EURURO Vol. 71 No. 4

638 692

with 13.6 mo in the placebo arm (HR: 0.63; p < 0.001). This
led to the recommendation that the study be halted and
unblinded. The benefit was observed regardless of age,
baseline pain intensity, and type of progression. All
secondary objectives were in favour of enzalutamide
(PSA, soft tissue response, QoL, time to PSA or objective
progression). No difference in terms of side effects was
observed in the two groups, with a lower incidence of grade
3–4 AEs in the enzalutamide arm. There was 0.6% incidence
of seizures in the enzalutamide group compared with none
in the placebo arm.
4.4. Bone-targeting agents
Most patients with CRPC have painful bone metastases.
External beam radiotherapy is highly effective , even as
a single fraction Apart from Ra 223, however, no bone-
targeted drug has been associated with improved survival.
Zoledronic acid has been used in mCRPC to reduce
skeletal-related events (SREs). This study was conducted
when no active anticancer treatments but docetaxel were
available. In total, 643 patients who had CRPC with
bone metastases were randomised to receive zoledronic
acid, 4 or 8 mg, every 3 wk for 15 consecutive months or
placebo. The 8-mg dose was poorly tolerated and was
reduced to 4 mg but did not show a significant benefit.
However, at 15 and 24 mo of follow-up, patients treated
with 4 mg zoledronic acid had fewer SREs compared with
the placebo group (44% vs 33%; p = 0.021) and, in particular,
had fewer pathologic fractures (13.1% vs 22.1%; p = 0.015).
Furthermore, the time to first SRE was longer in the
zoledronic acid group.
The toxicity (eg, jaw necrosis) of these drugs must
always be kept in mind. Patients should have a dental
examination before starting bisphosphonate therapy. The
risk of jaw necrosis is increased by a history of trauma,
dental surgery, or dental infection, as well as by long-term
intravenous bisphosphonate administration
Denosumab is a fully human monoclonal antibody
directed against RANKL (receptor activator of nuclear
factor kB ligand), a key mediator of osteoclast formation,
function, and survival. In M0 CRPC, denosumab has been
associated with increased bone metastasis–free survival
compared with placebo (median benefit: 4.2 mo; HR:
0.85; p = 0.028) This benefit did not translate into a
survival difference (43.9 vs 44.8 mo, respectively), and
neither the US Food and Drug Administration nor the
European Medicines Agency approved denosumab for this
indication.
The efficacy and safety of denosumab (n = 950) com-
pared with zoledronic acid (n = 951) in patients withmCRPC
was assessed in a phase 3 trial . Denosumab was
superior to zoledronic acid in delaying or preventing SREs,
as shown by time to first on-study SRE (pathologic fracture,
radiation or surgery to bone, or spinal cord compression) of
20.7 versus 17.1 mo, respectively (HR: 0.82; p = 0.008). Both
urinary N -telopeptide and bone-specific alkaline phospha-
tase were significantly suppressed in the denosumab arm
compared with the zoledronic acid arm (p < 0.0001). In a
recent post hoc reevaluation of end points, denosumab
showed identical results when comparing SREs and
symptomatic skeletal events
4.5. Palliative therapeutic options
CRPC is usually a debilitating disease, often affecting elderly
men. A multidisciplinary approach is often required with
input from urologists, medical oncologists, radiation
oncologists, nurses, psychologists, and social workers
. Critical issues of palliation must be addressed when
considering additional systemic treatment, including man-
agement of pain, constipation, anorexia, nausea, fatigue,
and depression, which often occur.
5. Conclusions
The present text represents a summary of the EAU-ESTRO-
SIOG. For more detailed information and a full list of
references, refer to the full-text version. These guidelines
are available on the EAU Web site
.
Author contributions: Philip Cornford had full access to all the data in the
study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Cornford, Mottet.
Acquisition of data: Cornford, Mottet, Bellmunt, De Santis, Joniau,
Rouvie`re, Wiegel.
Analysis and interpretation of data: Cornford, Mottet, Bellmunt, De Santis,
Joniau, Mason, van der Poel, Rouvie`re, Wiegel.
Drafting of the manuscript: Cornford.
Critical revision of the manuscript for important intellectual content:
Cornford, Mottet, Bellmunt, Bolla, Briers, De Santis, Gross, Henry, Joniau,
Lam, Mason, van der Poel, van der Kwast, Rouvie`re, Wiegel.
Statistical analysis: None.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Cornford.
Other (specify): None.
Financial disclosures: Philip Cornford certifies that all conflicts of
interest, including specific financial interests and relationships and
affiliations relevant to the subject matter or materials discussed in the
manuscript (eg, employment/ affiliation, grants or funding, consultan-
cies, honoraria, stock ownership or options, expert testimony, royalties,
or patents filed, received, or pending), are the following: P. Cornford is a
company consultant for Astellas, Ipsen and Ferring. He receives company
speaker honoraria from Astellas, Janssen, Ipsen and Pfizer and
participates in trials from Ferring, and receives fellowships and travel
grants from Astellas and Janssen. Joaquim Bellmunt is a company
consultant for Janssen, Astellas, Pierre Fabre, Genentech, Merck, Ipsen,
Pfizer, Novartis and Sanofi Aventis. He has received research support
from Takeda, Novartis and Sanofi and received travel grants from Pfizer
and Pierre Fabre. Bolla has received company speaker honoraria from
Ipsen and Astellas, has received honoraria or consultation fees from
Janssen, and has received fellowship and travel grants from Janssen,
AstraZeneca and Astellas. E. Briers has received grant and research
support from Ipsen, European Association of Urology, and Bayer; is an ex
officio board member for Europa UOMO; is an ethics committee and
advisory group member for REQUITE; is a member patient advisory
board member for PAGMI; and is a member of SCA and EMA PCWP. M. De
E U R O P E A N U R O L O G Y 7 1 ( 2 0 1 7 ) 6 3 0 – 6 4 2 638