International Journal of Urology (2016) 23, 726--733
13148
Review Article
Chemotherapy for metastatic castration-sensitive prostate cancer
Sunil Parimi1 and Kim N Chi1,2
1
British Columbia Cancer Agency, and 2Vancouver Prostate Center, Vancouver, British Columbia, Canada
Abbreviations & Acronyms
ADT = androgen deprivation
therapy
AR = androgen receptor
CRPC = castration-resistant
prostate cancer
CSPC = castration-sensitive
prostate cancer
CSS = cancer-specic
survival
DES = diethylstilbestrol
EC = endocrine
chemotherapy
ECOG = Eastern
Cooperative Oncology
Group
FFS = failure-free survival
LHRH = luteinizing
hormone-releasing hormone
ORCH = orchiectomy
ORR = objective response
rate
OS = overall survival
PFS = progression-free
survival
PSA = prostate-specic
antigen
QOL = quality of life
SOC = standard of care
SOC+D = standard of care
plus docetaxel
SOC+ZA = standard of care
plus zoledronic acid
SOC+ZA+D = standard of
care plus zoledronic acid
plus docetaxel
TTP = time to progression
Correspondence: Kim N Chi
M.D., F.R.C.P.C., British
Columbia Cancer Agency, 600
West 10th Avenue, Vancouver,
BC V5Z 4E6, Canada. Email:
kchi@bccancer.bc.ca
Received 18 April 2016;
accepted 29 May 2016.
Online publication 26 June 2016
726
doi: 10.1111/iju.
Abstract: Incorporation of docetaxel into metastatic castration-sensitive prostate
cancer treatment has added a new treatment option to a disease state that had
previously not seen change for decades. Early attempts of a chemo-hormonal approach
for castration-sensitive prostate cancer were not successful. With the demonstration of
survival benefits using docetaxel in patients with metastatic castration-resistant prostate
cancer, this encouraged continued research with docetaxel given earlier in the disease
course. Three randomized phase III trials have defined the benefits of docetaxel in the
metastatic castration-sensitive prostate cancer setting; however, there remain questions
and controversies on the appropriate and optimal patient selection.
Key words: castration sensitive, chemotherapy, docetaxel, metastatic, prostate cancer.
Introduction
Worldwide, prostate cancer is the second most common cancer and the fth leading cause of
death from cancer in men.1 Most men with newly diagnosed prostate cancer have localized
disease, which is treated with active surveillance, radical prostatectomy, external beam radia-
tion therapy or brachytherapy. Though these are carried out with curative intent, many
patients have the potential to develop recurrent disseminated disease, and a signicant propor-
tion of men continue to present with metastatic disease at diagnosis.2 For patients with meta-
static disease, the backbone of treatment is ADT by medical or surgical castration.3,4
Although ADT is initially effective in almost all patients, progression to CRPC is inevita-
ble, and occurs within approximately 23 years, heralded by a rise in PSA, progression of
metastatic lesions and/or development of progressive symptoms.5 Initially, castration resis-
tance appears to be driven mostly by persistent AR activation despite castrate levels of circu-
lating androgen levels. This occurs through several mechanisms including extragonadal
synthesis of androgens; changes to AR structure and expression through gene mutations,
amplication and mutations; as well as persistent AR signaling through complementary path-
ways and co-regulatory proteins.6,7
Several treatments for metastatic CRPC that improve outcomes are available, the rst of which
with proven efcacy for OS was docetaxel chemotherapy in 2004.8 Since then, CRPC treatment
options have expanded, with zoledronic acid, denosumab, sipuleucel-T, abiraterone acetate,
enzalutamide, radium-223 and cabazitaxel all part of our therapeutic armamentarium.916
With the success of these agents in the CRPC setting, multiple trials have been initiated
to explore their efcacy in earlier disease states including the castration-sensitive setting.
Trials with zoledronic acid added to ADT for patients with metastatic castration-sensitive
disease have already reported out, and unfortunately did not show any benet.16,17 More
recently, however, docetaxel chemotherapy when added to ADT has shown OS improve-
ments in metastatic CSPC, and now offers a new option for these patients. The present
review will outline the new era of up-front chemohormonal therapy, summarizing the stud-
ies that have led to this development, and addressing the controversies and questions that
remain to be claried.
Early studies of chemohormonal therapy for CSPC
Before the demonstration of docetaxel efcacy in the CRPC setting, several randomized con-
trolled trials had been carried out in patients with CSPC. Though none showed a survival
advantage for a chemohormonal approach, many showed benets through other end-points or
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 Chemotherapy for CSPC

when focusing on certain subgroups. These trials provided
the rst hints that chemotherapy might have a place in meta-
static CSPC (Table 1).
Some studies showed benets in TTP or PFS, although no
OS differences. For instance, Noguchi et al. randomized 57
patients with metastatic CSPC to receive ADT with either
estramustine phosphate or utamide.19 This produced a TTP
benet of 10.8 months. Similarly, Pummer et al. showed that
combining epirubicin with ADT versus ADT alone could
yield a 6-month benet in PFS.20
Other studies highlighted a benet in certain patient sub-
groups. Murphy et al. randomized 246 newly diagnosed
metastatic CSPC patients to one of three arms: DES 1 mg
orally three times daily or ORCH; DES plus cyclophos-
phamide 1 mg/m2 intravenously every 3 weeks; or
cyclophosphamide 1 mg/m2 intravenously plus estramustine
phosphate 600 mg/m2 orally every 3 weeks.21 No benet
in OS, PFS or ORR was seen. However, on subgroup
analysis, the cyclophosphamide plus estramustine arm
showed a signicant OS benet in those patients presenting
with pain on entry, compared with those without baseline
pain. In a trial carried out by Millikan et al., 286 patients
were randomized to ADT plus a regimen of ketoconazole
and doxorubicin alternating with vinblastine and estra-
mustine versus ADT alone.22 No differences were seen
with respect to TTP or OS in the entire population. How-
ever, a preplanned analysis of 126 patients with high-
volume disease (dened as three or more bony lesions or
visceral involvement) showed a strong trend towards TTP
benet favoring chemohormonal therapy (11.2 months in
the control arm vs 20.5 months in the chemohormonal arm,
P = 0.08).
Though all of these early trials lacked a survival benet,
they were all underpowered and used chemotherapy regimens
that had never shown survival benets in the CRPC setting.
Even still, the modest benets of these trials provided support
that a chemohormonal approach might have a place in meta-
static CSPC.

Table 1 Early trials exploring chemotherapy in metastatic CSPC

No. enrolled
Author, year of publication patients Treatment arms Key end-points Key results
Millikan et al., 2008 286 1. ADT + ketoconazole + doxorubicin alternating TTP TTP: 24 vs 35 months (P = 0.39)
with vinblastine + estramustine OS: 5.4 vs 6.1 years
2. ADT alone
Noguchi et al., 2004 57 1. Estramustine phosphate plus LHRH agonist PFS PFS: 25.4 vs 14.6 months (P = 0.03)
2. Flutamide plus LHRH agonist ORR: 76% vs 55%
CSS: 41.5 vs 29.8 months (P = 0.41)
OS: 35.9 vs 27.8 months (P = 0.796)
Kuriyama et al., 2001 142 1. Bilateral ORCH + DES + uracil/tegafur (EC arm) PFS PFS: Favored EC arm (P = 0.065)
2. Bilateral ORCH + DES (endocrine arm) CSS CSS: Favored EC arms (P = 0.132)
Change of Change of QOL score: No significant
QOL score differences
Wang et al., 2000 96 1. LHRH agonist and flutamide + mitoxantrone N/A OS: 27 vs 24 months (P = 0.09)
2. LHRH agonist and flutamide ORR: 55% vs 39% (P = 0.3)
Boel et al., 1999 178 1. ORCH + mitomycin C N/A TTP: 26 vs 29 months (P = 0.64)
2. ORCH Time to cancer related death: 31 vs
32 months
de Reijke, 1999 184 1. ORCH followed by mitomycin C N/A OS (P = 0.17)
2. ORCH alone Subjective progression (P = 0.25)
Objective progression (P = 0.08)
PFS (P = 0.67)
Pummer et al., 1997 145 1. ORCH followed by mitomycin C PFS PFS: 18 vs 12 months (P = 0.02)
2. Total androgen blockade plus weekly epirubicin OS OS: 30 vs 22 months (P = 0.12)
Janknegt et al., 1997 385 1. ORCH followed by estramustine phosphate TTP TTP: Risk ratio O + E vs O = 0.877
until progression (O + E) (P = 0.33)
2. ORCH (O) OS: Risk ratio O + E vs O = 0.978
(P = 0.87)
Osborne et al., 1990 137 1. Initial combined chemo-endocrine therapy OS OS: 22.0 vs 25.6 months (P = 0.55)
2. Endocrine therapy (DES or ORCH) alone followed Time to treatment failure: 18.4 vs
by cyclophosphamide-adriamycin 15 months (P = 0.83)
chemotherapy at progression
Murphy et al., 1986 296 1. Cyclophosphamide plus 5-fluorouracil plus DES N/A OS: No significant difference
2. Estramustine phosphate DFS: No significant difference
3. DES or bilateral ORCH
Murphy et al., 1983 246 1. DES plus cyclophosphamide OS OS: 91 vs 94 vs 92 weeks (P = 0.1)
2. Cyclophosphamide plus estramustine phosphate PFS N/A
3. DES or ORCH ORR ORR: 34% vs 33% vs 41%

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S PARIMI AND KN CHI
Taxanes and prostate cancer
Taxanes are a class of chemotherapeutic agents widely used
in many cancers. Both docetaxel and cabazitaxel are semisyn-
thetic taxanes that promote the assembly and stabilization of
microtubules.23 Cabazitaxel has shown activity in docetaxel-
resistant mouse xenograft models,24 and better bloodbrain
barrier penetration in vitro.25 The two agents have shown
important differences in adverse event proles as well, with
prospectively collected data suggesting less alopecia, nail
changes, neuropathy and dysgeusia with cabazitaxel com-
pared with docetaxel.26
Mechanistic studies have suggested that the particular ef-
cacy of taxanes in prostate cancer, as compared with other
chemotherapy agents, might be through indirect effects on
the AR. Through their inhibitory action on antimicrotubules,
taxanes have been shown to inhibit AR nuclear transport, and
interfere with AR-regulated gene transcription and associated
signaling pathways.27,28 These studies also support a doc-
etaxel-castration approach in CSPC as a form of combined
therapy against AR signaling. Preclinical efcacy studies with
docetaxel have also supported a chemohormonal approach.
Using the Shionogi and LNCaP xenograft models, which
mimic the human situation of androgen-dependent growth
and castration-induced regression followed by castration-resis-
tant regrowth, Eigl et al. compared three arms treated with
different sequences of taxane chemotherapy and castration
therapy: (i) initial castration and delayed paclitaxel at the time
of castration-resistant growth; (ii) initial paclitaxel and
delayed castration; or (iii) simultaneous castration plus pacli-
taxel.29 When compared with the other two arms, mice being
treated with simultaneous chemohormonal therapy showed a
signicant improvement in TTP and OS.
Taxanes in metastatic CRPC
The rationale for evaluating docetaxel in the castration-sensi-
tive setting stemmed from the clinical benet shown by two
members of the taxane family in the castration-resistant set-
ting: docetaxel and cabazitaxel. Three key trials established
these agents in CRPC. The TAX 327 trial was a three-arm
trial, comparing mitoxantrone 12 mg/m2 intravenously every
3 weeks, docetaxel 75 mg/m2 intravenously every 3 weeks
and docetaxel 30 mg/m2 intravenously weekly for 5 of every
6 weeks, with all patients receiving prednisone 5 mg orally
twice daily.30 The results showed a statistically signicant
survival advantage in the every three-weekly docetaxel arm
compared with the mitoxantrone arm by 2.4 months (18.9 vs
16.5 months, HR 0.76, 95% CI 0.620.94, P = 0.009).8 The
SWOG-9916 trial similarly showed a 1.9-month median OS
advantage for docetaxel (combined with estramustine) when
compared with mitoxantrone (17.5 vs 15.6 months, HR 0.8,
P < 0.02). Taxane therapy also showed benet in the sec-
ond-line chemotherapy setting of metastatic CRPC. Cabazi-
taxel was compared with mitoxantrone in patients who
progressed on docetaxel. The TROPIC trial showed cabazi-
taxel to have a 2.4-month median OS advantage (15.1 vs
12.7 months, HR 0.70, 95% CI 0.590.83, P < 0.0001) over
mitoxantrone.12
728
Docetaxel in metastatic CSPC
After the demonstration of docetaxel efcacy for metastatic
CRPC, phase III randomized trials were launched to evaluate
docetaxel in the castration-sensitive state. Three trials have
recently been reported that lay the groundwork for our cur-
rent use and understanding of docetaxel in this setting
(Table 2).
The rst phase III randomized controlled trial to report
was GETUG-AFU 15.31 A total of 385 patients with meta-
static CSPC were enrolled between October 2004 and
December 2008. Patients who initiated ADT within 2 months
of enrollment were included. They were randomized to
receive ADT alone (through ORCH or gonadotrophin-releas-
ing hormone agonists with or without non-steroidal anti-
androgens) versus ADT plus docetaxel 75 mg/m2 intravenous
every 21 days, for a planned nine cycles. Corticosteroids
were not given throughout the treatment course other than as
premedication. The primary end-point was OS. Secondary
end-points included clinical PFS (dened as time to radio-
graphic progression of pre-existing lesions, appearance of
new lesions or death) and biochemical PFS (dened as time
to PSA progression, clinical progression or death).
After a median follow up of 50 months, the median OS
was 58.9 months in the ADT plus docetaxel arm versus
54.2 months in the ADT alone arm, a non-signicant nding
(HR 0.9, 95% CI 0.71.2). Interestingly though, the median
biochemical PFS was 22.9 months in the ADT plus docetaxel
arm, compared with 12.9 months in the ADT alone arm (HR
0.72, 95% CI 0.570.91, P = 0.005). Clinical PFS was also
longer in the ADT plus docetaxel arm (23.5 vs 15.4 months,
HR 0.75, 95% CI 0.590.94, P = 0.015).
An updated analysis of OS was presented in 2015 after a
median follow up of 83.4 months.32 In addition, an
unplanned post-hoc analysis was aimed to re-categorize
patients to high-volume and low-volume disease subgroups,
as per denitions used in the CHAARTED trial (discussed
below). Doing so placed 47.5% of the patients in the high-
volume group (n = 202). For the overall group, the long-term
survival results showed a median OS of 62.1 months in the
ADT plus docetaxel arm versus 48.6 months in the ADT
alone arm, a non-signicant nding (HR 0.88, 95% CI 0.68
1.14, P = 0.3). Categorizing patients to high- and low-
volume disease did not show any signicant differences in
OS in these subgroups. Median OS difference when compar-
ing the treatment arms for high-volume disease was 39.8 ver-
sus 35.1 months for the docetaxel plus ADT and ADT alone
arms, respectively (HR 0.78, 95% CI 0.561.09, P = 0.14).
For patients with low-volume disease, the median OS was
not reached for the patients treated with ADT plus docetaxel,
and 83.4 months for the patients treated with ADT alone
(HR 1.02, 95% CI 0.671.55).
In summary, the GETUG-AFU 15 trial did not show an
OS benet when docetaxel was added to ADT. Nevertheless,
biochemical and clinical PFS had improved. It is important to
note that there were several limitations that might have pre-
vented the observation of a OS difference. First, the trial was
relatively underpowered and designed to detect a HR of 0.62
with 80% power. Second, nearly two-thirds of patients
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 Chemotherapy for CSPC

Table 2 Comparison of the three major clinical trials involving addition of docetaxel to ADT in metastatic castration sensitive prostate cancer

GETUG-AFU 15 CHAARTED STAMPEDE

Trial design
No. patients 385 790 2962
Planned no. cycles of docetaxel in treatment arm 9 6 6
Follow up (months) 82.9 28.9 43
Baseline characteristics in treatment arm(s) containing docetaxel
No. patients 192 397 1185
Median age (years) 63 64 6566
Performance status Median KPS = 100 ECOG 0 = 69.8% WHO PS 0 = 77.8%
ECOG 1 = 28.7% WHO PS 1+ = 22.2%
ECOG 2 = 1.5%
Patients with Gleason Score 810 (%) 55 60.7 72.6
Median PSA at randomization 27 50.9 66.5
Patients with high-volume disease 47.5 66.2 Not available
Adverse events in treatment arm(s) containing docetaxel
Patients completing planned number of cycles (%) 48 86 7177
Grade 34 febrile neutropenia (%) 7 6 1415
Deaths deemed possibly or probably related to treatment (%) 2 0.3 0.9

Median OS (months)

All High volume Low volume All High volume Low volume All M1 disease

Docetaxel- 60.9 39 83.1 57.6 49.2 Not reached SOC+D: 81 SOC+D: 60

containing SOC+ZA+D: 76 SOC+ZA+D: 55
arm(s)
ADT alone 46.5 35.1 Not reached 44 32.2 Not reached 72 45
Hazard ratio 0.9, P = 0.44 0.8, P = 0.35 1, P = 0.87 0.61, P < 0.001 0.60, P < 0.001 0.60, P = 0.11 SOC+D: 0.78, SOC + D: 0.76,
(HR, P-value) P = 0.006 P = 0.005
SOC+ZA+D: SOC+ZA+D:
0.82, P = 0.022 0.79, P = 0.015

receiving ADT alone crossed over to receive docetaxel at
TTP to castration resistance, compared with just one-quarter
of those in the ADT plus docetaxel arm, which could have
limited the ability to detect a survival benet. Finally,
approximately half the patients had good prognosis at base-
line (49% in ADT plus docetaxel arm and 50% in ADT alone
arm) as dened by the Glass criteria33 (appendicular vs axial
disease; ECOG performance status of 0 vs 13; PSA concen-
tration <65 ng/mL vs 65 ng/mL or more; and Gleason score
<8 vs 8) or by volume of disease.31
The E3805 Trial, also known as CHAARTED, was the
second phase III trial that reported to compare combined
ADT plus docetaxel versus docetaxel alone in patients with
metastatic CSPC.18 It was originally designed to include only
patients with high-volume disease (dened as the presence of
visceral metastases or 4 bone lesions with 1 beyond the
vertebral body and pelvis), with a planned sample size of 568
patients. Because of slow accrual, a protocol amendment was
made to include patients with low-volume disease, and the
sample size was increased to 790 patients to account for the
expected change in events by including these better prognosis
patients. In total, enrollment spanned between July 2006 and
December 2012.
Previous ADT was permissible in the adjuvant setting if
given for 24 months and the time from therapy completion
to disease progression was greater than 12 months. Patients
with metastatic CSPC could receive ADT, provided it was
started within 120 days of randomization in the present trial
and there was no evidence of disease progression. Docetaxel
was given at 75 mg/m2 on an every three-weekly basis for a
planned six cycles. Just like with GETUG-AFU 15, corticos-
teroids were not given other than as premedication. The trial
was powered to test the hypothesis that median OS would be
33.3% longer in the ADT plus docetaxel arm than the ADT
alone arm. Secondary end-points included complete serologi-
cal response (dened as a PSA value <0.2 ng/mL on two
consecutive readings at least 4 weeks apart) at 6 and
12 months, time to CRPC and time to clinical progression
(dened as increasing symptoms of bone metastases, clinical
deterioration as a result of cancer based on investigator
assessment, or radiographic progression according to the
Response Evaluation Criteria in Solid Tumors, version 1.0).
After a median follow up of 28.9 months, the median OS
showed a 13.6-month improvement in the combined doc-
etaxel plus ADT arm compared with the ADT alone arm
(57.6 vs 44.0 months, HR 0.61, 95% CI 0.470.80,
P < 001). The benet was even more apparent in the sub-
group with high-volume disease, with a median OS that was
17.0 months longer favoring the docetaxel plus ADT arm
(49.2 vs 32.2 months, HR for death 0.60, 95% CI 0.450.81,
P < 0.001). Survival data has not yet matured in patients
with low-volume disease subgroup for either arm, although

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S PARIMI AND KN CHI
there was still a trend for improved survival in the docetaxel
plus ADT treated patients (HR 0.60, 95% CI 0.321.13,
P = 0.11). Secondary end-points were all met in the experi-
mental versus control arm, including PSA level <0.2 ng/mL
at 6 months (32.0% vs 19.6%, P < 0.001), PSA levels
<0.2 ng/mL at 12 months (27.7% vs 16.8%, P < 0.001),
median time to CRPC (20.2 vs 11.7 months, HR 0.61, 95%
CI 0.510.72, P < 0.001) and median time to clinical pro-
gression (33.0 vs 19.8 months, HR 0.61, 95% CI 0.500.75,
P < 0.001).
The CHAARTED trial was the rst to convincingly show
OS benets of docetaxel in the metastatic CSPC setting. It
also showed a more pronounced benet among patients with
high-volume disease, which made up two-thirds of the
patients accrued to the study. These ndings were unprece-
dented, but issues regarding the benet in the better progno-
sis, low-volume disease were not fully resolved.
The most recent trial to report is the STAMPEDE trial,
which examined the use of several agents in CSPC, many of
which had proven efcacy in the castration resistant setting.34
The ability to address treatment questions for several thera-
peutic agents was achieved through the use of a multi-arm,
multi-stage platform design. Patients that were enrolled
included those with high-risk locally advanced cancer (de-
ned as being either node-positive or having two of three of
the following risk factors: stage T3/4, PSA 40 ng/mL or
Gleason score 810) and metastatic prostate cancer (which
comprised 62% of the enrolled patients) who were hormone
therapy nave (dened as starting ADT no longer than
12 weeks before study randomization).
Agents that were initially assessed in the trial included
zoledronic acid, docetaxel and celecoxib, and the study was
designed to evolve with additional arms including abi-
raterone, enzalutamide and prostate radiotherapy added later.
The results of the four arms were reported, and encompassed
2962 patients that were enrolled between October 2005 and
March 2013: 1184 patients to SOC therapy (dened as ADT
for at least 2 years), 593 to SOC+ZA; 592 to SOC+D; and
593 to SOC+ZA+D. Zoledronic acid was given at 4 mg
every 3 weeks, then four-weekly until 2 years. Docetaxel
was given at 75 mg/m2 every 3 weeks for a planned six
cycles, which was the same regimen as the previous two tri-
als. Unlike the other two trials, however, docetaxel was
given with a corticosteroid, prednisolone 10 mg daily,
throughout the treatment course. The primary end-points
were OS, dened as time from randomization to death from
any cause; and FFS, dened as time from randomization to
occurrence of one of the following: biochemical failure,
lymph node or metastatic progression, or prostate cancer-
related death.
At a median follow up of 43 months, only the docetaxel-
containing arms showed improvement in terms of the primary
end-points. The median OS was 81 months for SOC+D (HR
0.78, 95% CI 0.60.93, P = 0.006), and 76 months for
SOC+ZA+D (HR 0.82, 95% CI 0.690.97, P = 0.022), com-
pared to 71 months for SOC. The FFS was 37 months with
SOC+D (HR 0.61, 95% CI 0.530.70, P = 0.413 9 10 13)
and 36 months with SOC+ZA+D (HR 0.62, 95% CI 0.54
0.70, P = 0.134 9 10 12) compared with 20 months with
730
SOC. As well, the preplanned subgroup analysis of patients
with metastatic disease only showed an improvement in med-
ian OS when docetaxel was added to the regimen: 60 months
with SOC+D (HR 0.76, 95% CI 0.620.92, P = 0.005) and
55 months with SOC+ZA+D (HR 0.79, 95% CI 0.660.96,
P = 0.015) versus 45 months with SOC. Unlike in the
GETUG-AFU 15 and the CHAARTED studies, patients with
metastatic disease were not evaluated or stratied for progno-
sis or the presence of high- or low-volume disease. OS
results have not matured in the non-metastatic population as
of yet, but the docetaxel-containing arms were the only ones
to signicantly improve FFS in this subgroup (HR 0.60, 95%
CI 0.450.80, P = 0.283 9 10 13).
In summary, STAMPEDE was another large trial showing
OS benet when adding docetaxel to SOC in metastatic
CSPC. Unfortunately, the trial did not collect data on whether
patients had high- versus low-volume disease or other prog-
nostic stratication, but it did support the CHAARTED trials
OS benet in the unselected metastatic CSPC population.
A meta-analysis by Tucci et al. compiled and analyzed
aggregate study-level data from the results of all three trials.35
It included 2951 patients, of which 2262 patients had meta-
static disease. A total of 40% (n = 1181) of the patients were
assigned to docetaxel plus ADT, and 60% (1770) to ADT
alone. There was no heterogeneity (I2 = 48%, P = 0.15),
showing that differences in the ndings between trials
included in this meta-analysis were not statistically signi-
cant. The results of the meta-analysis showed a 27% reduc-
tion in the risk of death of metastatic patients (HR 0.73, 95%
CI 0.600.90, P = 0.002) given docetaxel, and 33% reduction
in risk of death in those with high-volume metastatic disease
(HR 0.67, 95% CI 0.510.88). Similar OS benets were seen
with docetaxel in the entire study population (HR 0.74, 95%
CI 0.610.91, P = 0.003). In subgroup analysis, there was no
signicant interaction between docetaxel and the disease vol-
ume (P = 0.5). However, this was a low-powered statistical
calculation, partially owing to the low number of events and
limited follow up. In addition, there was no differentiation of
STAMPEDE patients to low- or high-volume disease.
The Tucci meta-analysis certainly supported docetaxels
use in an upfront setting, and the lack of heterogeneity found
between the trials further increased condence in the ndings.
Nevertheless, a criticism of this work is that only aggregate
study-level data was compiled.34 Analysis on individual
patient data would have been preferable, as it allows for bet-
ter standardization, comparison of data across trials and fol-
low up.36
Discussion
Two large phase III trials and a meta-analysis have conrmed
the OS benets of using six cycles of docetaxel in metastatic
CSPC patients. Thus, ADT plus docetaxel is now a standard
treatment option in metastatic CSPC. Nevertheless, unre-
solved issues do remain.
There is still controversy as to whether patients with good
prognosis, as dened by low-volume disease burden, should
be treated with combined chemohormonal therapy. Neither
the 2015 European Society for Medical Oncology Clinical
2016 The Japanese Urological Association

Practice Guidelines37 nor the 2016 European Association of
Urology Guidelines38 mention the volume of disease when
advocating for docetaxel in metastatic CSPC, only that they
must be t enough to tolerate the drug. There is a strong case
to be made for treating all metastatic CSPC patients uni-
formly with a chemohormonal approach. CHAARTED and
STAMPEDE included patients with both high and low-
volume disease and the primary analysis of these studies
along with the meta-analysis support an approach that treats
all comers without differentiating prognostic subgroups. In
contrast, there is a rationale for carefully selecting patients to
whom we give chemotherapy. Docetaxel is not without its
side-effects, including treatment-related deaths and a clini-
cally important rate of neutropenic sepsis. In the GETUG-
AFU 15 study, 21% of patients in the ADT-docetaxel arm
stopped treatment early because of toxicity, there were four
treatment-related deaths in the rst 108 patients randomized
to ADT-docetaxel, and a 68% febrile neutropenia rate even
with protocol-mandated prophylactic granulocyte colony-sti-
mulating factor. In the STAMPEDE study, the febrile neu-
tropenia incidence was even higher at 15%. Caution clearly
needs to be taken with this approach, and giving docetaxel to
all patients with a good prognosis might be too high a risk
for the absolute benet gained. In the CHAARTED study,
the benets observed with docetaxel plus ADT at the interim
analysis appear to be driven by the events in patients with
high-volume disease. The non-chemotherapy arms of STAM-
PEDE had a very similar OS to the control arm of
CHAARTED, suggesting that the two patient populations
were similar; that is, the majority of patients with metastatic
disease had poor prognosis, high-volume disease when
enrolled. Thus, in addition to considering factors, such as age
and comorbidities, as tness for docetaxel (recognizing that
there are no validated, objective measures to do this), we
would advocate also considering prognosis and burden of dis-
ease to better individualize this important treatment decision.
The decision process to proceed with docetaxel in a patient
that is of marginal tness with poor prognosis high-volume
disease should be different than if they had low-volume
oligometastases. It has also recently been shown that hor-
monal sensitivity (as dened by the lowest PSA level after
rst-line ADT) was an independent predictor for OS in a
multivariate model.39 Further studies should be carried out to
Table 3 Ongoing phase III trials involving targeted therapy in the metastatic CSPC setting
Clinicaltrial.gov number Status of trial
NCT01715285 Accrual completed
NCT02677896 Currently recruiting participants
NCT01957436 Currently recruiting participants
NCT02446405 Currently recruiting participants
NCT01978873 Currently recruiting participants
NCT02489318 Currently recruiting participants
NCT01809691 Currently recruiting participants
2016 The Japanese Urological Association
Chemotherapy for CSPC
determine if hormonal sensitivity can help decide which
patients can be treated with ADT alone as opposed to chemo-
hormonal therapy.
The use of daily corticosteroids while taking docetaxel is
also debatable. Patients in the STAMPEDE trial used corti-
costeroids daily while on trial, but not in CHAARTED or
GETUG-AFU 15, prompting the question of whether they are
necessary other than as premedication. Corticosteroids have
historically been used alongside prostate cancer chemotherapy
regimens to manage treatment and tumor-related side-
effects,40 and have a modest effect on PSA decline.41 How-
ever, corticosteroids are associated with important toxicities
of their own, including hypertension, weight gain, hyper-
glycemia, steroid-induced myopathy and infections.40 In light
of the toxicity prole, and because OS benets were seen
with and without corticosteroids, it is justiable to omit them
from daily use while receiving chemohormonal therapy. They
might still have a role with respect to their other palliative
benets, such as appetite stimulation and minimizing meta-
static bone pain. However, use for these purposes should be
on a case-by-case basis.
A third issue left to be resolved is whether patients with
high-risk, non-metastatic prostate cancer should routinely be
given docetaxel, given the FFS advantage seen from the
STAMPEDE trial. Taxanes have been and continue to be
evaluated in the non-metastatic setting of prostate cancer
across several disease states.4250 Given the absence of a
denitively demonstrated overall survival benet, treating this
patient population should remain investigational at this time.
Finally, when applying the ndings of CHAARTED and
STAMPEDE worldwide, it must be noted that differing
screening and treatment practices, as well as genetic and
environmental factors, might lead to inter-regional differences
in treatment outcomes. Differing survival rates have already
been seen in patients on ADT alone across various countries.
A study by Miyamoto et al.39 showed a 5-year OS of 62.5%
in a cohort of 79 metastatic CSPC Japanese patients on ADT,
a number much higher than that in the ADT-only arm for meta-
static CSPC patients in the STAMPEDE trial (5-year OS 39%),
which only enrolled UK and Swiss patients.34 It has been pro-
posed that differences in OS amongst metastatic CSPC patients
on ADT might arise, because countries with rigorous screening
processes might detect most cancers before they metastasize,
Experimental arm Control arm
Abiraterone acetate + prednisone + ADT Placebo + ADT
Enzalutamide + ADT Placebo + ADT
A: ADT + abiraterone acetate + prednisone ADT
B: ADT + radiotherapy
C: ADT + abiraterone acetate + prednisone
+ radiotherapy
Enzalutamide + ADT Conventional non-steroidal
anti-androgen + ADT
Cabazitaxel + ADT ADT
JNJ-56021927 (ARN-509) + ADT Placebo + ADT
Orteronel (TAK-700) + ADT Bicalutamide + ADT
731
S PARIMI AND KN CHI
selecting for aggressive tumors in the metastatic state that pro-
gress between screening intervals.51 It is therefore plausible
that patients with these more aggressive cancers might also
derive more benet from docetaxel compared with patients in
countries with less stringent screening programs.
Conclusion
The landscape of metastatic CSPC has denitively changed
with the incorporation of a familiar drug: docetaxel. After
having no changes to the treatment regimen for several dec-
ades, this disease state has now seen unprecedented survival
benets with this addition, although guides to the optimal
patient selection for a chemohormonal approach remain unde-
ned. Use of docetaxel in metastatic CSPC stemmed from
the success of docetaxel in patients with CRPC. Looking to
the future, the role for other agents approved for CRPC, in
particular the AR axis-targeting agents, abiraterone acetate
and enzalutamide, are being evaluated in the castration-sensi-
tive setting (Table 3), and hold the promise of continued
improvements in the outcomes for these patients.
Conflict of interest
None declared.
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