© The Canadian Journal of Urology™; 19(Supplement 1); October 2012
aggressive, bulkydisease, or earlymetastatic disease, the
first therapeutic approach is hormonal ablation. The
accepted theory is that the growth and spreadof prostate
cancer is stimulatedby testosterone. By inducing surgical
ormedical castration in apatient, the clinician commonly
sees a lowering of prostate-specific antigen (PSA) levels
and regression or stabilization of the prostate cancer.
20
However, the use of the anti-testosterone agents can
cause bone-related and metabolic problems. The onset
of bone metastases signals impending skeletal-related
events and pain or death.
21
Denosumab (Xgeva)
As mentioned, the primary treatment approach
for extensive prostate cancer is hormonal ablation.
However, when a patient no longer responds to this
treatment, he is said to have castration-resistant prostate
cancer and is usually offered chemotherapy.
19
The treatment approach for men with prostate
cancer andbonemetastasis has been togive intravenous
agents such as zoledronic acid (Zometa) to reduce the
progression of the bone metastasis. The problemwith
this agent is that the patient’s renal function must be
carefully monitored, and the drug must be given in a
chemotherapy unit, in most cases.
22
Denosumab is a synthetic human monoclonal
antibody against RANK ligand (RANKL), which is
the main driver of osteoclast formation. It is believed
that in bone metastasis, osteoclasts cause the bone
destruction.
23
The benefit of denosumab is that it is given
subcutaneously, the clinician only needs to monitor the
patient’s calcium levels for the first few months, and it
avoids concerns about potential renal or liver effects.
In a study of 1904 patients with castration-resistant
prostate cancer who were randomized to denosumab
or zoledronic acid, the median time to the first on-
study, skeletal-related event was 20.7 months with
denosumab and 17.1months with zoledronic acid. The
conclusion was that denosumab represents a novel,
easily used treatment option that was better than
zoledronic acid in preventing skeletal-related events
in men with castration-resistant prostate cancer.
24
Denosumab is now approved and covered by many
provincial insurance plans for that indication.
Abiraterone acetate (Zytiga)
Abiraterone acetate targets extragonadal androgen
production by inhibiting the CYP17 lyase enzyme,
which is a potentiator of androgen biosynthesis.
It represents a new approach to more efficient
hormonal ablation in an ORAL agent, compared to
the injectable anti-hormonal agents LHRH analogues
and antagonists.
Recently Health Canada and the US Food and
Drug Administration (FDA) have approved Zytiga
for men with prostate cancer who have not responded
to chemotherapy. Based on a recent study, the drug’s
manufacturer is applying to broaden the indication to
include men with castration-resistant prostate cancer
who have not yet had chemotherapy. At theAmerican
Society of Clinical Oncology (ASCO) meeting this
summer, an investigator presented this study, which
compared abiraterone plus prednisone to placebo
plus prednisone in chemotherapy-naïve patients with
castration-resistant prostate cancer. Progression-free
survival in the placebo arm was 8.3 months, but it
was estimated to be double that in the treatment
arm. Progression-free survival was “estimated,”
because the benefit was so obvious that the study was
terminated early and the patients on placebo were
given abiraterone. It appears that overall survival in
this difficult-to-treat population is increased by 25%
in the treatment arm compared to placebo.
25
Enzalutamide (Xtandi)
At the end of August 2012, the FDA approved
enzalutamide (Xtandi [formerly called MDV3100]),
an anti-androgenic/chemotherapeutic agent for men
with castration-resistant prostate cancer who have
not responded to chemotherapy. The approval was
largely based on a study of patients with castrate-
resistant prostate cancer after attempts at salvage with
chemotherapy, where it was found that thosewhowere
treated with enzalutamide had a median survival of
18.4
months, whereas those receiving placebo had
a median survival of 13.6 months. Enzalutamide
is an oral agent that provides competitive binding
at the level of the androgen receptor, prevents the
translocation of the androgen receptor from the
cytoplasm to the nucleus, and, within the nucleus,
inhibits binding at the DNA level.
26
Conclusion
In all areas of the management of urological diseases,
there is constant investigation to determine if the
mechanism of action of older drugs can be enhanced,
or if older drugs can be applied to new indications,
or if newer drugs can be developed to attack “old”
diseases for whichwe still do not have an ideal, reliable
cure. The initial diagnosis and management of some
of these conditions, because of the ease of utilization
and safety of some of these newer agents, is now often
shifting to the family physician from the urologist
or sometimes to the urologist from the medical
oncologist.
BARKIN AND FOLIA
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