EURURO Vol. 71 No. 4

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was presented more recently based on the TAX 327 study
cohort: The independent prognostic factors were visceral
metastases, pain, anaemia (haemoglobin <13 g/dl), bone
scan progression, and prior estramustine.
Patients were categorised into three risk groups of low
risk (no or one factor), intermediate (two factors), and high
risk (three or four factors) and showed three significantly
different median OS estimates of 25.7, 18.7, and 12.8 mo,
respectively . Age by itself is not a contraindication to
docetaxel, but attention must be paid to closer monitoring
and comorbidities In men with mCRPC who are
thought to be unable to tolerate the standard regimen, using
docetaxel 50 mg/m2 every 2 wk might be considered. It was
well tolerated with fewer grade 3–4 AEs and prolonged time
to treatment failure .
The only bone-targeted drug associated with a survival
benefit is Ra 223, an alpha emitter. In a large phase 3 trial
(ALSYMPCA), 921 patients with symptomatic mCRPC who
failed or were unfit for docetaxel were randomised to six
injections, with one injection administered every 4 wk, of
50 kBq/kg Ra 223 or placebo, plus standard of care. The
primary end point was OS. Ra 223 significantly improved
median OS by 3.6 mo (HR: 0.70; p < 0.001) It was also
associated with prolonged time to first skeletal event and
improvement in pain scores and QoL. The associated
toxicity was mild and, apart from slightly more haemato-
logic toxicity and diarrhoea with Ra 223, did not differ
significantly from that in the placebo arm . Ra 223 was
effective and safe regardless of whether or not the patients
were pretreated with docetaxel
Treatment decisions will need to be individualised, and a
summary of the issues regarding sequencing were discussed
in a paper produced following the St Gallen Consensus
Conference . Baseline examinations should include
history and clinical examination as well as baseline blood
tests (PSA, full blood count, renal function, liver function,
alkaline phosphatase), bone scan, and CT of chest abdomen
and pelvis PSA alone is not reliable enough for
monitoring disease activity in advanced CRPC because
visceral metastases may develop in men without rising
PSA Instead, the PCWG2 recommends a combination of
bone scintigraphy and CT scans, PSA measurements, and
clinical benefit in assessingmenwith CRPC Amajority of
experts suggested regular review and repeated blood profile
every 2–3 mo, with bone scintigraphy and CT scans at least
every 6 mo, even in the absence of a clinical indication
. This reflects that the agents with a proven OS benefit all
have potential toxicity and considerable cost, and patients
with no objective benefit should have treatment modified.
This panel stressed that such treatments should not be
stopped for PSA progression alone. Instead, at least two of
three criteria (PSA progression, radiographic progression, and
clinical deterioration) should be fulfilled to stop treatment.
4.3. Second-line treatment options and beyond in metastatic
castration-resistant prostate cancer
The second-line options available will be affected by
the treatment chosen as first-line treatment for CRPC.
Generally, because of concerns about cross-resistance
between hormone-manipulating agents , if either
abiraterone or enzalutamide were used as first-line
treatment and the patient remains clinically suitable,
docetaxel would be offered next. In men who responded
to first-line docetaxel, retreatment is associated with a PSA
response in approximately 60% with a median time to
progression of approximately 6 mo, whereas treatment-
associated toxicity was minimal and similar to that of first-
line docetaxel . No survival improvement has been
demonstrated with docetaxel rechallenge in responders.
Cabazitaxel is a taxane with activity in docetaxel-
resistant cancers. It was studied in a large prospective
randomised phase 3 trial (TROPIC trial) comparing cabazi-
taxel plus prednisone versus mitoxantrone plus prednisone
in 755 patients with mCRPC who had progressed after or
during docetaxel-based chemotherapy Patients re-
ceived a maximum of 10 cycles of cabazitaxel (25 mg/ m2)
or mitoxantrone (12 mg/m2) plus prednisone (10 mg/d),
respectively. OS was the primary end point, which was
significantly longer with cabazitaxel (median: 15.1 vs
12.7 mo; p < 0.0001). Treatment-associated World Health
Organisation grade 3–4 AEs developed significantly more
often in the cabazitaxel arm, particularly haematological
toxicity (68.2% vs 47.3%; p < 0.0002) but also nonhaema-
tological toxicity (57.4% vs 39.8%; p < 0.0002). This drug
should be administered preferably with prophylactic
granulocyte colony-stimulating factor and by physicians
with expertise in handling neutropenia and sepsis
Positive preliminary results of the large phase 3 COU-AA-
301 trial were reported after a median follow-up of 12.8 mo
, and the final results have been reported more recently
. A total of 1195 patients with mCRPC were randomised
2:1 to abiraterone acetate plus prednisone or placebo plus
prednisone. All patients had progressive disease based on
the PCWG2 criteria after docetaxel therapy (with a
maximum of two previous chemotherapeutic regimens).
The primary end point was OS, with a planned HR of 0.8 in
favour of abiraterone. After a median follow-up of 20.2 mo,
median survival in the abiraterone group was 15.8 mo
compared with 11.2 mo in the placebo arm (HR: 0.74;
p < 0.0001). The benefit was observed in all subgroups, and
all secondary objectives were in favour of abiraterone (PSA,
radiologic tissue response, time to PSA or objective
progression). The incidence of the most common grade
3–4 side effects did not differ significantly between arms,
but mineralocorticoid-related side effects were more
frequent in the abiraterone group, mainly grades 1–2 (fluid
retention, oedema, and hypokalaemia).
The planned preliminary analysis of the AFFIRM study
was published in 2012 This trial randomised
1199 patients with mCRPC in a 2:1 fashion to enzalutamide
or placebo. The patients had progressed after docetaxel
treatment, according to the PCWG2 criteria. Corticosteroids
were not mandatory but could be prescribed and were
received by 30% of the population. The primary end point
was OS, with an expected HR benefit of 0.76 in favour of
enzalutamide. After a median follow-up of 14.4 mo, median
survival in the enzalutamide group was 18.4 mo compared
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