NcXHF

INVITED ARTICLES
GENITOURINARY CANCER
Clinical Research in Metastatic Prostate Cancer: A Focus on
Impact and Value
Maha Hussain, MD, FACP, FASCO, and Robert S. DiPaola, MD
Despite substantial and continued reduction in mortality,
prostate cancer continues to be a major cause of cancer
death in men in the United States, with an estimated 27,540
deaths in 2015. 1 Historically, prostate cancer was one of the
earliest examples of success in targeted therapy. More than 7 decades
ago the key biologic and therapeutic breakthrough by
Huggins et al established that prostate cancer is an androgen receptor
(AR) pathway–driven and androgen-dependent disease,
and that surgical or medical castration can induce substantial
and prolonged regressions for patients with prostate cancer. 2,3
Despite a high response rate with androgen deprivation, most
patients with metastatic disease progress to castration resistance,
with a median survival in the prostate-specifıc antigen
(PSA) era of about 4 years. 4
In cancer therapy development, cytotoxic chemotherapy
was one of the major products of the “war on cancer” during
the past 4 decades. With androgen deprivation therapy
(ADT) as a backbone of treatment for metastatic prostate
cancer, efforts were directed at adding cytotoxic agents following
castration resistance. Several chemotherapeutic
agents were tested without a major breakthrough until 2004,
with the approval of docetaxel, the fırst nonhormone agent
that demonstrated a survival benefıt in patients with metastatic
castration-resistant prostate cancer (mCRPC), thus establishing
a new benchmark and validating the role of
targeting the microtubule in this disease. 5,6 Subsequent investments
in prostate cancer research over the last 2 decades
have led to major biologic discoveries with many targets and
agents, resulting in several U.S. Food and Drug Administration
(FDA) approvals (Table 1) 7 and additional testing in
clinical trials.
ANDROGEN RECEPTOR SIGNALING CONTINUES TO
MATTER BUT IS NOT THE WHOLE STORY
Perhaps one of the most important biologic discoveries was
the understanding that progression to castration resistance is
partly an adaptive process. Furthermore, despite clear evidence
to support AR-independent mechanisms, unlike prior
dogmas, AR-dependent signaling continues to be relevant. 8
Biologic data on the importance of AR signaling was the basis
for developing several agents targeting AR or relevant enzymatic
pathways. The principle was validated by results
from phase III trials with abiraterone and enzalutamide that
demonstrated survival improvements in patients with
mCRPC. 9,10 The biologic discoveries regarding progression
to castration resistance led to studies of several other experimental
agents targeting additional pathways. 8,11-13 Efforts to
target the immune system and bone have led to survival improvement
with sipuleucel-T and radium 223 dichloride. 7
Therefore, in 2015, oncologists have several standard treatment
options with proven clinical benefıts to offer patients, both
docetaxel-naive (sipuleucel-T, abiraterone/prednisone, radium
223 dichloride, enzalutamide) and docetaxel-treated patients
(cabazitaxel/prednisone, abiraterone, enzalutamide, radium
223 dichloride), as well as an array of additional opportunities
for clinical trials.
SO ARE WE THERE YET?
Over the past 2 decades, we have witnessed unprecedented
progress in the understanding of the biology of prostate cancer
and substantial returns on investment in research with
the development of therapies for patients with mCRPC. This
is reflected by multiple approvals that FDA has issued since
1996. These approvals were based on positive phase III trials
for agents that have demonstrated an effect on overall survival,
pain, or skeletal-related events—all clinical benefıt
outcomes relevant for managing this group of patients. However,
in a similar time period, more phase III trials proved
negative despite very promising biologic, preclinical, and
phase II trial data (Table 2). 14-27 Surprisingly, multiple large
studies that attempted to build on docetaxel by adding targeted
therapy (DN101, GVAX, atrasentan, zibotenan, bev-
From the University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ.
Disclosures of potential conflicts of interest are found at the end of this article.
Corresponding author: Maha Hussain, MD, FACP, FASCO, University of Michigan Comprehensive Cancer Center, 1500 E. Medical Center Dr., Ann Arbor, MI 48109; email: mahahuss@umich.edu.
© 2015 by American Society of Clinical Oncology.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK 17