EURURO Vol. 71 No. 4

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regarding asymptomatic metastatic patients because of the
lack of high-quality studies. Current insights are mainly
based on flawed underpowered randomised controlled
trials (RCTs) with mixed patient populations (eg, locally
advanced, M1a, M1b status) and a variety of ADT treatments
and follow-up schedules. ADT was shown to be the most
cost-effective therapy if started at the time that the patient
developed symptomatic metastases . A Cochrane
review extracted four good-quality RCTs: the VACURG I
and II trials, the MRC trial, and the Eastern Cooperative
Oncology Group (ECOG) 7887 study . These studies
were conducted in the pre-PSA era and included patients
with advanced PCa who received early versus deferred ADT
as either primary therapy or adjuvant after RP. No
improvement in OS was observed in the M1a/b population,
although early ADT significantly reduced disease progres-
sion and associated complications.
3.1. Hormonal therapy
3.1.1. Luteinising hormone-releasing hormone: agonists and
antagonists
Surgical castration is considered the gold standard for ADT.
Current methods have shown that the mean testosterone
level after surgical castration is 15 ng/dl and
testosterone levels <20 ng/dl are associated with improve-
ment in outcomes compared with men who only reach a
level of between 20 and 50 ng/dl . Luteinising
hormone-releasing hormone (LHRH) agonists have replaced
surgical castration as the standard of care in hormonal
therapy because these agents have potential for reversibili-
ty, avoid the physical and psychological discomfort
associated with orchiectomy, and have a lower risk of
cardiotoxicity than observed with diethylstilbestrol while
providing similar oncologic efficacy . LHRH antagonists
are also available. They bind immediately and competitively
to LHRH receptors, leading to a rapid decrease in luteinising
hormone, follicle-stimulating hormone, and testosterone
levels without the flare phenomenon seen with agonists,
which may be particularly important for patients with
symptomatic locally advanced or metastatic disease. In
addition, an extended follow-up study has been published
suggesting better progression-free survival compared with
monthly leuprorelin However, definitive superiority
over the LHRH agonists remains to be proven, and a lack of
long-acting depot formulation makes them less practical.
3.1.2. Antiandrogens
Nonsteroidal antiandrogens (NSAAs) do not suppress
testosterone secretion but are commonly used to amelio-
rate the clinical effects of the initial testosterone surge
associated with LHRH agonists Pharmacologic side
effects differ between agents, with bicalutamide showing a
more favourable safety and tolerability profile than
flutamide and nilutamide . All three agents share a
common potential for liver toxicity (occasionally fatal), and
liver enzymes must be monitored regularly. When used as
monotherapy, it is claimed that libido and overall physical
performance are preserved . In general, bone mineral
density (BMD) is maintained with bicalutamide
however, a Cochrane systematic review comparing
NSAA monotherapy and castration (either medical or
surgical) revealed that NSAAs were considered to be less
effective in terms of OS, clinical progression, and treatment
failure, and treatment discontinuation due to adverse
events (AEs) was more common.
Systematic reviews of antiandrogens in combination
with LHRH agonists have shown that combined androgen
blockade using an NSAA appears to provide a small survival
advantage (<5%) versus monotherapy (surgical castration
or LHRH agonists) .
3.2. Intermittent androgen deprivation therapy
Three independent reviews and a meta-analysis
have evaluated the clinical efficacy of intermittent ADT
(IAD). All of these reviews included eight RCTs of which only
three were conducted in patients with M1 disease only.
SWOG 9346 trial is the largest trial conducted in M1b
patients. Of 3040 selected patients, only 1535 had an
adequate PSA response (<4 ng/ml) to allow randomisation
(ie, only 50% of M1b patients might be candidates for IAD).
In addition, the prespecified noninferiority limit was not
achieved (median OS: 5.8 vs 5.1 yr; hazard ratio [HR]: 1.1;
95% confidence interval [CI], 0.99–1.23), suggesting that we
cannot rule out a 20% greater risk of death with intermittent
therapy than with continuous therapy. More concrete
conclusions are hampered by a lack of events. Other trials
did not show any survival difference with an HR for OS of
1.04 (95% CI, 0.91–1.19). These reviews and the meta-
analysis came to the following conclusion: There was no
difference in OS or CSS between IAD and continuous
androgen deprivation. A recent review of the available
phase 3 trials highlighted the limitations of most trials and
suggested a cautious interpretation of the noninferiority
results. There is a trend favouring IAD in terms of QoL,
especially regarding treatment-related side effects such as
hot flushes.
3.3. Hormonal treatment combined with chemotherapy
Three large RCTs were conducted . All trials
compared ADT alone as the standard of care with ADT
combined with immediate docetaxel (75 mg/m2 every
3 wk; within 3 mo of ADT initiation). The primary objective
in all three studies was OS.
In the GETUG 15 trial , all patients had newly
diagnosed M1 PCa, either primary or after a primary
treatment. They were stratified based on prior local
treatment and Glass risk factors In the CHAARTED
trial , the same inclusion criteria applied, although
patients were stratified according to disease volume; high
volume was defined as either presence of visceral metasta-
ses or four or more bone metastases, with at least one
outside the spine and pelvis. The third study, STAMPEDE
, was a multiarm, multistage trial in which the reference
arm (standard of care, mostly ADT) included 1184 patients.
One of the experimental arms was ADT combined with
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