with current agents. 28 The
latter is an area that must be addressed considering all the
implications.
THERAPY COST IS ESCALATING
“Price is what you pay. Value is what you get,” is one of Warren
Buffett’s favorite admonitions, highlighting that price
and value are not always the same. Perceived expectations,
quality, value, effectiveness, and side effects are critical factors
in a patient’s satisfaction with his or her treatment. Historically,
physicians, professional societies, and regulatory
bodies in the United States have shied away from discussing
fınancial costs of care. However, this discussion is very timely
and critical. We owe it to our patients and society that therapy
development must take into account the cost relative to
the true benefıt, value, and effect of the specifıc therapy. Table
3 highlights the average wholesale price of current agents. Although
this may vary somewhat by vendor, or actual charge,
the overall fınancial effect in the context of partial clinical activity
calls for much needed improvement and reform of our
current processes surrounding clinical trials and drug approval.
The recent data on the detection of AR-V7 in circulating
tumor cells from patients with castration-resistant
prostate cancer and its association with resistance to enzalutamide
and abiraterone, 29 if validated, is an example of the
potential for better individualized selection of therapy to
maximize benefıt and reduce cost.
THE CHARGE MOVING FORWARD: A FOCUS ON
TRUE IMPACT AND VALUE
Albert Einstein said, “Most of the fundamental ideas of science
are essentially simple, and may, as a rule, be expressed in
18 2015 ASCO EDUCATIONAL BOOK | asco.org/edbook