International Journal of Urology (2018) 25, 220--231 doi: 10.1111/iju.

13512

Review Article

Current treatment strategies for advanced prostate cancer

Kazumasa Komura,1 Christopher J Sweeney,2 Teruo Inamoto,1 Naokazu Ibuki,1 Haruhito Azuma1 and
Philip W Kantoff3
1
Department of Urology, Osaka Medical College, Takatsuki, Osaka, Japan, 2Department of Medical Oncology, Dana-Farber Cancer
Institute, Boston, MA, and 3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

Abbreviations & Acronyms

Abi = abiraterone
ADT = androgen deprivation therapy
APC = advanced prostate cancer
AR = androgen receptor
ASI = androgen signaling inhibitor
C20 = cabazitaxel 20 mg/m2
C25 = cabazitaxel 25 mg/m2
CRPC = castration-resistant prostate
cancer
CTC = circulating tumor cell
ctDNA = circulating tumor DNA
D75 = DNA docetaxel 75 mg/m2
dNLR = derived neutrophil-to-
lymphocyte ratio
DOC = docetaxel
Enz = enzalutamide
EZH2 = enhancer of zeste homolog 2
FDA = US Food and Drug
Administration
FISH = fluorescent in situ hybridization
GCSF = granulocyte colony-
stimulating factor
HR = hazard ratio
HSPC = hormone-sensitive prostate
cancer
IHC = immunohistochemistry
LHRHA = luteinizing hormone-
releasing hormone analog
mCRPC = metastatic castration-
resistant prostate cancer
NEPC = neuroendocrine prostate
cancer
NLR = neutrophil-to-lymphocyte ratio
OS = overall survival
PARP = poly adenosine
diphosphate-ribose polymerase
PBMC = peripheral blood
mononuclear cell
PC = prostate cancer
PFS = progression-free survival
PSA = prostate-specific antigen
RB1 = retinoblastoma 1
RCT = randomized controlled trial
SOC = standard of care
ZA = zoledronic acid
Correspondence: Philip W Kantoff
M.D., Department of Medicine,
Memorial Sloan Kettering Cancer Center,
1275 York Avenue, New York, NY
10065, USA. Email: kantoff@mskcc.org
Received 1 September 2017; accepted
9 November 2017.
Online publication 20 December 2017
Abstract: During the past decade, treatment strategies for patients with advanced
prostate cancer involving stage IV (T4N0M0, N1M0 or M1) hormone-sensitive prostate
cancer and recurrent prostate cancer after treatment with curative intent, as well as
castration-resistant prostate cancer, have extensively evolved with the introduction and
approval of several new agents including sipuleucel-T, radium-223, abiraterone,
enzalutamide and cabazitaxel, all of which have shown significant improvement on
overall survival. The appropriate use of these agents and the proper sequencing of these
agents are still not optimized. The results of several recently reported randomized
controlled trials and retrospective studies could assist in developing a treatment strategy
for advanced prostate cancer. In addition, prospective studies and molecular
characterization of tumors to address these issues are ongoing.
Key words: castration-resistant prostate cancer, precision medicine, prostate cancer,
sequential therapy.
Introduction
PC is the most common malignancy in men.1 Historically, since Charles Huggins first
reported the effect of ADT for patients with metastatic PC in 1941, suppression of AR signal-
ing through ADT has remained the mainstay of treatment for metastatic PC for more than
70 years. Current ADT includes surgical castration or medical castration using luteinizing hor-
mone-releasing hormone agonists or antagonists with or without anti-androgen drugs.
Although ADT offers near certain remissions lasting 1–2 years in most patients, cancer cells
become resistant with the emergence of mCRPC. In 2004, docetaxel, a chemotherapeutic inhi-
bitor of microtubule depolymerization, was approved for mCRPC patients; however, docetaxel
offered a modest 2.5 months median prolongation in OS.2,3 Acquired resistance to the drug
eventually emerges.
For the past decade, much progress has been made in the understanding of APC, which
includes stage IV (T4N0M0, N1M0 or M1) HSPC and recurrent PC after treatment with cura-
tive intent as the new high-throughput technologies, such as next-generation sequencing,
which has uncovered the mutational landscape of PC. In addition, five additional drugs were
approved by the FDA for the treatment of CRPC with an improvement of OS, including a
chemotherapeutic (cabazitaxel),4 two ASIs (abiraterone5 and enzalutamide6), an immunothera-
peutic (sipuleucel-T7) and an alpha-emitting bone-seeking radioisotope (radium-2238). These
newly developed agents, however, now raise new questions: what constitutes optimal
sequencing or pairing of drugs? And what biomarkers could be used to predict the treatment
efficacy for precision medicine? By now, a number of prospective and retrospective studies
have offered some information to address these issues. In the present article, we review the
overview of the current status for the treatment of APC and provide the latest findings of new
molecular biomarkers for disease prediction.
Five newly developed agents the FDA approved
Since docetaxel was approved for mCRPC patients after showing a survival advantage over
mitoxantrone in 2004, five newly developed drugs were additionally approved by 2014.2,3
Table 1 summarizes phase 3 trials of those drugs.

220 © 2017 The Japanese Urological Association

 Current treatment strategy for CRPC

Table 1 Results of randomized clinical trials for advanced prostate cancer drugs

Year Drug name Trial name Patient enrollment Intervention Results (median overall survival)

2004 Docetaxel TAX3273 1006 men with mCRPC Docetaxel 75 mg/m2 every 3 weeks vs Docetaxel every 3 weeks:
docetaxel 30 mg/m2 weekly vs 18.9 months
mitoxantrone 12 mg/m2 every 3 weeks Docetaxel weekly: 17.4 months
(prednisone 5 mg twice daily to all patients) Mitoxantrone: 16.5 months
Docetaxel every 3 weeks vs
mitoxantrone:
HR 0.76, P = 0.009
Docetaxel weekly vs mitoxantrone:
HR 0.91, P = 0.36
2004 Docetaxel SWOG99162 770 men with mCRPC Docetaxel 60 mg/m2 every Docetaxel + estramustine:
3 weeks + estramustine 280 mg 3 times 17.5 months
daily on days 1–5 vs mitoxantrone Mitoxantrone + prednisone:
12 mg/m2 every 3 weeks + prednisone 15.6 months
5 mg twice daily HR 0.80, P = 0.02
2010 Cabazitaxel TROPIC4 755 men who progressed after Cabazitaxel 25 mg/m2 every 3 weeks vs Cabazitaxel: 15.1 months
docetaxel mitoxantrone 12 mg/m2 every 3 weeks Mitoxantrone: 12.7 months
(prednisone 5 mg twice daily to all patients) HR 0.70, P < 0.0001
2010 Sipuleucel-T IMPACT7 512 men with mCRPC without visceral Sipuleucel-T given every 2 weeks 3 times vs Sipuleucel-T: 25.8 months
metastasis† placebo Placebo: 21.7 months
2:1 randomization HR 0.78, P = 0.03
2011 Abiraterone COU-AA-3015 1195 men previously treated with Abiraterone 1000 mg daily vs placebo Abiraterone: 14.8 months
Acetate docetaxel (prednisone 5 mg twice daily to all patients) Placebo: 10.9 months
2:1 randomization HR 0.74, P < 0.001
2012 Enzalutamide AFFIRM6 1199 men previously treated with Enzalutamide 160 mg daily vs placebo Enzalutamide: 18.4 months
docetaxel Placebo: 13.6 months
2:1 randomization HR 0.63, P < 0.001
2012 Abiraterone COU-AA-30213 1088 chemotherapy-na€ıve men with Abiraterone 1000 mg daily vs placebo Abiraterone: 34.7 months
Acetate mCRPC (prednisone 5 mg twice daily to all patients) Placebo: 30.3 months
HR 0.81, P < 0.0033
2013 Radium-223 ALSYMPCA8 921 men with mCRPC with at least Radium-223 every 4 weeks 6 times vs placebo Radium: 14.9 months
two bone metastases, no visceral Placebo: 11.3 months
metastasis, no lymph nodes >3 cm HR 0.70, P < 0.001
2:1 randomization
2014 Enzalutamide PREVAIL19 1717 asymptomatic or minimally Enzalutamide 160 mg vs placebo Enzalutamide: 32.4 months
symptomatic, chemotherapy-na€ıve, Placebo: 30.4 months
no prior abiraterone or HR 0.70, P < 0.01
ketoconazole
2015 Docetaxel CHAARTED22 790 metastatic hormone-sensitive Docetaxel 75 mg/m2 every 3 weeks for 6 ADT + docetaxel: 57.6 months
prostate cancer cycles + ADT vs ADT alone ADT alone: 44.0 months
HR 0.61, P < 0.001
2015 Docetaxel STAMPEDE23 2962 locally advanced high-risk or SOC only vs SOC + ZA (4 mg) every 3 weeks SOC only: 71 months
mCRPC vs SOC + DOC 75 mg/m2 every 3 weeks SOC + ZA: not reached
2:1:1:1 randomization with prednisolone 10 mg daily vs SOC + DOC: 81 months
SOC + ZA + DOC SOC + ZA + DOC: 76 months
SOC vs SOC + ZA
HR 0.94, P = 0.45
SOC vs SOC + DOC
HR 0.78, P = 0.006
SOC vs SOC + ZA + DOC
HR 0.82, P = 0.022
2016 Cabazitaxel FIRSTANA9 1168 patients who had progressed C20 every 3 weeks vs C25 every 3 weeks vs C20: 24.5 months
after castration D75 every 3 weeks (prednisone 5 mg twice C25: 25.2 months
1:1:1 randomization daily to all patients) D75: 24.3 months
C20 vs D75: HR 1.009, P = 0.9967
C25 vs D75: HR 0.97, P = 0.7574
2017 Abiraterone NCT0026847626 1917 locally advanced high-risk or ADT + abiraterone 1000 mg daily vs ADT ADT + abiraterone: 83% of 3 years OS
Acetate metastatic hormone-sensitive alone (prednisone 5 mg twice daily to all ADT alone: 76% of 3 years OS
prostate cancer patients) HR 0.63, P < 0.001
2017 Abiraterone LATITUDE25 1199 metastatic hormone-sensitive ADT + abiraterone 1000 mg daily vs ADT plus ADT + abiraterone: not reached
Acetate prostate cancer placebo (prednisone 5 mg twice daily to all ADT + placebo: 34.7 months
patients) HR 0.62, P < 0.001

†Patients who reported moderate-to-severe PC-related pain and/or use of narcotics for cancer-related pain were also excluded.

© 2017 The Japanese Urological Association 221

K KOMURA ET AL.
Sipuleucel-T
Sipuleucel-T is a cellular immunotherapy consisting of
autologous PBMCs followed by leukapheresis. The
patient’s PBMCs are cultured (activated) with a recombi-
nant human protein (PAP-GM-CSF) consisting of prostatic
acid phosphatase linked to granulocyte-macrophage col-
ony-stimulating factor, and re-injected to the patients three
times at 2-week intervals. This therapy was approved in
2010 based on the result from the IMPACT study in
which 512 patients having mCRPC without visceral
metastasis were assigned to a sipuleucel-T arm or a pla-
cebo (injection of PBMCs not treated).7 The sipuleucel-T
arm had a 4.1-month OS advantage compared with the
placebo (HR 0.78, 95% CI 0.61–0.98, P = 0.03), whereas
there was no significant advantage in PFS (3.7 and
3.6 months of the median PFS in sipuleucel-T and pla-
cebo, respectively) and PSA response rate (2.6% and
1.3% of 50% reduction of PSA in sipuleucel-T and pla-
cebo, respectively). Modest side-effects including chills,
fever and headache were reported, which are comparable
with other new agents.
Cabazitaxel
Cabazitaxel, approved by the FDA in 2010 for patients with
mCRPC who progressed after docetaxel,4 is a novel tubulin-
binding taxane that differs from docetaxel because of its
poor affinity for P-glycoprotein (P-gp), an adenosine triphos-
phate-dependent drug efflux pump. Preclinical and early
clinical studies demonstrated that cabazitaxel showed activ-
ity in docetaxel-resistant tumors, and this was confirmed by
the TROPIC study. In the study, 755 patients were ran-
domly assigned, and the median OS was 15.1 months in the
cabazitaxel group and 12.7 months in the mitoxantrone
group. The HR for death of men treated with cabazitaxel
was 0.70 (95% CI 0.59–0.83, P < 0.0001). The median PFS
was 2.8 months in the cabazitaxel group and 1.4 months in
the mitoxantrone group (HR 0.74, 95% CI 0.64–0.86,
P < 0.0001). Febrile neutropenia was observed in 8% of
patients of the cabazitaxel group and 1% in the mitox-
antrone group. Accordingly, using cabazitaxel for patients
with neutrophil counts of <1500 cells/mm3 is a contraindica-
tion, and the FDA states that prophylactic GCSF should be
considered for patients with high-risk features (age
>65 years, poor PS, previous episodes of febrile neutrope-
nia, extensive prior radiation ports, poor nutritional status or
other serious comorbidities). The FIRSTANA study recently
showed that 20 mg/m2 was less toxic and as effective as
25 mg/m2 of cabazitaxel, so 20 mg/m2 without GCSF sup-
port is now the preferred dose.9
Abiraterone acetate
Abiraterone, which was first approved by the FDA in 2011
for use in patients with mCRPC who have been previously
treated with docetaxel, is a potent P450 c17 (CYP17) inhibi-
tor, an enzyme that has two distinct activities: 17–20 lyase
and 17-alpha hydroxylase. This enzymatic action is used in
222
the conversion of pregnenolone and progesterone to 17-OH
pregnenolone and 17-OH progesterone, and from there to
dehydroepiandrosterone and androstenedione, which is the
penultimate step in testosterone production. Thus, this drug in
turns interrupts androgen production at three sources: the tes-
tis, the adrenal glands and the tumor itself.10–12 In the COU-
AA-301 trial, 1195 patients previously treated with docetaxel
were randomly assigned to abiraterone plus prednisone or
placebo plus prednisone groups.5 The primary end-point of
OS showed an improvement of OS for 3.9 months compared
with the placebo. All secondary end-points also favored abi-
raterone, with a PSA response rate of 29% versus 6%. The
most common side-effect was fatigue, which was similar in
both groups. There were more mineralocorticoid symptoms
consisting of fluid retention in the abiraterone group, and
more hypokalemia in the abiraterone group despite the major-
ity of these side-effects being assigned as grade 1. In the
COU-AA-302 trial, 1088 chemotherapy-na€ıve patients were
randomized to abiraterone plus prednisone or to a placebo
plus prednisone.13,14 The primary end-points were OS and
radiographic PFS. There was an 8.2-month improvement in
radiographic PFS favoring abiraterone. OS was improved
with abiraterone–prednisone (median not reached, vs
27.2 months for prednisone alone; HR 0.75, 95% CI
0.61–0.93, P = 0.01), but did not cross the efficacy bound-
ary.13 The final OS results in the trial showed an improve-
ment of OS of 4.4 months in abiraterone group (HR 0.81,
95% CI 0.70–0.93, P = 0.033).14
Enzalutamide
Enzalutamide is a potent blocker targeting the AR signaling
pathway at several steps, exerting its effect by blocking bind-
ing of androgens to AR,15 by inhibiting nuclear translocation
of activated AR16 and by impairing binding of activated AR
with DNA.17,18 This drug was approved by the FDA in 2012
for mCRPC with progression after docetaxel. In the AFFIRM
trial, 1199 patients who were previously treated with a doc-
etaxel chemotherapy were randomly assigned into enzalu-
tamide or placebo.6 The primary end-point of OS showed an
improvement of OS for 4.8 months favoring enzalutamide
(HR 0.63, 95% CI 0.53–0.75, P < 0.001). There was also
improvement in the secondary end-points of radiographic
PFS (median survival of 8.3 months vs 2.9 months; HR 0.40,
P < 0.001) and the time to the first skeletal-related event
(median survival of 16.7 months vs 13.3 months; HR 0.69,
P < 0.001). In the PREVAIL trial, 1717 patients with asymp-
tomatic or minimally symptomatic mCRPC who had not
received chemotherapy, abiraterone or ketoconazole were ran-
domized to enzalutamide or a placebo.19 The primary end-
points were radiographic PFS and OS. At 12 months, the
radiographic PFS was 65% in the enzalutamide group versus
14% in the placebo group, and median survival had not been
reached in the enzalutamide group and was 3.9 months in the
placebo group (HR 0.19, P < 0.001). The median OS were
32.4 and 30 months in the enzalutamide arm and the placebo
group, respectively (HR 0.71, 95% CI 0.60–0.84, P < 0.001).
The most common adverse events in both trials were fatigue,
hot flashes and headache. Of note, in the AFFIRM trial, there
© 2017 The Japanese Urological Association

were five seizures in the enzalutamide arm and none in the
placebo arm. Warning of using enzalutamide to the patients
with a history of seizures has been described by the FDA,
which could lead to the result of the PREVAIL trial where
one seizure was noted in each arm.
Radium-223
Radium-223, which was FDA-approved in 2013, is an alpha-
emitting radiopharmaceutical, and selectively targets bone
metastases with alpha particles. Radium is a “calcium
mimetic”, which accumulates preferentially in areas of bone
with increasing turnover, such as osteoblastic metastasis, and
the emitted alpha particle radiation causes double-strand
breaks in DNA within 100 lm of the range, which offers a
selective effect to the target region without damage to the sur-
rounding tissue. In the ALSYMPCA trial, 921 patients were
eligible to participate in the study according to the criteria of
mCRPC having two or more bone metastases detected on
skeletal scintigraphy and no known visceral metastases.8 All
the patients were receiving the best standard of care, and
patients who had received docetaxel 4 weeks before the enroll-
ment were included. The primary end-point was OS, and the
secondary end-points included time to the first symptomatic
skeletal event and biochemical failure. The final analysis
showed significant improvement for OS in the radium-223
group compared with the placebo group (14.9 and
11.3 months of median OS in radium-223 and placebo group,
respectively: HR 0.70, 95% CI 0.58–0.83, P < 0.001). The
time to the first symptomatic skeletal event, the secondary
end-point, were also significantly prolonged in the radium-223
group compared with the placebo group (median of
15.6 months vs 9.8 months: HR 0.66, 95% CI 0.52–0.83,
P < 0.001). It should be mentioned that radium-223 was very
well tolerated with no increase in grade 3–4 toxicity. The
FDA approved this drug for mCRPC patients without regard
to prior docetaxel use, although the design of the ALSYMPCA
trial was intended for patients who were not thought to be eli-
gible to receive chemotherapy or who chose not to receive it.
Treatment strategy and biomarkers for
APC
As the five new drugs emerged and represented significant
improvement in the treatment of mCRPC, it was natural that
Table 2 Median OS in months according to disease volume in RCTs for patients with mHSPC
GETUG-AFU 15 (n = 385)20 CHAARTED (n = 790)22
ADT + ADT +
Docetaxel ADT HR 95% CI P-value Docetaxel
All cohort All cohort
60.9 46.5 0.9 0.7–1.2 0.44 57.6
High-volume disease High-volume disease
39.8 35.1 0.78 0.56–1.09 0.14 49.2
Low-volume disease Low-volume disease
Not reached 83.4 1.02 0.67–1.55 0.9 Not reached Not reached
© 2017 The Japanese Urological Association
Current treatment strategy for CRPC
one of the next areas of research was determining whether
combination use or sequential therapy was superior. Further-
more, the focus was not only on mCRPC. The treatment
strategy for APC including stage IV (T4N0M0, N1M0 or
M1) HSPC and recurrent PC after the treatment with curative
intent are also now evolving.
Docetaxel as SOC in hormone-sensitive APC
Having shown docetaxel prolonged OS in CRPC, it was then
evaluated in metastatic hormone-sensitive disease. As shown
in Table 2, in 2013, the result of the GETUG-AFU 15 trial
was reported in which 385 men with mHSPC were random-
ized to receive ADT plus docetaxel (75 mg/m2 every
3 weeks, up to nine cycles) or ADT alone.20 Although the
addition of docetaxel was associated with an improvement in
biochemical PFS (22.9 vs 12.9 months; HR 0.7, 95% CI 0.6–
0.9, P = 0.0021), there was no improvement in OS with the
addition of docetaxel, even with long-term follow up (62.1 vs
48.6 months; HR 0.88, 95% CI 0.68–1.14, P = 0.3).21 In
contrast, the Eastern Cooperative Oncology Group led the
CHAARTED trial, in which 790 men with mHSPC were ran-
domly assigned to ADT or ADT plus six cycles of docetaxel
chemotherapy given at 75 mg/m2 every 3 weeks and showed
dramatic improvement of OS in the ADT plus docetaxel
group than the ADT alone (57.6 vs 44.0 months; HR 0.61,
95% CI 0.47–0.80, P < 0.001).22 In parallel, the STAM-
PEDE trial, which assigned 2962 men with either high-risk
localized (24%), node-positive (15%) or mHSPC (61%) to
four treatment arms: SOC alone, SOC plus zoledronic acid,
SOC plus docetaxel or SOC plus zoledronic acid and doc-
etaxel, also showed that the addition of docetaxel to SOC eli-
cited significant improvement in OS (81.0 vs 71.0 months in
SOC plus docetaxel vs SOC alone, respectively; HR 0.78,
95% CI 0.66–0.93, P = 0.006).23 It should be mentioned that
the composition of enrolled patients largely differed in the
GETUG-AFU 15 trial compared with the other two larger
studies. CHAARTED was initially designated as a trial for
high-volume metastatic disease, defined as the presence of
visceral metastasis and/or four or more osseous metastases.
The protocol was later amended to allow enrollment of low-
volume disease. The final result was enriched with high-
volume patients (65.8%). In comparison, the GETUG-AFU
15 trial was not initially powered to evaluate this effect of
volume of disease. Subgroup analysis according to volume
STAMPEDE: M1 subgroup (n = 1087)23
ADT +
ADT HR 95% CI P-value Docetaxel ADT HR 95% CI P-value
All M1 subgroup
44 0.61 0.47–0.8 <0.001 65 43 0.73 0.59–0.89 0.002
High-volume disease
32.2 0.6 0.45–0.81 <0.001 - - - - -
Low-volume disease
0.6 0.32–1.13 0.11 - - - - -
223
K KOMURA ET AL.

disease was later analyzed, and this retrospective evaluation
still did not show significant improvement in OS.21 The med-
ian OS and number of death events were substantially differ-
ent between these two trials (54.2 months with 176 deaths in
GETUG-AFU 15, and 44 months with 237 deaths in
CHAARTED), implying that the smaller GETUG-15 trial
coupled with the better prognosis of enrolled patients might
have resulted in the difference between the trials. A potential
selection criteria for benefit in CHAARTED was a prespeci-
fied subgroup analysis of patients with high- versus low-
volume disease showing an unprecedented 17-month OS
improvement with the addition of docetaxel with high-volume
mHSPC (49.2 vs 32.2 months; HR 0.60, 95% CI 0.45–0.81,
P < 0.001), whereas docetaxel originally conferred a rela-
tively modest 2.9-month OS benefit in mCRPC. A long-term
efficacy in the CHAARTED trial was later reported showing
that this benefit on OS was not seen in patients with low-
volume disease.24 Nevertheless, the strongly positive sub-
group analysis favoring high-volume disease was sufficiently
convincing that docetaxel for mHSPC has been embraced by
the National Comprehensive Cancer Network, and has since
become a SOC for high-volume of metastatic disease. Given
that subgroup analysis of metastatic patients (n = 1087) in
STAMPEDE trials also showed substantial improvement of
OS for 22 months (65 vs 43 months; HR 0.73, 95% CI 0.59–
0.89, P = 0.002), we believe that docetaxel should be consid-
ered in addition to ADT in patients with high-volume
mHSPC.
Abiraterone in M1 HSPC patients
How new ASIs, including abiraterone and enzalutamide,
should be deployed with other approved agents for the treat-
ment of CRPC has been controversial. As of now, both
agents are approved as pre-docetaxel and post-docetaxel treat-
ment for CRPC.5,6,13,14,19 Recently, two RCTs (LATITUDE25
and STAMPEDE arm G26) further reported that combination
use of abiraterone with ADT in mHSPC also offers improve-
ment of OS compared with ADT alone. These data showed
the robust effect of ASIs for the treatment of APC, but also
raise the controversial discussion for the optimal sequence or
combination use of those agents. The STAMPEDE arm G
cohort involved patients with non-metastatic high-risk disease
(characterized by T3 or T4, tumor-positive lymph nodes;
Gleason’s score of 8–10 and/or serum PSA level of ≥40 ng/
mL): 915 and 1002 patients in non-metastatic and metastatic
groups, respectively. The advantage on OS of combination
use of abiraterone was only observed in M1 patients, not in
M0 patients. The LATITUDE trial enrolled only M1 patients,
and showed a significant improvement on OS by combination
use of abiraterone with ADT. A systematic review of the M1
cohort in STAMPEDE arm G (1002 patients) and LATI-
TUDE (1199 patients) reported that survival benefit might be
greater in younger patients (aged <75 years) despite the small
sample size of older patients (137/1002 and 202/1199 in
STAMPEDE arm G and LATITUDE, respectively).27 As
these two studies did not define low and high tumor burden
in their analysis, whether this survival benefit with the combi-
nation of abiraterone is delivered in lower tumor burden
patients remains unknown. Nevertheless, abiraterone should
be considered an option in addition to ADT for men with
mHSPC.
Sequential therapy using ASIs
There have been a number of studies reporting sequential use
of ASIs, namely enzalutamide followed by abiraterone28–32
and abiraterone followed by enzalutamide (Table 3).31–38
Data seem to show a blunted effect of each after the use of
the other, suggesting cross-resistance. It remains unclear
which patients benefit from one agent as the first agent com-
pared with the other. Further investigation is still required in
prospective and randomized settings to validate the optimal
treatment decision-making. Recently, a phase 4, multicenter,
single-arm, open label study of enzalutamide in 214 patients
who progressed on abiraterone after treatment of >6 months
for CRPC noted a median time to biochemical progression of
5.7 months and radiographic progression of 8.1 months,

Table 3 Clinical outcomes in the retrospective studies for sequential therapy using abiraterone and enzalutamide

Prior % Patients with PSA decline

Year Authors Sequence docetaxel n of ≥50% by 2nd ASI Median OS
2013 Noonan et al.30 Enz ? Abi + 30 4 11.5 months
2013 Loriot et al.28 Enz ? Abi + 38 8 7.2 months
2017 Terada et al.31 Enz ? Abi 85 13 899 days
2017 Mori et al.32 Enz ? Abi +† 46 6.5 13.5 months
2014 Schrader et al.37 Abi ? Enz + 35 28.6 7.1 months
2014 Badrising et al.34 Abi ? Enz + 61 21 7.3 months
2014 Thomsen et al.38 Abi ? Enz + 24 17 4.8 months
2014 David et al.36 Abi ? Enz + 23 39.1 8.5 months
2015 Brasso et al.35 Abi ? Enz + 137 18 8.3 months
2015 Azad et al.33 Abi ? Enz 47 26 8.6 months
2015 Azad et al.33 Abi ? Enz + 68 22 10.6 months
2017 Terada et al.31 Abi ? Enz + 113 29 919 days
2017 Mori et al.32 Abi ? Enz +† 23 39.1 14 months

†A total of 23 out of 46 in ‘Enz ? Abi’ and nine out of 23 in “Abi ? Enz” treated with prior docetaxel.

224 © 2017 The Japanese Urological Association

 Current treatment strategy for CRPC

leading to the conclusion that enzalutamide still remained

active in patients with mCRPC previously treated with abi-
raterone.39
Prognostic factors to assist decision-making
The duration of response to prior ADT has been proposed to be
the prognostic factor for the efficacy of subsequent ASI,40–42
based on several retrospective studies.43–45 These studies
consistently showed that shorter response to first-line ADT
is associated with poor PSA response rate and shorter PFS.
Those findings were further observed in the post-hoc analy-
sis from the COU-AA-301 trial, which showed that the
patients in the lowest quartile of duration of prior ADT had
the shortest OS and radiographic PFS.46 Another potential
prognostic factor for the treatment of ASIs is the extent
of PSA decline. Brasso et al. first reported that patients
who had >30% or 50% of PSA decline with enzalutamide
had longer OS compared with patients who had no such
PSA decline (11.4 vs 7.1 months, P = 0.001, and 12.6 vs
7.4 months, P = 0.007, respectively).35 Subsequently, several
studies reported the clinical value of the PSA decline within
4 weeks from the initiation of ASI (Table 4).35,47–50 Impor-
tantly, all these studies showed that patients who did not
respond to ASI within 4 weeks had a poor prognosis for not
only PFS, but also OS, implying that other agents, such as
taxanes, should be considered for these patients rather than
trying another ASI.
At the Advanced Prostate Cancer Consensus Conference
2017, clinically and biologically relevant issues for the treat-
ment of APC, including prognostic factors, were discussed.51
A number of factors potentially predicting the treatment out-
come, such as serum lactate dehydrogenase32,52 and alkaline
phosphatase,53 have been recognized as potential markers for
the treatment of APC. In addition, a number of studies
including post-hoc analysis have further provided new
insights for a higher NLR predicting lower response rate to
abiraterone,54 and a higher dNLR (dNLR = absolute neu-
trophil count / white blood cells – absolute neutrophil count)
predicting shorter OS to docetaxel55 (post-hoc analysis from
VENICE and TAX327 studies), whereas cabazitaxel had a
comparable effect on OS in patients with a higher NLR in a
post-hoc analysis from TROPIC study.56 Taken together,
these findings provide some information for clinicians in the
decision-making of treatment for APC.
Cross-resistance between classes of agents
It is clear that cross-resistance between abiraterone and enza-
lutamide exists based on the blunted activity of use of one
agent after the other. Shared resistance mechanisms involve
alternative strategies to activate the AR, such as intratumor
steroid biosynthesis,57 activation of the glucocorticoid recep-
tor58 and emergence of an AR splice variant, such as
ARV7,59 as well as activation of non-AR survival pathways.
With regard to the interaction between ASIs and docetaxel,
Schweizer et al. reported, in the retrospective study of 119
mCRPC patients, shorter PFS in patients (n = 24) who were
treated with abiraterone followed by docetaxel compared with
patients (n = 95) treated with only docetaxel (PFS of
7.6 months in docetaxel and 4.4 months in abiraterone fol-
lowed by docetaxel, P = 0.003), implying the cross-resistance
between ASIs and docetaxel.60 In contrast, de Bono et al.
recently reported, in the post-hoc analysis from the COU-
AA-302 trial (chemotherapy-na€ıve men with mCRPC), clini-
cal advantage for subsequent docetaxel treatment in patients
with mCRPC whose disease progressed after treatment with
abiraterone acetate.61 Although the modest effect might be
observed in patients who were treated with docetaxel after
progression with an ASI, subsequent chemotherapy still
seems to offer benefit for the treatment of CRPC.62 Cabazi-
taxel, which had benefit for OS in the patients after progres-
sion with docetaxel (TROPIC), has been consistently reported
to have less cross-resistance with ASIs in several retrospec-
tive studies.63–66 Biological findings, which showed growth
inhibition of enzalutamide-resistant PC cell lines by cabazi-
taxel compared with docetaxel in vivo,67 also support the use
of cabazitaxel after ASIs. Given that the FIRSTANA trial
reported that there was no survival difference when compar-
ing docetaxel and cabazitaxel as the first chemotherapy to
CRPC,9 cabazitaxel should be offered to patients progressing
after docetaxel. In addition, the PROSELICA trial showed
non-inferiority for OS of cabazitaxel at a dose of 20 mg/m2
compared with 25 mg/m2, although the PSA response rate was
higher in 25 mg/m2.68 Of note, in the study, grade 4 neutrope-
nia was observed in 21.3% (20 mg/m2) and 48.6% (25 mg/
m2) of patients, and neutropenic sepsis/infection for 2.2%
(20 mg/m2) and 6.1% (25 mg/m2) of patient, suggesting the
advantage of 20 mg/m2 with regard to side-effects. These find-
ings help with the determination of the optimal dose of cabazi-
taxel for individual patients using cabazitaxel after docetaxel at

Table 4 The impact of PSA decline within 4 weeks from initiation of ASIs

Pre- Post- PSA decline

Year Authors ASI n docetaxel docetaxel (% patients with PSA decline) P-value for OS

2015 Brasso et al.35 Enz 137 0 137 30% decline at 4 weeks (38%) P = 0.001 (11.4 vs 7.1 months)
50% decline at 4 weeks (18%) P = 0.007 (12.6 vs 7.4 months)
2016 Rescigno et al.50 Abi 274 117 157 30% decline at 4 weeks (46%) P < 0.001 (25.8 vs 15.1 months)
2016 Kato et al.49 Enz 51 25 26 30% decline at 4 weeks (60.8%) P = 0.003
50% decline at 4 weeks (45.1%) P = 0.002
2016 Fuerea et al.48 Abi/Enz/Orteronel 118 28 90 30% decline at 4 weeks P = 0.03 (27.9 vs 17.3 months)
50% decline at 4 weeks P < 0.01 (32.2 vs 15.9 months)
2016 Facchini et al.47 Abi 87 0 87 50% decline at 2 weeks (56%) P = 0.01

© 2017 The Japanese Urological Association 225

K KOMURA ET AL.
20 mg/m2 without GCSF support. Finally, the TAXYNERGY
trial recently reported that patients who did not achieve ≥30%
PSA response with taxane after 12 weeks of therapy would
benefit from switching to other taxane, which could serve as a
prognostic marker for treatment decision-making.69
Molecular biomarkers for disease prediction
and new therapeutic targets
As shown in Table 5, AR-V7, a truncated splice variant with
no ligand binding domain, has become an attractive biomar-
ker predicting the effect of ASIs. Investigators have sought to
develop the methods for the quantitative assessment of this
splice isoform from CTCs59 and PBMCs.70 The data from
recent studies suggested that patients harboring AR-V7 in
CTCs have a higher likelihood of primary resistance to ASIs
and might be considered for taxane therapy, implying clinical
use as a reliable biomarker for precision medicine.71–73 The
AR-V7 assays, however, require further refinement before
they are ready for clinical use. Furthermore, ctDNA analyses
assessing AR amplification and/or mutation in univariate
analyses also appear to be prognostic for a poorer response to
ASIs.74,75 Nakagawa et al. reported that there were some
patients who experienced negative conversion of AR-V7 in
CTCs by treatment with taxanes, suggesting a possibility of
re-sensitization from primary resistance to ASIs after taxane
therapy.76 There are some evidence of the interaction between
AR signaling and taxanes, including inhibition of AR nuclear
localization by taxanes,69,77,78 AR induced long-non-coding
RNA79 and drug-efflux genes.80 In addition, it is clear that
epigenetic modifications by disease progression affects AR
signature leading to tumorgenesis,81 development of CRPC82
and drug resistance.83 Genetic alternations, such as PTEN
loss, have been investigated and proved that patients with this
loss seem to be associated with worse outcome.84,85 In addi-
tion, other genetic alternations cause the dysregulation of AR
signaling, which might be exploited to develop a new molec-
ular biomarker for disease prediction. ERG, one of the ery-
throblast transformation-specific transcription factors, often
fuses with the promoter region of the TMPRSS2 gene
(21q21.2-3), called TMPRSS2/ERG fusion, and upregulation
of the ERG expression level by AR binding to the promoter
of TMPRSS2 plays a pivotal role in tumorgenesis with co-
operation of other important somatic mutations.86 Additional
effects of ERG overexpression interacting with microtubule
dynamics leading to taxane resistance was shown,87 and
Table 5 Potential biomarkers predicting the treatment outcome for APC
Target Type of marker
ARv7 CTCs and PBMCs
TMPRSS2-ERG IHC, FISH and ctDNA
PTEN IHC and FISH
BRCA2 IHC, CTCs and FISH
TP53, RB1 CTC and ctDNA
226
detection of TMPRSS2/ERG fusion as a biomarker might
have clinical potential for the prediction of taxane sensitiv-
ity.88,89
Mutations in the DNA repair pathway are now intensely
focused on the field of cancer research. The BRCA2 muta-
tion, for example, is known as a significant predisposition
marker for aggressive prostate cancer,90,91 and defect of
BRCA2 might be a predictive biomarker for the exceptional
response to DNA-damaging chemotherapeutics, such as cis-
platin.92 In addition, a phase 2 study (TOPARP-A) showed
that the oral PARP inhibitor, olaparib, had antitumor activity
in 33% of mCRPC patients who had progressed after ASIs
treatment and chemotherapy, with a strikingly higher
response rate in patients with a deleterious mutation of DNA
repair genes including BRCA1/2, ATM, Fanconi’s anemia
genes and CHEK2 (88%; 14/16 patients) versus patients with-
out those mutations (6%; 2/33 patients).93 Subsequently, a
phase 3 study was recently carried out to evaluate the effi-
cacy and safety of olaparib versus ASIs in mCRPC, which
progressed on the first ASI treatment and has homologous
recombination repair gene mutations (the PROfound trial:
NCT02987543).
Intratumor heterogeneity renders varied adaptation to the
targeted therapy. NEPC has been identified as an aggressive
phenotype of APC,94,95 and epithelial plasticity in response
to initial ADT reflects developing the clonal evolution to
NEPC from primary adenocarcinoma.96 Inactivated mutations
in major tumor suppressors, TP53 and RB1, were shown to
characterize the NEPC or basal-like cell signature, distinct
from canonical AR-dependent luminal-like adenocarcinoma,
and cells with those mutations were less sensitive to ASIs by
decreased AR dependency.96,97 An upregulation of epigenetic
regulator, EZH2, was accompanied with the functional loss
of those tumor suppressors, and its inhibitor was recently
reported to restore the sensitivity to ASIs, suggesting an epi-
genetic approach for the treatment of NEPC.98 Of note, the
mutation of TP53 and RB1 was detectable with whole exome
sequencing of ctDNA in mCRPC patients, suggesting its
application to identify this aggressive subtype.99 Given the
numerous genetic alterations potentially serving as a useful
biomarker for precision medicine, an extensive evaluation of
rigorous biomarkers following REMARK guidelines with all
relevant covariates in the multivariate analysis is required to
truly determine the prognostic and predictive value of these
new biomarkers. Furthermore, the assays themselves and
appropriate cut-points are currently yet to be optimized.
Comments
Detection of AR-V7 in CTCs in CRPC patients associated with resistance to ASIs but not
with taxans59,70–73
ERG positive tumor associated with taxane resistance87–89
Worse prognosis and low response rate to abiraterone in patients with PTEN loss84,85
Defect of BRCA2 as a predictive biomarker for the exceptional response to DNA damage
chemotherapeutic and PARP inhibitors90–93
Mutation of TP53 and RB1 associated with NEPC and higher sensitivity to EZH2 inhibitor94–99
© 2017 The Japanese Urological Association
 Current treatment strategy for CRPC

be managed according to their individual health status, not

Treatment algorithm for APC to individual
according to age, and has developed a simple assessment of
patients
health status screening for patients aged >70 years, called G8
Evaluating health status in elderly PC patients clearly affects screening (Fig. 1a).100 In short, they proposed a G8 scoring
treatment decision-making. The International Society of Geri- model that classifies patients into three categories according
atric Oncology recommended that older men with PC should to their individual health status; fit, vulnerable and frail.

(a)
G8 geriatric assessment instrument to determine baseline characteristics

Items Score for possible responses G8 screening test

Has food intake declined over the past 3 0 = Severe decrease in food intake
months owing to loss of appetite, digestive
A problems, difficulties with chewing or 1 = Moderate decrase in food intake
swallowing difficulties? 2 = No decrease in food intake
0 = Weight loss of more than 3 kg G8 Score of >14 G8 Score of <14
1 = Does not know
B Weight loss during the past 3 months
2 = Weight loss between 1 kg and
3 kg
0 = Bed or chair bound
1 = Able to get out of bed or chair Reversible impairment Irreversible impairment
C Mobility
but does not go out by by
2 = Goes out geriatric intervention geriatric intervention
0 = Severe dementia or depression
D Neuropsychological problems 1 = Mild dementia
2 = No psychological problems
0 ≤ 19.0 kg/m2
1 = 19.0–20.9 kg/m2
E Body–mass index
2 = 21.0–22.9 kg/m2 Fit Vulnerable Frail
2
3 > 23.0 kg/m
Does the patient take more than three 0 = Yes
F
prescribed drugs per day? 1 = No
Standard treatment Adapted treatment
0 = Not as good
By comparison with other people of the
0.5 = Does not know
G sama age, how does the patient consider
1 = As good Assessment of impairment consists of ADL, IADL, malnutrition, neuropsychological problems, CISR-G.
his health status?
2 = Better ADL: activities of daily living, IADL: instrumental activities of daily living,
0 > 85 years CISR-G: cumulative illness score rating-geriatrics.
H Age 1 = 80–85 years Details in recommendation of the SIOG Prostate Cancer Working Group
2 ≤ 80 years (Droz et al, Lancet Oncol 2014;15:e404-14)
Total score 0–17

(b) mHSPC
or
Recurrent high risk PC after the treatment with curative intent

Low tumor burden High tumor burden

ADT ADT + abiraterone ADT + docetaxel

(M0 or M1) (M1) (M1)

ADT response <12 months G8 Fit

No Yes Frail or
Visceral metastasis screening vulnerable
Symptomatic

ASIs Docetaxel Enzalutamide Docetaxel ASIs

PSA decline <30% at 4 weeks

Fit Fit Fit G8 Fit

Frail G8 or Frail G8 or Frail G8 or Frail or
screening screening screening screening vulnerable
vulnerable vulnerable vulnerable

ASIs Docetaxel ASIs Cabazitaxel Enzalutamide Cabazitaxel ASIs Cabazitaxel

G8 Fit
Frail or
screening vulnerable

ASIs Cabazitaxel ASIs Enzalutamide ASIs

* Radium-223 is considered for mCRPC with symptomatic bone

and non-visceral metastases.
ASIs

Fig. 1 (a) Left panel: the G8 screening questionnaire. Right panel: decision tree to determine patient health status. (b) Putative algorithm for the treatment of
APC based on the provided findings.

© 2017 The Japanese Urological Association 227

K KOMURA ET AL.

Patients assigned to “fit” should undergo the standard treat-
ment option as younger patients. “Vulnerable” patients who
have reversible impairment by adequate medical intervention
should also receive standard treatment. “Frail” patients with
non-reversible impairment should be considered for adapted
treatment. An international collaborative study subsequently
showed an advantage of using G8 score to assess tolerability
for the treatment with taxanes, and concluded that treatment
decision-making should be determined by individual health
assessment, not by age.101
Figure 1b shows the putative algorithm for the treatment
of APC based on the provided findings. A result of a system-
atic review, which analyzed 13 retrospective studies of
sequential therapy for patients after progression on docetaxel,
showed that a sequence that includes cabazitaxel seems to
confer an advantage for OS compared with successive use of
ASIs, indicating that the standard option after docetaxel
includes subsequent cabazitaxel for patients assigned to “fit
or vulnerable” health status.102 It should be mentioned that
ASIs might have some effect after progression on cabazitaxel,
and patients whose health status descends to “frail” as a
result of progression of the disease could still benefit from
subsequent treatment with ASIs.103 Radium-223 is considered
an appropriate option for patients with symptomatic bone and
non-visceral metastases. Comparable toxicity when using
radium-223 with other ASIs was reported,104 and a prelimi-
nary report from a phase 1/2a study showed that radium-223
with docetaxel had greater percentage decline in total alkaline
phosphatase and in bone formation markers, bone alkaline
phosphatase and P1NP, than the treatment with only doc-
etaxel.105 Phase 3 clinical trials are ongoing assessing the
efficacy of radium-223 with abiraterone or enzalutamide to
determine whether the combination is required.
In conclusion, accumulative evidence from RCTs showed
that incorporation of docetaxel as a SOC for high metastatic
burden HSPC offers a benefit in OS, and abiraterone will be
considered as another option with the results of recent
phase 3 studies. Ultimately, access to the agents will be the
major determining factor. In addition, available retrospective
studies potentially revealed predictive value including dura-
tion of ADT response and the extent of PSA decline by ASIs,
to assist in treatment decision-making and deciding which
agent to use next. A number of RCTs are currently ongoing
(Table 6) to further answer several clinical questions for
sequential and combination therapy. Of them, ENZAMET
(enzalutamide with ADT in mHSPC), NCT01650194

Table 6 Active clinical trials to determine optimal sequence or combination using new drugs for APC

Clinical trial Study

identification Trial name start Phase Patients Intervention Primary outcome

NCT01650194 2012 II mCRPC Enzalutamide + abiratetone + prednisone vs PSA response and safety
enzalutamide or abiraterone or prednisone
NCT01995513 PLATO 2013 IV Chemo-na€ıve Enzalutamide + abiratetone + prednisone vs PFS
mCRPC placebo + abiratetone + prednisone
NCT01957436 PEACE-1 2013 III mHSPC ADT  docetaxel vs ADT + abiraterone  OS and PFS
docetaxel vs radiation + ADT  docetaxel +
radiation vs radiation + ADT + abiraterone
NCT01949337 ALLIANCE 2013 III mCRPC Enzalutamide vs enzalutamide + abiratetone + OS
prednisone
NCT02125357 2014 II mCRPC Abiraterone followed by enzalutamide vs PSA response rate to 2nd ASI
enzalutamide followed by abiraterone
NCT02200614 ARAMIS 2014 III High-risk non-metastatic ODM-201 vs placebo Metastatic free survival
CRPC
NCT02429193 BARRIER-P 2015 II mCRPC Enzalutamide + abiratetone + prednisone vs Change in AR abnormalities
enzalutamide or abiraterone or prednisone (ARv7 or AR mutation)
NCT02485691 CARD 2015 III mCRPC after progression Cabazitaxel + prednisone vs abiraterone or rPFS
on docetaxel and first enzalutamide + prednisone
ASI
NCT02489318 TITAN 2015 III mHSPC ARN-509 + ADT  docetaxel vs placebo OS and rPFS
+ ADT  docetaxel
NCT02446405 ENZAMET 2015 III mHSPC Enzalutamide + LHRHA or surgical castration vs OS
non-steroidal anti-androgen vs LHRHA or
surgical castration
NCT02799602 ARASENS 2016 III mHSPC ODM-201 + ADT + docetaxel vs OS
placebo + ADT + docetaxel
NCT02677896 ARCHES 2016 III mHSPC Enzaltamide + ADT vs placebo + ADT rPFS
NCT02987543 PROfound 2016 III mCRPC with homologous Olaparib vs enzalutamide or abiraterone rPFS
recombination repair
deficiency
NCT02446444 ENZARAD 2017 III High-risk localized PC Enzaltamide + LHRHA + radiation vs non- OS
steroidal anti-androgen + LHRHA + radiation

228 © 2017 The Japanese Urological Association


(combination of ASIs in mCRPC) and NCT02125357 (cross-
over with ASIs in mCRPC) have recently completed accrual,
and will provide new evidence for the treatment of APC.
Nevertheless, much work including biomarkers development
is required to clarify that best treatment strategy for individ-
ual patients.
Conflict of interest
PWK is a scientific advisory or data safety monitoring board
member for Astellas, Bayer, Bellicum, BIND Biosciences,
BN ImmunoTherapeutics, DRGT, Genetech/Roche, Ipsen
Pharmaceuticals, Janssen, Metamark (no longer in business),
Merck, MTG Therapeutics, New England Research Institutes,
Omnitura, OncoCellMDX, OncoGenex, Progeniry, Sanofi,
Tarveda Therapeutics and Thermo Fisher, and has investment
interest with Bellicum, DRGT and Tarveda Therapeutics. CJS
has received consulting fees from Astellas, Bayer, Genetech,
Janssen, Pfizer and Sanofi, and has received research funding
from Astellas, Janssen, Sotio and Sanofi.
References
1 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J. Clin.
2017; 67: 7–30.
2 Petrylak DP, Tangen CM, Hussain MH et al. Docetaxel and estramustine
compared with mitoxantrone and prednisone for advanced refractory pros-
tate cancer. N. Engl. J. Med. 2004; 351: 1513–20.
3 Tannock IF, de Wit R, Berry WR et al. Docetaxel plus prednisone or
mitoxantrone plus prednisone for advanced prostate cancer. N. Engl. J.
Med. 2004; 351: 1502–12.
4 de Bono JS, Oudard S, Ozguroglu M et al. Prednisone plus cabazitaxel or
mitoxantrone for metastatic castration-resistant prostate cancer progressing
after docetaxel treatment: a randomised open-label trial. Lancet 2010; 376:
1147–54.
5 de Bono JS, Logothetis CJ, Molina A et al. Abiraterone and increased sur-
vival in metastatic prostate cancer. N. Engl. J. Med. 2011; 364: 1995–2005.
6 Scher HI, Fizazi K, Saad F et al. Increased survival with enzalutamide
in prostate cancer after chemotherapy. N. Engl. J. Med. 2012; 367:
1187–97.
7 Kantoff PW, Higano CS, Shore ND et al. Sipuleucel-T immunotherapy for
castration-resistant prostate cancer. N. Engl. J. Med. 2010; 363: 411–22.
8 Parker C, Nilsson S, Heinrich D et al. Alpha emitter radium-223 and sur-
vival in metastatic prostate cancer. N. Engl. J. Med. 2013; 369: 213–23.
9 Sartor AO, Stephane O, Lisa S et al. Cabazitaxel vs docetaxel in chemother-
apy-naive (CN) patients with metastatic castration-resistant prostate cancer
(mCRPC): a three-arm phase III study (FIRSTANA). J. Clin. Oncol. 2016;
34: 5006.
10 Attard G, Belldegrun AS, de Bono JS. Selective blockade of androgenic
steroid synthesis by novel lyase inhibitors as a therapeutic strategy for treat-
ing metastatic prostate cancer. BJU Int. 2005; 96: 1241–6.
11 Barrie SE, Haynes BP, Potter GA et al. Biochemistry and pharmacokinetics
of potent non-steroidal cytochrome P450(17alpha) inhibitors. J. Steroid Bio-
chem. Mol. Biol. 1997; 60: 347–51.
12 Potter GA, Barrie SE, Jarman M, Rowlands MG. Novel steroidal inhibitors
of human cytochrome P45017 alpha (17 alpha-hydroxylase-C17,20-lyase):
potential agents for the treatment of prostatic cancer. J. Med. Chem. 1995;
38: 2463–71.
13 Ryan CJ, Smith MR, de Bono JS et al. Abiraterone in metastatic prostate
cancer without previous chemotherapy. N. Engl. J. Med. 2013; 368: 138–
48.
14 Ryan CJ, Smith MR, Fizazi K et al. Abiraterone acetate plus prednisone
versus placebo plus prednisone in chemotherapy-naive men with metastatic
castration-resistant prostate cancer (COU-AA-302): final overall survival
analysis of a randomised, double-blind, placebo-controlled phase 3 study.
Lancet Oncol. 2015; 16: 152–60.
© 2017 The Japanese Urological Association
Current treatment strategy for CRPC
15 Chen Y, Clegg NJ, Scher HI. Anti-androgens and androgen-depleting thera-
pies in prostate cancer: new agents for an established target. Lancet Oncol.
2009; 10: 981–91.
16 Guerrero J, Alfaro IE, Gomez F, Protter AA, Bernales S. Enzalutamide, an
androgen receptor signaling inhibitor, induces tumor regression in a mouse
model of castration-resistant prostate cancer. Prostate 2013; 73: 1291–305.
17 Dalal K, Roshan-Moniri M, Sharma A et al. Selectively targeting the DNA-
binding domain of the androgen receptor as a prospective therapy for pros-
tate cancer. J. Biol. Chem. 2014; 292: 4359.
18 Hoffman-Censits J, Kelly WK. Enzalutamide: a novel antiandrogen for
patients with castrate-resistant prostate cancer. Clin. Cancer Res. 2013; 19:
1335–9.
19 Beer TM, Armstrong AJ, Rathkopf DE et al. Enzalutamide in metastatic
prostate cancer before chemotherapy. N. Engl. J. Med. 2014; 371: 424–
33.
20 Gravis G, Fizazi K, Joly F et al. Androgen-deprivation therapy alone or
with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15):
a randomised, open-label, phase 3 trial. Lancet Oncol. 2013; 14: 149–58.
21 Gravis G, Boher JM, Joly F et al. Androgen deprivation therapy (ADT) plus
docetaxel versus ADT alone in metastatic non castrate prostate cancer:
impact of metastatic burden and long-term survival analysis of the random-
ized phase 3 GETUG-AFU15 trial. Eur. Urol. 2016; 70: 256–62.
22 Sweeney CJ, Chen YH, Carducci M et al. Chemohormonal therapy in meta-
static hormone-sensitive prostate cancer. N. Engl. J. Med. 2015; 373: 737–
46.
23 James ND, Sydes MR, Clarke NW et al. Addition of docetaxel, zoledronic
acid, or both to first-line long-term hormone therapy in prostate cancer
(STAMPEDE): survival results from an adaptive, multiarm, multistage, plat-
form randomised controlled trial. Lancet 2016; 387: 1163–77.
24 Sweeney C, Chen YH, Liu G et al. Long term efficacy and QOL data of
chemohormonal therapy (C-HT) in low and high volume hormone na€ıve
metastatic prostate cancer (PrCa): E3805 CHAARTED trial. Ann. Oncol.
2016; 27: 720PD-PD.
25 Fizazi K, Tran N, Fein L et al. Abiraterone plus prednisone in metastatic,
castration-sensitive prostate cancer. N. Engl. J. Med. 2017; 377: 352–60.
26 James ND, de Bono JS, Spears MR et al. Abiraterone for prostate cancer
not previously treated with hormone therapy. N. Engl. J. Med. 2017; 377:
338–51.
27 Rydzewska LHM, Burdett S, Vale CL et al. Adding abiraterone to androgen
deprivation therapy in men with metastatic hormone-sensitive prostate can-
cer: a systematic review and meta-analysis. Eur. J. Cancer 2017; 84: 88–
101.
28 Loriot Y, Bianchini D, Ileana E et al. Antitumour activity of abiraterone
acetate against metastatic castration-resistant prostate cancer progressing
after docetaxel and enzalutamide (MDV3100). Ann. Oncol. 2013; 24: 1807–
12.
29 Maughan BL, Luber B, Nadal R, Antonarakis ES. Comparing sequencing of
abiraterone and enzalutamide in men with metastatic castration-resistant
prostate cancer: a retrospective study. Prostate 2017; 77: 33–40.
30 Noonan KL, North S, Bitting RL, Armstrong AJ, Ellard SL, Chi KN. Clini-
cal activity of abiraterone acetate in patients with metastatic castration-resis-
tant prostate cancer progressing after enzalutamide. Ann. Oncol. 2013; 24:
1802–7.
31 Terada N, Maughan BL, Akamatsu S et al. Exploring the optimal sequence
of abiraterone and enzalutamide in patients with chemotherapy-naive castra-
tion-resistant prostate cancer: the Kyoto-Baltimore collaboration. Int. J.
Urol. 2017; 24: 441–8.
32 Mori K, Kimura T, Onuma H et al. Lactate dehydrogenase predicts com-
bined progression-free survival after sequential therapy with abiraterone and
enzalutamide for patients with castration-resistant prostate cancer. Prostate
2017; 77: 1144–50.
33 Azad AA, Eigl BJ, Murray RN, Kollmannsberger C, Chi KN. Efficacy
of enzalutamide following abiraterone acetate in chemotherapy-naive
metastatic castration-resistant prostate cancer patients. Eur. Urol. 2015a;
67: 23–9.
34 Badrising S, van der Noort V, van Oort IM et al. Clinical activity and toler-
ability of enzalutamide (MDV3100) in patients with metastatic, castration-
resistant prostate cancer who progress after docetaxel and abiraterone treat-
ment. Cancer 2014; 120: 968–75.
35 Brasso K, Thomsen FB, Schrader AJ et al. Enzalutamide antitumour activity
against metastatic castration-resistant prostate cancer previously treated with
229
K KOMURA ET AL.
docetaxel and abiraterone: a multicentre analysis. Eur. Urol. 2015; 68: 317–
24.
36 David T, Natalie C, Omi P. Enzalutamide after failure of docetaxel and abi-
raterone in metastatic castrate resistant prostate cancer (mCRPC): results
from an expanded access program. J. Clin. Oncol. 2014; 32: 188.
37 Schrader AJ, Boegemann M, Ohlmann CH et al. Enzalutamide in castra-
tion-resistant prostate cancer patients progressing after docetaxel and abi-
raterone. Eur. Urol. 2014; 65: 30–6.
38 Thomsen FB, Roder MA, Rathenborg P, Brasso K, Borre M, Iversen P.
Enzalutamide treatment in patients with metastatic castration-resistant pros-
tate cancer progressing after chemotherapy and abiraterone acetate. Scand.
J. Urol. 2014; 48: 268–75.
39 De Bono JS, Chowdhury S, Feyerabend S et al. Efficacy and safety of enza-
lutamide (ENZA) in patients with metastatic castration-resistant prostate can-
cer (mCRPC) previously treated with abiraterone acetate (Abi): a
multicenter, single-arm, open-label study. J. Clin. Oncol. 2017a; 35: 165.
40 Sonpavde G, Wang CG, Galsky MD, Oh WK, Armstrong AJ. Cytotoxic
chemotherapy in the contemporary management of metastatic castration-
resistant prostate cancer (mCRPC). BJU Int. 2015; 116: 17–29.
41 Chi K, Hotte SJ, Joshua AM et al. Treatment of mCRPC in the AR-axis-tar-
geted therapy-resistant state. Ann. Oncol. 2015; 26: 2044–56.
42 Fitzpatrick JM, Bellmunt J, Fizazi K et al. Optimal management of meta-
static castration-resistant prostate cancer: highlights from a European Expert
Consensus Panel. Eur. J. Cancer 2014; 50: 1617–27.
43 Yohann L, Christophe M, Laurence A et al. Personalizing treatment in
patients with castrate-resistant prostate cancer: a study of predictive factors
for secondary endocrine therapies activity. J. Clin. Oncol. 2012; 30: 213.
44 Loriot Y, Eymard JC, Patrikidou A et al. Prior long response to androgen
deprivation predicts response to next-generation androgen receptor axis tar-
geted drugs in castration resistant prostate cancer. Eur. J. Cancer 2015; 51:
1946–52.
45 Antoine A, Denis M, Aude F et al. Duration of response to androgen-depri-
vation therapy (ADT) and efficacy of secondary hormone therapy, docetaxel
(D), and cabazitaxel (C) in metastatic castration-resistant prostate cancer
(mCRPC). J. Clin. Oncol. 2014; 32: 282.
46 Bellmunt J, Kheoh T, Yu MK et al. Prior endocrine therapy impact on abi-
raterone acetate clinical efficacy in metastatic castration-resistant prostate
cancer: post-hoc analysis of randomised phase 3 studies. Eur. Urol. 2016;
69: 924–32.
47 Facchini G, Caffo O, Ortega C et al. Very early PSA response to abi-
raterone in mCRPC patients: a novel prognostic factor predicting overall
survival. Front. Pharmacol. 2016; 7: 123.
48 Fuerea A, Baciarello G, Patrikidou A et al. Early PSA response is an inde-
pendent prognostic factor in patients with metastatic castration-resistant
prostate cancer treated with next-generation androgen pathway inhibitors.
Eur. J. Cancer 2016; 61: 44–51.
49 Kato H, Furuya Y, Miyazawa Y et al. Consequences of an early PSA
response to enzalutamide treatment for Japanese patients with metastatic cas-
tration-resistant prostate cancer. Anticancer Res. 2016; 36: 6141–9.
50 Rescigno P, Lorente D, Bianchini D et al. Prostate-specific antigen decline
after 4 weeks of treatment with abiraterone acetate and overall survival in
patients with metastatic castration-resistant prostate cancer. Eur. Urol. 2016;
70: 724–31.
51 Gillessen S, Attard G, Beer TM et al. Management of patients with
advanced prostate cancer: the report of the advanced prostate cancer consen-
sus conference APCCC 2017. Eur. Urol. 2017; 17: 30497–9.
52 Wulaningsih W, Holmberg L, Garmo H et al. Serum lactate dehydrogenase
and survival following cancer diagnosis. Br. J. Cancer 2015; 113: 1389–96.
53 Gravis G, Boher JM, Fizazi K et al. Prognostic factors for survival in non-
castrate metastatic prostate cancer: validation of the glass model and devel-
opment of a novel simplified prognostic model. Eur. Urol. 2015; 68: 196–
204.
54 Leibowitz-Amit R, Templeton AJ, Omlin A et al. Clinical variables associ-
ated with PSA response to abiraterone acetate in patients with metastatic
castration-resistant prostate cancer. Ann. Oncol. 2014; 25: 657–62.
55 van Soest RJ, Templeton AJ, Vera-Badillo FE et al. Neutrophil-to-lympho-
cyte ratio as a prognostic biomarker for men with metastatic castration-resis-
tant prostate cancer receiving first-line chemotherapy: data from two
randomized phase III trials. Ann. Oncol. 2015a; 26: 743–9.
56 Lorente D, Mateo J, Templeton AJ et al. Baseline neutrophil-lymphocyte
ratio (NLR) is associated with survival and response to treatment with
230
second-line chemotherapy for advanced prostate cancer independent of base-
line steroid use. Ann. Oncol. 2015; 26: 750–5.
57 Chang KH, Li R, Kuri B et al. A gain-of-function mutation in DHT synthe-
sis in castration-resistant prostate cancer. Cell 2013; 154: 1074–84.
58 Arora VK, Schenkein E, Murali R et al. Glucocorticoid receptor confers
resistance to antiandrogens by bypassing androgen receptor blockade. Cell
2013; 155: 1309–22.
59 Antonarakis ES, Lu C, Wang H et al. AR-V7 and resistance to enzalu-
tamide and abiraterone in prostate cancer. N. Engl. J. Med. 2014; 371:
1028–38.
60 Schweizer MT, Zhou XC, Wang H et al. The influence of prior abiraterone
treatment on the clinical activity of docetaxel in men with metastatic castra-
tion-resistant prostate cancer. Eur. Urol. 2014; 66: 646–52.
61 de Bono JS, Smith MR, Saad F et al. Subsequent chemotherapy and treat-
ment patterns after abiraterone acetate in patients with metastatic castration-
resistant prostate cancer: post hoc analysis of COU-AA-302. Eur. Urol.
2017b; 71: 656–64.
62 Ueda Y, Matsubara N, Takizawa I et al. A multicenter retrospective analysis
of sequential treatment of abiraterone acetate followed by docetaxel in Japa-
nese patients with metastatic castration-resistant prostate cancer. Jpn. J. Clin.
Oncol. 2015; 45: 774–9.
63 van Soest RJ, Nieuweboer AJM, de Morree ES et al. The influence of prior
novel androgen receptor targeted therapy on the efficacy of cabazitaxel in
men with metastatic castration-resistant prostate cancer. Eur. J. Cancer
2015b; 51: 2562–9.
64 Sella A, Sella T, Peer A et al. Activity of cabazitaxel after docetaxel and
abiraterone acetate therapy in patients with castration-resistant prostate can-
cer. Clin. Genitourin. Cancer 2014; 12: 428–32.
65 Pezaro CJ, Omlin AG, Altavilla A et al. Activity of cabazitaxel in castra-
tion-resistant prostate cancer progressing after docetaxel and next-generation
endocrine agents. Eur. Urol. 2014; 66: 459–65.
66 Al Nakouzi N, Le Moulec S, Albiges L et al. Cabazitaxel remains active in
patients progressing after docetaxel followed by novel androgen receptor
pathway targeted therapies. Eur. Urol. 2015; 68: 228–35.
67 van Soest RJ, de Morree ES, Kweldam CF et al. Targeting the androgen
receptor confers in vivo cross-resistance between enzalutamide and doc-
etaxel, but not cabazitaxel, in castration-resistant prostate cancer. Eur. Urol.
2015c; 67: 981–5.
68 De Bono JS, Hardy-Bessard A-C, Kim C-S et al. Phase III non-inferiority
study of cabazitaxel (C) 20 mg/m2 (C20) versus 25 mg/m2 (C25) in patients
(pts) with metastatic castration-resistant prostate cancer (mCRPC) previously
treated with docetaxel (D). J. Clin. Oncol. 2016; 34: 5008.
69 Antonarakis ES, Tagawa ST, Galletti G et al. Randomized, noncompara-
tive, phase II trial of early switch from docetaxel to cabazitaxel or vice
versa, with integrated biomarker analysis, in men with chemotherapy-
naive, metastatic, castration-resistant prostate cancer. J. Clin. Oncol.
2017; 35: 3181–8.
70 Qu F, Xie W, Nakabayashi M et al. Association of AR-V7 and prostate-
specific antigen RNA levels in blood with efficacy of abiraterone acetate
and enzalutamide treatment in men with prostate cancer. Clin. Cancer Res.
2017; 23: 726–34.
71 Antonarakis ES, Lu C, Luber B et al. Androgen receptor splice variant 7
and efficacy of taxane chemotherapy in patients with metastatic castration-
resistant prostate cancer. JAMA Oncol. 2015; 1: 582–91.
72 Scher HI, Lu D, Schreiber NA et al. Association of ar-v7 on circulating
tumor cells as a treatment-specific biomarker with outcomes and survival in
castration-resistant prostate cancer. JAMA Oncol. 2016; 2: 1441–9.
73 Onstenk W, Sieuwerts AM, Kraan J et al. Efficacy of cabazitaxel in castra-
tion-resistant prostate cancer is independent of the presence of AR-V7 in
circulating tumor cells. Eur. Urol. 2015; 68: 939–45.
74 Azad AA, Volik SV, Wyatt AW et al. Androgen receptor gene aberra-
tions in circulating cell-free DNA: biomarkers of therapeutic resistance in
castration-resistant prostate cancer. Clin. Cancer Res. 2015b; 21: 2315–
24.
75 Romanel A, Gasi Tandefelt D, Conteduca V et al. Plasma AR and abi-
raterone-resistant prostate cancer. Sci. Transl. Med. 2015; 7: 312re10.
76 Nakazawa M, Lu C, Chen Y et al. Serial blood-based analysis of AR-V7 in
men with advanced prostate cancer. Ann. Oncol. 2015; 26: 1859–65.
77 Zhu ML, Horbinski CM, Garzotto M, Qian DZ, Beer TM, Kyprianou N.
Tubulin-targeting chemotherapy impairs androgen receptor activity in pros-
tate cancer. Cancer Res. 2010; 70: 7992–8002.
© 2017 The Japanese Urological Association

78 Martin SK, Pu H, Penticuff JC, Cao Z, Horbinski C, Kyprianou N. Multinu-
cleation and mesenchymal-to-epithelial transition alleviate resistance to com-
bined cabazitaxel and antiandrogen therapy in advanced prostate cancer.
Cancer Res. 2016; 76: 912–26.
79 Misawa A, Takayama K, Urano T, Inoue S. Androgen-induced long non-
coding RNA (lncRNA) SOCS2-AS1 promotes cell growth and inhibits
apoptosis in prostate cancer cells. J. Biol. Chem. 2016; 291: 17861–80.
80 Zhu Y, Liu C, Armstrong C, Lou W, Sandher A, Gao AC. Antiandrogens
inhibit ABCB1 efflux and ATpase activity and reverse docetaxel resistance
in advanced prostate cancer. Clin. Cancer Res. 2015; 21: 4133–42.
81 Pomerantz MM, Li F, Takeda DY et al. The androgen receptor cistrome is
extensively reprogrammed in human prostate tumorigenesis. Nat. Genet.
2015; 47: 1346–51.
82 Wang Q, Li W, Zhang Y et al. Androgen receptor regulates a distinct transcrip-
tion program in androgen-independent prostate cancer. Cell 2009; 138: 245–56.
83 Komura K, Jeong SH, Hinohara K et al. Resistance to docetaxel in prostate
cancer is associated with androgen receptor activation and loss of KDM5D
expression. Proc. Natl Acad. Sci. USA 2016; 113: 6259–64.
84 Punnoose EA, Ferraldeschi R, Szafer-Glusman E et al. PTEN loss in circulat-
ing tumour cells correlates with PTEN loss in fresh tumour tissue from castra-
tion-resistant prostate cancer patients. Br. J. Cancer 2015; 113: 1225–33.
85 Ferraldeschi R, Nava Rodrigues D, Riisnaes R et al. PTEN protein loss and
clinical outcome from castration-resistant prostate cancer treated with abi-
raterone acetate. Eur. Urol. 2015; 67: 795–802.
86 Tomlins SA, Rhodes DR, Perner S et al. Recurrent fusion of TMPRSS2 and
ETS transcription factor genes in prostate cancer. Science 2005; 310: 644–8.
87 Galletti G, Matov A, Beltran H et al. ERG induces taxane resistance in cas-
tration-resistant prostate cancer. Nat. Commun. 2014; 5: 5548.
88 Rajpar S, Carmel A, Merabet Z et al. The benefit of combining docetaxel to
androgen deprivation therapy in localized and metastatic castration-sensitive
prostate cancer as predicted by ERG status: An analysis of two GETUG
phase III trials. J. Clin. Oncol. 2017; 35: 5012.
89 Reig O, Marin-Aguilera M, Carrera G et al. TMPRSS2-ERG in blood and
docetaxel resistance in metastatic castration-resistant prostate cancer. Eur.
Urol. 2016; 70: 709–13.
90 Tryggvadottir L, Vidarsdottir L, Thorgeirsson T et al. Prostate cancer pro-
gression and survival in BRCA2 mutation carriers. J. Natl Cancer Inst.
2007; 99: 929–35.
91 Narod SA, Neuhausen S, Vichodez G et al. Rapid progression of prostate
cancer in men with a BRCA2 mutation. Br. J. Cancer 2008; 99: 371–4.
92 Cheng HH, Pritchard CC, Boyd T, Nelson PS, Montgomery B. Biallelic
inactivation of BRCA2 in platinum-sensitive metastatic castration-resistant
prostate cancer. Eur. Urol. 2016; 69: 992–5.
© 2017 The Japanese Urological Association
Current treatment strategy for CRPC
93 Mateo J, Carreira S, Sandhu S et al. DNA-repair defects and olaparib in
metastatic prostate cancer. N. Engl. J. Med. 2015; 373: 1697–708.
94 Beltran H, Rickman DS, Park K et al. Molecular characterization of neu-
roendocrine prostate cancer and identification of new drug targets. Cancer
Discov. 2011; 1: 487–95.
95 Epstein JI, Amin MB, Beltran H et al. Proposed morphologic classification
of prostate cancer with neuroendocrine differentiation. Am. J. Surg. Pathol.
2014; 38: 756–67.
96 Beltran H, Prandi D, Mosquera JM et al. Divergent clonal evolution of cas-
tration-resistant neuroendocrine prostate cancer. Nat. Med. 2016; 22: 298–
305.
97 Mu P, Zhang Z, Benelli M et al. SOX2 promotes lineage plasticity and
antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science
2017; 355: 84–8.
98 Ku SY, Rosario S, Wang Y et al. Rb1 and Trp53 cooperate to suppress
prostate cancer lineage plasticity, metastasis, and antiandrogen resistance.
Science 2017; 355: 78–83.
99 Beltran H, Romanel A, Casiraghi N et al. Whole exome sequencing (WES)
of circulating tumor DNA (ctDNA) in patients with neuroendocrine prostate
cancer (NEPC) informs tumor heterogeneity. J. Clin. Oncol. 2017; 35:
5011.
100 Droz J-P, Aapro M, Balducci L et al. Management of prostate cancer in
older patients: updated recommendations of a working group of the Inter-
national Society of Geriatric Oncology. Lancet Oncol. 2014; 15: e404–
14.
101 Droz J-P, Efstathiou E, Yildirim A et al. First-line treatment in senior
adults with metastatic castration-resistant prostate cancer: a prospective
international registry. Urol. Oncol. Sem. Original Invest. 2016; 34:
234.e21–e29.
102 Maines F, Caffo O, Veccia A et al. Sequencing new agents after docetaxel
in patients with metastatic castration-resistant prostate cancer. Crit. Rev.
Oncol. Hematol. 2015; 96: 498–506.
103 Caffo O, De Giorgi U, Fratino L et al. Clinical outcomes of castration-resis-
tant prostate cancer treatments administered as third or fourth line following
failure of docetaxel and other second-line treatment: results of an Italian
multicentre study. Eur. Urol. 2015; 68: 147–53.
104 Dan TD, Eldredge-Hindy HB, Hoffman-Censits J et al. Hematologic toxicity
of concurrent administration of radium-223 and next-generation antiandro-
gen therapies. Am. J. Clin. Oncol. 2017; 40: 342–7.
105 Michael JM, Yohann L, Karim F et al. Effects of radium-223 (Ra-223) with
docetaxel versus docetaxel alone on bone biomarkers in patients with bone-
metastatic castration-resistant prostate cancer (CRPC): a phase I/IIa clinical
trial. J. Clin. Oncol. 2017; 35: 154.
231