EURURO Vol. 72 No. 4

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4.2.2.1. Cytotoxic chemotherapy. There is increasing evidence
that older age per se is not a contraindication to
chemotherapy. Docetaxel 75 mg/m2
[9_TD$DIFF] every 3 wk plus daily
prednisone is the standard of care in CRPC improving OS
while reducing pain and improving quality of life when
compared to mitoxantrone plus prednisone. The OS benefit
for men aged 75 yr was similar to that for younger
patients, but there were more G3/4 toxicities and dose
reductions . A two-weekly docetaxel regimen was
associated with an increase in OS of 2 5 mo, and fewer
cases of grade 3–4 neutropenia compared with a three-
weekly regimen . In a prospective registry study in
patients aged 70 yr, those with frailty related to cancer
also benefited from a taxane-based therapy (regimen
adapted in 52%) .
Cabazitaxel is combined with prednisone in patients
progressing during or after a docetaxel-based regimen
Safety was analysed by age (<70, 70–74, and 75 yr)
among 746 men . The number of cabazitaxel cycles,
dose reductions for any cause, dose delays possibly related
to cabazitaxel adverse events, and tolerability were similar
in the three age groups. Prophylactic granulocyte colony-
stimulating factor (G-CSF) use was more common in men
aged 70 yr. In multivariate analysis, age 75 yr, first
treatment cycle, and baseline neutrophil count <4000/mm3
were associated with higher risk of grade 3 neutropenia
and/or neutropenic complications. Prophylactic G-CSF
reduced this risk by 30% (odds ratio 0.70; p = 0.04). A
recent phase 3 study comparing cabazitaxel 20 mg/m2
versus 25 mg/m2 every 3 wk plus daily prednisone in
mCRPC patients progressing after docetaxel concluded that
20 mg/m2 was noninferior in terms of OS and was better
tolerated .
The toxicity of chemotherapy in older patients can be
predicted. Two published models use somewhat different
criteria, but geriatric, chemotherapy, and biological char-
acteristics are predictive in both Severe toxicity rates
were relatively high with both models, indicating that older
patients should be monitored closely. There is strong
evidence to support primary prophylaxis with G-CSF in this
setting . Alternatively, the chemotherapy regimen could
be adapted.
4.2.2.2. Endocrine therapies. Abiraterone in combination with
prednisone is effective in both chemotherapy-treated and
chemotherapy-naive mCRPC patients . In chemother-
apy-naive mCRPC, median OS was significantly longer in the
abiraterone plus prednisone group than for placebo plus
prednisone (34.7 vs 30.3 mo; HR 0.81; p = 0.0033)
Elderly patients in both treatment arms had higher
rates of fluid retention and cardiac disorders than younger
patients, although dose reductions or treatment interrup-
tions due to adverse events were few in both groups.
Abiraterone demonstrated clinical benefit and was well
tolerated in elderly men with chemotherapy-naive mCRPC.
Thus, abiraterone is also an option for patients who may not
tolerate therapies with higher toxicity.
Enzalutamide increased OS compared to placebo in the
postchemotherapy setting in mCRPC (AFFIRM trial)
. The effect in elderly patients was similar to that in
the total study population, but some side effects were more
common . In the PREVAIL trial, oral enzalutamide
160 mg/d was compared to placebo in chemotherapy-naive
mCRPC . Some 72% of men in the enzalutamide group
but only 63% in the placebo group were alive at cutoff (29%
reduction in risk of death; HR 0.71; p < 0.001). Fatigue and
hypertension were the most common adverse events
associated with enzalutamide. Among patients aged >75
yr (35% of the total), the median treatment duration was
16.6 and 5.0 mo in the enzalutamide and placebo arms,
respectively . In the elderly subgroup, OS was greater
for enzalutamide than for placebo (32.4 vs 25.1 mo; HR
0.61; p = 0.0001), that is, elderly men benefited from
enzalutamide, which was generally well tolerated, but
fatigue and falls may be related side effects. Since
enzalutamide is a strong CYP3A4 inducer, drug interactions
should be carefully checked.
4.2.2.3. Treatment sequencing. Progression on one of the novel
hormonal agents is usually associated with poor response to
subsequent use of another one. The optimum sequencing of
life-extending therapies has not been determined .
Symptomatic patients with mCRPC—both fit and frail—
should receive first-line docetaxel, while those who are
disabled or have severe comorbidities or are reluctant to
receive chemotherapy should receive novel endocrine
agents. At progression after docetaxel, cabazitaxel and
novel endocrine agents are appropriate for fit patients.
Chemotherapy-naive fit patients who have experienced
failure on a novel endocrine agent should receive second-
line taxane chemotherapy since cross resistance means they
are unlikely to respond to a second endocrine agent.
Patients need to be fully informed of the benefits and side
effects so that they can indicate a preference.
4.2.2.4. RT/radiopharmaceuticals and bone-targeted therapy. RT is
the first-choice treatment for localised painful metastasis in
elderlymen with prostate cancer. A phase 3 study of patients
with painful metastases and no visceral metastases who had
progressed after docetaxel or who were unfit for or unwilling
to have chemotherapy compared Ra-223 with placebo
Ra-223 extended OS, delayed skeletal-related events,
and improved quality of life in older and younger patients.
Therefore, patients without visceral or bulky lymph node
metastases who are receiving first-line treatment for mCRPC
after failure of docetaxel are eligible to receive Ra-223.
In patients with newly diagnosed metastatic or nonmet-
astatic prostate cancer, adding zoledronic acid to ADT did
not benefit failure-free survival, skeletal-related events, or
OS . In CRPC and bone metastases, zoledronic acid (4 mg
intravenously) or denosumab (120 mg subcutaneously)
every 4 wk is recommended to decrease the risk of
disease-related skeletal complications such as pathologic
fractures. Both drugs have been approved by the US Food
and Drugs Administration and the European Medicines
Agency in this setting . Preventive measures (calcium
and vitamin D supplementation, and an initial dental check)
are of utmost importance
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