2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

DEVELOPMENTS IN PROSTATE CANCER THERAPY
agents have most likely been treated with antiandrogens,
such as flutamide and nilutamide, in the past. Finally,
agents modulating the androgen signaling axis frequently
result in PSA reduction, another familiar signal of treatment
effect. However, a major challenge now is how to best
position these oral agents to maximize efficacy. MDV3100
has shown success in patients in whom docetaxel-based
chemotherapy has failed, which is in the same patient group
as those who benefited from abiraterone. Therefore, with
two highly active oral agents, there will be concerns regarding
which agent should be initially administered in patients
in whom chemotherapy has failed. The treatment landscape
will also be affected when the results of the clinical trials
conducted in patients before chemotherapy are available.
The sequencing and/or role of combination therapy is important
and practical and must be further explored in future
clinical trials.
Cell Signaling Pathways
Angiogenesis, the process of new blood vessel formation, is
a crucial step in the propagation of malignant tumor growth
and metastasis. Among the multiple proangiogenic factors
that promote the process of vessel formation, vascular endothelial
growth factor (VEGF) is one of the most important.
Bevacizumab is a humanized monoclonal antibody directed
against VEGF-A and causes potent inhibition of VEGF
receptor (VEGFR) signaling and angiogenesis. Bevacizumab
is approved for use in combination with chemotherapy for
patients with metastatic colorectal, breast, and lung cancers.
In prostate cancer, bevacizumab has been evaluated
in several clinical trials, including the Cancer and Leukemia
Group B (CALGB) phase II trial of bevacizumab in combination
with docetaxel and estramustine in 79 patients with
metastatic CRPC. 18 A PSA decrease of more than 50%
from baseline occurred in 81% of patients, the median time
to progression was 9 months, and overall survival was
21 months. These favorable trials led to a recent phase
III randomized placebo-controlled trial of docetaxel, prednisone,
and bevacizumab compared with docetaxel and
prednisone in 1,050 patients with chemotherapy-naive metastatic
CRPC with the primary endpoint of overall survival.
Final results published in 2011 reported that although there
was median progression-free survival in the bevacizumab
arm of 9.9 months compared with the 7.5 months of the
control arm (p � 0.0001), the overall survival time was not
statistically significant. 19 Bevacizumab has notable toxicities,
including hypertension, thromboembolism, hemorrhage,
gastrointestinal perforation, and proteinuria. Unfortunately,
a negative study with bevacuzimab poses a challenge for
further development of agents modulating the VEGF signaling
axis. Multitargeted tyrosine kinase inhibitors against
VEGFR, such as cediranib and sunitinib, have been evaluated
in phase II and III clinical trials, respectively, but the
response rates have not been overwhelmingly encouraging.
In fact, the phase III sunitinib trial was recently terminated
for futility.
However, a novel VEGFR tyrosine kinase inhibitor that is
showing tremendous response rates in imaging studies,
including bone scans, is cabozantinib (XL184). Cabozantinib
is an inhibitor of multiple kinase signaling pathways, including
MET, RET, VEGFR2/KDR, and KIT. MET is a
receptor tyrosine kinase that has roles in oncogenic signaling,
angiogenesis, and metastasis. Androgen deprivation
activates MET signaling in prostate cancer cells. Activated
MET is particularly highly expressed in bone. Preclinical
studies have suggested that MET signaling may promote
survival of prostate cancer cells. 20 In a recent phase II study,
cabozantinib showed promising activity in men with bone
metastases, with substantial improvement in bone scans in
most patients. Patients with metastatic CRPC with progressive
measurable disease received cabozantinib at 100 mg/d
orally during 12 weeks, with a primary endpoint of objective
response rates. Accrual was halted at 168 patients based on
an observed high rate of clinical activity. Of the 100 evaluable
patients with a median age of 68, 86% of patients had
complete or partial resolution of lesions on bone scan as
early as week 6. A total of 64% had improved pain, and the
most common related grade 3/4 adverse events were fatigue
(11%), hypertension (7%), and hand-foot syndrome (5%); no
related grade 5 adverse events were reported. The PSA
changes were independent of clinical activity, and the overall
week 12 disease control rate was 71%. 21 Current studies
are proceeding with a lower dose of cabozantinib to improve
drug tolerability (NCT01347788, NCT01428219). The relationship
between c-met inhibition and metastatic bone disease
has yet to be properly elucidated, but multiple research
efforts are under way to improve our understanding of this
novel finding.
Another antiangiogenesis inhibitor in a phase III clinical
trial is tasquinimod. Tasquinimod is an orally active
quinolone-3-carboxamide. Nearly 70% of men who took tasquinimod
in a phase II trial did not progress at 6 months
compared with 30% of men who took placebo. The phase III
study is now open and expects to enroll 1200 patients
(NCT01234311).
Bone Targeting
Until recently, the only standard of care was to administer
vitamin D, calcium, and a bisphosphonate, such as zoledronic
acid, to help minimize bone resorption, which leads to
reduction of SREs. Denosumab, a humanized monoclonal
antibody with specificity for the RANK ligand, was shown to
be superior to zoledronic acid in a study of 1,901 men with
CRPC. Denosumab delayed or prevented SREs more effectively
than zoledronic acid. 22 The median time to first
on-study SRE, the primary endpoint, was 20.7 months for
denosumab compared with 17.1 months for zoledronic acid
(HR, 0.82; 95% CI, 0.71 to 0.95; p � 0.0002). No differences
were found in PSA time, overall disease progression, or
overall survival. The two treatment groups had a similar
frequency of serious toxicities; the cumulative incidence of
osteonecrosis of the jaw was similar in the two groups (2.3%
for denosumab vs. 1.3% for zoledronic acid). These results,
combined with two other pivotal phase III trials of the same,
led to the FDA approval of denosumab for prevention of
skeletal complications in patients with bone metastases
from solid tumors, except multiple myeloma.
Denosumab was also found to improve bone metastasis–
free survival (29.5 months) compared with placebo in men
with M0 CRPC disease (25.2 months). However, no survival
benefits were seen with denosumab in the phase III trial
that was reported at the European Multidisciplinary Cancer
Congress and the European Society for Medical Oncology
Meeting 2011. In September 2011, denosumab received FDA
approval for its indication to increase bone mass in patients
at high risk for fracture receiving androgen deprivation
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