2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

therapy for nonmetastatic prostate cancer. Fortunately, for
men with CRPC, there are now two FDA-approved agents to
help improve and strengthen metastatic bones. Zoledronic
acid is administered via intravenous infusion and requires
monitoring of renal function. Denosumab is administered
via subcutaneous injection and requires monitoring of calcium
and other electrolytes. Both agents have a role in the
treatment of prostate cancer.
Another agent that targets the osteoclasts, osteoblasts,
and bone microenvironment is dasatinib. Dasatinib is an
oral tyrosine kinase inhibitor with activity against Src
kinases. A phase I/II trial evaluating dasatinib alone and in
combination with docetaxel chemotherapy in CRPC reported
activity with bone turnover markers with mild PSA response.
23 Currently, a phase III trial with an estimated
enrollment of 1,500 patients comparing docetaxel and dasatinib
with docetaxel and placebo is under way
(NCT00744497).
A new drug that targets bone signaling pathways leading
to actual overall survival is radium-223 chloride. Radium-
223 chloride is an intravenously administered radiopharmaceutical
that targets bone metastasis with high-energy,
short-range �-particles. At the European Multidisciplinary
Cancer Congress and the European Society for Medical
Oncology Meeting 2011, results from a trial of nearly 1,000
patients with CRPC with 2:1 randomization to either
radium-223 chloride or placebo revealed a superior median
overall survival of 14 months in the radium-223 chloride
arm compared with the 11.2 months in the placebo arm. 24
This 30% reduction in the risk of death (HR, 0.695, p �
0.00185) in overall survival is important because the typical
treatment of bone targeting agents results in mediating
symptom relief and not necessarily affecting survival. The
study results were promising enough that the data safety
and monitoring committee for this study halted the accrual.
The adverse effects include hematologic effects, such as
anemia, and mild gastrointestinal toxicities. Next steps in
the development of radium-223 chloride are eagerly
awaited.
Cytotoxic Therapy
In 2004, our current stand-of-care chemotherapy, docetaxel,
in combination with prednisone had shown efficacy
in patients with CRPC. An overall survival benefit of almost
t3 months and a PSA response of more than 50% were seen
in almost one-half of patients compared with mitoxantrone
and prednisone. 9,25 In March 2010, the efficacy results of a
new taxane, cabazitaxel, for use in docetaxel-treated pa-
Authors’ Disclosures of Potential Conflicts of Interest
Author
Employment or
Leadership
Positions
Consultant or
Advisory Role
tients with CRPC were presented. This large, multicenter
study showed an overall survival benefit of 3 months when
compared with mitoxantrone. 26,27 On the basis of these
results, the FDA-approved cabazitaxel as a second-line
therapy for prostate cancer. As expected, clinical trials
conducted in 2011 are primarily combination therapy evaluating
cabazitaxel with chemotherapy, such as docetaxel
(NCT01308567), abiraterone (NCT01522536), and tasquinimod
(NCT01513733). Clinical trials evaluating optimal sequencing
of cabazitaxel and abiraterone and other future
agents must be efficiently designed to quickly meet its
objectives.
Conclusion
In the last several years, notable advances have been
made in the field of prostate cancer. Treatments emerging
from our knowledge of the cell biology, androgen regulation,
immunology, and chemoresistance of prostate cancer have
led to the development of mechanism-based drug discovery.
This in turn has led to various clinical trials based on a
sound biologic rationale. Several phase III trials testing
rational drug combinations in prostate cancer are ongoing.
However, clinical trials to determine optimal sequence of
therapy are yet to be conducted.
The role of immunotherapy, including the 2010 FDAapproved
sipuleucel-T, is also an important part of the
treatment paradigm and one that would benefit from biomarker
identification. Sipuleucel-T is the first therapeutic
cancer vaccine to gain FDA approval for patients with
metastatic CRPC. The landmark phase III study of
sipuleucel-T showed an overall survival benefit of 4.1
months; however, tumor response rates were minimal. 28
The study validated the efficacy of immunotherapy in prostate
cancer and has led to an investigation of additional
clinical trials of sipuleucel-T in prostate cancer. Additional
promising agents in phase III clinical trials include anti-
CTLA-4 (NCT01057810) and ProstVAC-V/F (NCT01322490).
Multiple new drugs have recently been approved for the
treatment of prostate cancer, but they all have not been able
to demonstrate cure of the disease. In addition to targeting
the different mechanisms of action discussed in this publication,
multiple other molecular targets also promise to
provide the next generation of advances. We must continue
to maintain a close collaboration between basic and clinical
science so that our knowledge of the molecular physiology
can lead to strategic development of further viable drug
targets.
Stock
Ownership Honoraria
Research
Funding
Madhuri Bajaj*
Elisabeth I. Heath Amgen;
AstraZeneca;
BiPar Sciences;
Bristol-Myers
Squibb;
GlaxoSmithKline;
Pfizer; Seattle
Genetics;
Zymogenetics
*No relevant relationships to disclose.
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BAJAJ AND HEATH
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