EUROPEAN UROLOGY 66 (2014) 459–465

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Platinum Priority – Prostate Cancer

Editorial by Robert J. Jones on pp. 466–467 of this issue

Activity of Cabazitaxel in Castration-resistant Prostate Cancer

Progressing After Docetaxel and Next-generation Endocrine
Agents

Carmel J. Pezaro, Aurelius G. Omlin, Amelia Altavilla, David Lorente, Roberta Ferraldeschi,
Diletta Bianchini, David Dearnaley, Christopher Parker, Johann S. de Bono, Gerhardt Attard *
Prostate Cancer Targeted Therapy Group and Academic Urology Unit, Royal Marsden NHS Foundation Trust and Institute of Cancer Research, Sutton, Surrey, UK

Article info Abstract

Article history: Background: Cabazitaxel, abiraterone, and enzalutamide are survival-prolonging treat-
Accepted November 29, 2013 ments in men with castration-resistant prostate cancer (CRPC) progressing following
Published online ahead of docetaxel chemotherapy. The sequential activity of these agents has not been studied
and treatment sequencing remains a key dilemma for clinicians.
print on December 16, 2013 Objective: To describe the antitumour activity of cabazitaxel after docetaxel and next-
generation endocrine agents.
Keywords: Design, setting, and participants: We report on a cohort of 59 men with progressing
CRPC treated with cabazitaxel, 37 of whom had received prior abiraterone and 9 of
Castration-resistant prostate
whom had received prior enzalutamide.
cancer Outcome measurements and statistical analysis: Changes in prostate-specific antigen
Cabazitaxel (PSA) level were used to determine activity on abiraterone, enzalutamide, and caba-
Abiraterone zitaxel treatment. Radiologic tumour regressions according to Response Evaluation Crite-
Enzalutamide ria in Solid Tumors (RECIST) and symptomatic benefit were evaluated for cabazitaxel
therapy.
Treatment sequencing Results and limitations: The post–endocrine-therapy patients received abiraterone
(n = 32), sequential abiraterone and enzalutamide (n = 5) or enzalutamide (n = 4). These
patients received a median of 7 mo of abiraterone and 11 mo of enzalutamide. A median
of six cabazitaxel cycles (range: 1–10 cycles) were delivered, with 50% PSA declines in
16 of 41 (39%) patients, soft tissue radiologic responses in 3 of 22 (14%) evaluable
patients, and symptomatic benefit in 9 of 37 evaluable patients (24%). Median overall
survival and progression-free survival were 15.8 and 4.6 mo, respectively. Antitumor
activity on cabazitaxel was less favourable in the abiraterone- and enzalutamide-naı̈ve
cohort (n = 18), likely reflecting biologic differences in this cohort. These data were
obtained from a retrospective analysis.
Conclusions: This is the first report of cabazitaxel activity in CRPC progressing after
treatment with docetaxel and abiraterone or enzalutamide. We demonstrate significant
cabazitaxel activity in this setting.
Patient summary: We looked at the antitumour activity of the chemotherapy drug
cabazitaxel in men previously treated with docetaxel chemotherapy and the hormonal
drugs abiraterone and enzalutamide. Cabazitaxel appeared active when given after
abiraterone and enzalutamide. We can reassure men that cabazitaxel can be used after
these novel endocrine treatments.
# 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.

* Corresponding author. Prostate Cancer Targeted Therapy Group, Royal Marsden NHS Foundation
Trust, Section of Medicine, Institute of Cancer Research, Downs Road, Sutton, Surrey SM2 5PT, UK.
Tel. +44 2087224029.
E-mail address: gerhardt.attard@icr.ac.uk (G. Attard).

0302-2838/$ – see back matter # 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.eururo.2013.11.044
460 EUROPEAN UROLOGY 66 (2014) 459–465
1. Introduction
Cabazitaxel is one of six survival-prolonging therapies now
available for men with metastatic castration-resistant
prostate cancer (CRPC) [1–6]. The randomised phase 3
TROPIC trial, performed in the postdocetaxel setting but in
abiraterone- and enzalutamide-naı̈ve patients, demonstrat-
ed that cabazitaxel therapy was associated with a median
2.8-mo improvement in survival compared to mitoxan-
trone, along with more declines in prostate-specific antigen
(PSA), more soft tissue responses, and a longer progression-
free survival (PFS).
Although cabazitaxel belongs to the same family of
taxane chemotherapies as docetaxel, the TROPIC trial
demonstrated that cabazitaxel was active after docetaxel
failure, even in patients who progressed 3 mo after
completing docetaxel. A number of retrospective reports
published to date suggest significant cross-resistance
between abiraterone and enzalutamide [7–10]. Preclinical
and translational data have suggested that taxanes may, in
part, act by interrupting tubulin-dependent androgen
receptor (AR) translocation to the nucleus [11]. We have
previously reported lower than expected activity with
docetaxel when used after abiraterone, suggesting the
possibility of cross-resistance between these agents [12],
although the underlying mechanisms remain unclear.
Therefore, we hypothesised that cross-resistance might
reduce the activity of cabazitaxel when administered after
potent AR inhibition with abiraterone or enzalutamide.
The activity of cabazitaxel after abiraterone or enzaluta-
mide has not been formally reported. In light of the multiple
treatment options now available and with increased funding
limitations, data on the activity of sequential treatments
are important. Prospective data from subset analyses of
patients exposed to abiraterone in the postdocetaxel, phase 3
PROSELICA trial (ClinicalTrials.gov identifier NCT01308580)
will not be available soon. Therefore, we now report
preliminary data on the antitumour activity of cabazitaxel
after docetaxel and abiraterone or enzalutamide.
2. Patients and methods
We identified patients from our database of trial partici-
pants who were treated with cabazitaxel chemotherapy at
the Royal Marsden National Health Service Foundation
Trust (RM) in Sutton, Surrey, United Kingdom. Patients were
included if they received at least one dose of cabazitaxel.
Patients were assigned to the postabiraterone cohort if they
received a minimum of 4 wk of abiraterone, with or without
enzalutamide exposure, and to the postenzalutamide
cohort if they received a minimum of 4 wk of enzalutamide.
All patients signed informed consent to data collection in
institutional review board–approved protocols. Patients
received cabazitaxel in the setting of clinical trials (n = 43)
and expanded access programmes (n = 16).
Baseline characteristics, including exposure and response
to prior therapies, were collected using the electronic
hospital record. PSA responses were assessed after 12 wk
of therapy using Prostate Cancer Working Group (PCWG)
2 criteria [13] and, while on cabazitaxel, using the criteria
applied in the phase 3 TROPIC study, namely 50% PSA
decline in patients with a baseline value 20 mg/l [3]. PFS
was defined as the interval between first dose of cabazitaxel
and the first date of progression as measured by PSA
progression, tumour progression, clinical progression, or
death.
All clinical trial patients underwent imaging by computed
tomography (CT) and bone scan at baseline and every 6 to 12
wk, as required by protocol. Patients treated outside of trials
had CT and bone scan imaging at baseline and every 3–6 mo
per local practice guidelines. Radiographic responses were
assessed using Response Evaluation Criteria in Solid Tumors
(RECIST) 1.1 in patients with measurable soft tissue disease
[14]. Symptomatic benefit was assessed by improvement in
pain in the absence of increased analgesia use. Predicted
patient survivals were calculated using the Armstrong
nomogram for men undergoing chemotherapy for CRPC
[15]. Date of CRPC was determined using PCWG criteria.
All patients maintained a castrate level of testosterone
throughout the period of cabazitaxel treatment, by means of
orchiectomy or luteinising hormone-releasing hormone
analogue therapy. Patients still alive or lost to follow-up
were censored as of 1 August 2013. Descriptive statistics
and Kaplan-Meier survival analyses were performed using
GraphPad Prism v. 5.0a and IBM SPSS Statistics v. 20 (IBM
Corp, Armonk, NY, USA).
3. Results
3.1. Patient characteristics
Of the 476 patients in the RM CRPC trial database, a total of 59
received cabazitaxel between January 2008 and August 2013.
The baseline features of the abiraterone and enzalutamide-
naı̈ve cohort and the postabiraterone or postenzalutamide
cabazitaxel cohorts are described in Table 1. The median age
at first cabazitaxel dose was 68.9 yr. All patients were treated
with first-line docetaxel, with a median of 8 cycles (range:
3–12 cycles) administered. Additionally, 32 men received
abiraterone, 5 received abiraterone and enzalutamide, and 4
received enzalutamide, making a total of 41 men treated with
either abiraterone or enzalutamide prior to cabazitaxel (see
Supplemental Figure for study flow chart). The majority of
patients (n = 44) were progressing, according to PSA level, at
commencement of cabazitaxel, although progression by
clinical symptoms (28 patients) and measurable soft tissue
disease (28 patients) were also frequent (Table 1). Patients
received a median of six cycles of cabazitaxel (range: 1–10
cycles). The median follow-up was 16.4 mo and 25 patients
were alive and censored in the survival analysis. Four patients
continued on treatment at the time of analysis and treatment
data were incomplete for three patients.
3.2. Treatment responses in the postabiraterone cohort
3.2.1. Response to docetaxel
In the cohort of patients treated with both docetaxel and
abiraterone prior to cabazitaxel (n = 37), patients had
 EUROPEAN UROLOGY 66 (2014) 459–465 461

Table 1 – Patient characteristics

Prior abiraterone Abiraterone-naı̈ve (n = 22)

with or without enzalutamide
(n = 37) Prior enzalutamide Enzalutamide-naı̈ve
(n = 4) (n = 18)

Age at prostate cancer diagnosis, yr, median 62.0 51.0 61.4

Gleason score at diagnosis, median 8* 8 8 **
Median number of cycles of docetaxel 9 8 7
Reason for discontinuation of docetaxel; no. (%)
Disease progression 12 (32) 1 (25) 7 (39)
Nonprogression: Toxicity 7 (19) 1 (25) 2 (11)
Completion of cycles 16 (43) 2 (50) 7 (39)
NA 2 2
Interval on abiraterone, mo, median 7.2 – –
Interval on enzalutamide, mo, median 10.9 y 10.2 –
Age at cabazitaxel, yr, median 69.7 57.1 67.4
Cabazitaxel delivered on-trial, no. (%) 28 (76) 3 (75) 12 (67)
Performance status, no. (%)
0 2 (5) 0 (0) 1 (6)
1 29 (78) 3 (75) 13 (72)
2 4 (11) 1 (25) 3 (17)
NA 2 – 1
Metastatic involvement at start of cabazitaxel, no. (%)
Bone 32 (86) 3 (75) 17 (94)
Lymph nodes 20 (54) 2 (50) 12 (67)
Visceral 13 (35) 1 (25) 4 (22)
NA 2 – 1
Type of progression at start of cabazitaxel, no. (%)
PSA 29 (78) 2 (50) 13 (72)
Clinical 18 (49) 2 (50) 8 (44)
BS 12 (32) 1 (25) 3 (17)
Soft tissue (by RECIST) 18 (49) 3 (75) 7 (39)
NA 2 – 1
Baseline laboratory values, median
z
– Haemoglobin, g/l (normal range: 130–170) 10.9 11.7 10.7
– ALP, U/l (normal range: 24–110) 150 z 214 165
– Albumin, g/l (normal range: 30–50) 34 z 35 33
– LDH, U/l (normal range: 98–192) 217 z 207 288
– PSA, mg/l (normal range: <4) 717 § 137 312 #
Baseline pain grade (CTCAE v.4.0), no. (%)
0 4 (11) 0 2 (11)
1 26 (70) 3 (75) 9 (50)
2 4 (11) 1 (25) 8 (44)
NA 3 1
^
Armstrong predicted survival at start of cabazitaxel, mo, median (95% CI) 14.0 (12.4–15.6) 13.1 11.7 (10.1–14.5)

NA = not available; PSA = prostate-specific antigen; BS = bone scan; RECIST = Response Evaluation Criteria in Solid Tumors; ALP = alkaline phosphatase;
LDH = lactate dehydrogenase; CTCAE = Common Terminology Criteria for Adverse Events; CI = confidence interval.
*
NA for seven patients.
**
NA for four patients.
y
n = 5 patients.
z
NA for three patients.
#
NA for one patient.
§
NA in two patients.
^
No CI data.

received a median of nine cycles of docetaxel. Two patients
(5%) had disease progression at the first response assessment,
with stable disease in a further 10 patients (27%). The most
common reason for discontinuing docetaxel was reaching
the end of the planned number of treatment cycles (in 16
patients [43%]); seven patients (19%) discontinued treat-
ment due to toxicity (Table 1). Progressive disease
prompted discontinuation of docetaxel in 12 patients
(32%). Four patients received abiraterone prior to docetaxel
(on a phase 1–2 trial of abiraterone in chemotherapy-naı̈ve
CRPC [ClinicalTrials.gov identifier NCT00473512]), but the
median interval between the last cycle of docetaxel and
commencement of abiraterone in the remaining patients
was 7.8 mo (range: 1.1–59.4 mo).
3.2.2. Response to novel endocrine therapy
Abiraterone was administered for a median of 7.2 mo
(range: 1.8–63.5 mo). A total of 14 patients (38%) had 50%
PSA declines while on abiraterone therapy. Nine patients
(24%) progressed within 3 mo of starting abiraterone.
The median interval between development of CRPC and
cabazitaxel commencement was 36.9 mo.
In the five patients treated with enzalutamide and
abiraterone, enzalutamide was administered for a median
462 EUROPEAN UROLOGY 66 (2014) 459–465

Table 2 – Activity on cabazitaxel

Prior abiraterone with or Abiraterone-naı̈ve (n = 22)

without enzalutamide (n = 37)
Prior enzalutamide Enzalutamide-naı̈ve
(n = 4) (n = 18)

Cycles of cabazitaxel, no., median 6 5 5

50% decline in maximum PSA level, no. (%) 15 (41) 1 (25) 3 (17)
Soft tissue: evaluable patients 20 2 10
Partial response, no. (%) 3 (15) 0 1 (10)
Symptoms: evaluable patients 33 4 16
Benefit, no. (%) 9 (27) 0 6 (38)

PSA = prostate-specific antigen.

Table 3 – Serial response to docetaxel, abiraterone, and cabazitaxel

Docetaxel Abiraterone Cabazitaxel

50% PSA Comments <50% PSA Comments 50% PSA <50% PSA Comments
decline, decline, decline, decline,
no. (%) no. (%) no. (%) no. (%)

Discontinued due to PD (n = 12) 2 (17) Plus 2 patients who 7 (58) Plus 1 patient who 3 (25) 8 (67) NA = 1
received abiraterone received abiraterone (Included all
before docetaxel before docetaxel 3 pre-docetaxel
abi patients)
Discontinued without PD (n = 25) 9 (36) Plus 1 patient who 15 (60) – 12 (48) 12 (48) NA = 1
(EOT = 16, toxicity = 7, NA = 2) received abiraterone (Included the
before docetaxel pre-docetaxel
abiraterone patient)

PSA = prostate-specific antigen; PD = progressive disease; NA = not available; EOT = end of treatment cycles.

of 10.8 mo (range: 5.2–14.6 mo). One patient (20%) had a in four patients), symptomatic benefit was observed in
50% PSA decline while on enzalutamide therapy. 9 (27%). As shown in Table 3 and Figure 1, there was no
correlation between a favourable biochemical response to
3.2.3. Response to cabazitaxel abiraterone and response to subsequent cabazitaxel. Of
Of these 37 patients, 15 (41%) had a 50% PSA decline while 14 patients who had a 50% decline in PSA level while
receiving cabazitaxel (Table 2). A median of six cycles of on abiraterone, four (29%) had a 50% decline in PSA on
cabazitaxel were delivered (four patients ongoing at the cabazitaxel treatment, whereas of the 23 patients with
time of analysis). Of 20 patients with RECIST-evaluable <50% decline while on abiraterone, 11 (49%) had a 50%
disease, three (15%) achieved a confirmed partial response PSA decline while on subsequent cabazitaxel treatment
on treatment. Of 33 evaluable patients (no baseline pain (Table 4).
[(Fig._1)TD$IG]
50
40
30
20
10
0
-10
-20
-30
-40
-50
-60
-70
-80
-90
- 100
% PSA changee on abirateronee
% PSA changee on cabazitaxel

Fig. 1 – Waterfall plot showing maximum change (percentage) in prostate-specific antigen (PSA) level from baseline on abiraterone and cabazitaxel
treatments. Paired bars represent individual patients. Stars represent patients exposed to enzalutamide prior to cabazitaxel. Increases in PSA level are
capped at 50%.
 EUROPEAN UROLOGY 66 (2014) 459–465
Table 4 – Serial prostate-specific antigen response to abiraterone
and cabazitaxel
Abiraterone Cabazitaxel
50% PSA <50% PSA decline,
decline, no. (%) no. (%)
50% PSA decline (n = 14) 4 (29)
<50% PSA decline (n = 23) 11 (49)
PSA = prostate-specific antigen.
From first dose of cabazitaxel, the median survival
in this cohort was 20.3 mo (95% confidence interval [CI],
14.0–26.6). The median PFS was 5.5 mo (95% CI, 4.2–6.8).
From first diagnosis of prostate cancer, the median survival
was 10.9 yr (95% CI, 9.7–12.2). The observed survival
compared favourably to the predicted median survival of
14.0 mo (95% CI, 12.4–15.6) using the Armstrong nomo-
gram.
Three of the five patients previously treated with both
abiraterone and enzalutamide had a subsequent 50% PSA
decline while receiving cabazitaxel. None of these patients
had achieved a 50% PSA decline while on either abiraterone
or enzalutamide.
3.3. Treatment responses in the postenzalutamide cohort
Four patients were treated with enzalutamide prior to
cabazitaxel, receiving a median of eight cycles of docetaxel
(range: 5–10 cycles) and 10.2 mo of enzalutamide (range:
1.2–17.2 mo). These patients were generally younger at
prostate cancer diagnosis and at initiation of cabazitaxel
(Table 1). One of the patients had a 50% PSA decline while
receiving cabazitaxel (Table 2). This patient also had a
significant PSA decline and soft tissue response while on
enzalutamide.
Considering all 41 patients exposed to potent inhibition
of AR signalling with either abiraterone or enzalutamide,
the median overall survival from commencement of
cabazitaxel was 15.8 mo (95% CI, 11.0–20.5) and the
median PFS was 4.6 mo (95% CI, 3.0–6.1).
3.4. Treatment responses in the abiraterone-naı̈ve cohort
3.4.1. Response to docetaxel
In the patients treated with docetaxel followed by cabazi-
taxel (n = 18), patients had received a median of seven cycles
of docetaxel. Seven patients (39%) had achieved the planned
number of docetaxel treatment cycles and a further two
(11%) discontinued treatment for toxicity (Table 1). Seven
patients (39%) discontinued docetaxel due to disease
progression. In this cohort, disease progression and stable
disease were present at the first response assessment
on docetaxel in three (17%) and five patients (28%),
respectively. The median interval between the last cycle of
docetaxel and commencement of cabazitaxel was 6.8 mo.
From development of CRPC, there was a median interval of
15.7 mo to commencement of cabazitaxel.
463
3.4.2. Response to cabazitaxel
Of the 18 patients not previously treated with novel
endocrine therapies, 3 (17%) had a 50% PSA decline while
on cabazitaxel (Table 2). The median number of cabazitaxel
cycles administered was five. Only 1 of the 10 patients (10%)
with RECIST-evaluable disease had a partial response. Of the
10 (71)
16 patients evaluable for symptomatic benefit (no pain at
12 (52)
baseline in two patients), 6 (38%) reported symptomatic
benefit while on treatment.
From first dose of cabazitaxel, the median survival in this
cohort was 9.6 mo (95% CI, 8.5–10.7). The median PFS was
3.5 mo (95% CI, 2.0–4.9). From first diagnosis of prostate
cancer, the median survival was 3.9 yr (95% CI, 2.2–5.6). In
this instance, the observed survival fell short of the
predicted survival by Armstrong nomogram (median:
11.7 mo; 95% CI, 10.1–14.5).
3.4.3. Response to subsequent therapy
Nine patients received abiraterone after cabazitaxel
(including three patients treated with prior enzalutamide).
The median duration of abiraterone administered was
3.0 mo. Of the nine patients, two achieved a 50% PSA
decline on abiraterone treatment. Neither of these patients
had achieved a 50% PSA decline while on cabazitaxel.
4. Discussion
We report significant antitumour activity with cabazitaxel
in abiraterone- and enzalutamide-naı̈ve patients and in
patients exposed to these novel AR-targeting treatments.
Patients previously treated with abiraterone or enzalutamide
received a similar number of cabazitaxel cycles to that
delivered in the phase 3 TROPIC trial and achieved
comparable benefit in terms of PSA declines, shrinkage of
soft tissue disease, and symptomatic benefit. The observed
median survival of 15.8 mo was also in line with the median
survival of 15.1 mo reported in the TROPIC trial. Activity on
cabazitaxel appeared more modest in the cohort not treated
with abiraterone nor enzalutamide; interestingly, this cohort
had also received fewer docetaxel cycles and had shorter
intervals from both CRPC diagnosis and docetaxel cessation
and subsequent commencement of cabazitaxel therapy,
suggesting differences in the underlying disease biology
that might be best dissected using molecular stratification
techniques. Of note, nine patients subsequently received
abiraterone after cabazitaxel, further complicating any
comparison between cohorts. Formal comparison of activity
between treatment cohorts was, therefore, beyond the scope
of this paper.
We report higher antitumour activity with cabazitaxel in
abiraterone- and enzalutamide-treated patients than we
have previously reported with docetaxel post abiraterone
[12]. This observation could be a result of bias introduced by
the change in the therapeutic landscape between patients
treated in our docetaxel study and this one, including the
earlier institution of treatment for CRPC and an increase in
the referral of fitter CRPC patients for clinical studies.
Nonetheless, cabazitaxel is active in docetaxel-resistant
preclinical models [16,17] and has a low affinity for the
464 EUROPEAN UROLOGY 66 (2014) 459–465
adenosine triphosphate-dependent P-glycoprotein, a drug
efflux pump associated with taxane resistance [16,18,19].
Since the AR amino-terminal domain has been reported to
be critically important to tubulin binding [20], one could
hypothesise that the constitutively activated AR splice
variants, which generally lack the carboxy-terminal ligand-
binding domain and could result in resistance to abiraterone
and enzalutamide, would still be inhibited by tubulin-
binding drugs. In our cohort, lack of PSA response to
abiraterone (defined as <50% maximum PSA decline) did
not predict response to subsequent cabazitaxel therapy.
Indeed, the rate of decline in PSA while receiving cabazitaxel
was higher in patients who had not had a decline on
abiraterone (Table 4). and this observation merits further
interrogation in future studies. Likewise, in the small number
of patients exposed to enzalutamide, failure to achieve
reduction in PSA level with enzalutamide treatment did not
preclude subsequent biochemical response to cabazitaxel.
Further research is needed to establish predictive factors for
treatment response to improve personalisation of CRPC
treatment and to reduce the harms associated with ineffec-
tive therapies.
As a single-institution case series, these data have the
limitations of retrospective analyses and the cohort sizes do
not allow far-reaching conclusions. Imbalances in the disease
characteristics between the cohorts are possible, due to the
lack of standardised data on treatment sequencing. Following
the TROPIC subgroup analysis that demonstrated cabazitaxel
activity in patients progressing on docetaxel, clinicians may
have felt emboldened to manage such patients by proceeding
directly to cabazitaxel. However, these patients may also
have more complex or less favourable disease biology
compared to patients that respond well to serial AR-targeting
treatments. We report the predicted survival calculated
using the Armstrong nomogram to provide information on
differences between the two patient populations, although
this nomogram has not been validated in abiraterone-treated
patients.
5. Conclusions
Currently, no consensus on treatment sequencing exists and,
in the absence of predictive markers, all approved post-
docetaxel treatments are viable options. Prospective trials
looking at optimal treatment sequencing are warranted,
although these are challenging to design and interpret. To the
best of our knowledge, this is the first report of significant
activity with cabazitaxel after docetaxel and abiraterone or
enzalutamide, supporting cabazitaxel as an important and
active treatment option in patients previously exposed to
potent inhibition of AR signalling.
Author contributions: Gerhardt Attard had full access to all the data in
the study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Pezaro, Omlin, Altavilla, Lorente, Ferraldeschi,
Bianchini, Dearnaley, Parker, de Bono, Attard.
Acquisition of data: Pezaro, Omlin, Altavilla, Lorente, Ferraldeschi,
Bianchini.
Analysis and interpretation of data: Pezaro, Omlin, Lorente.
Drafting of the manuscript: Pezaro, Omlin.
Critical revision of the manuscript for important intellectual content:
Pezaro, Omlin, Altavilla, Lorente, Ferraldeschi, Bianchini, Dearnaley,
Parker, de Bono, Attard.
Statistical analysis: Pezaro, Lorente.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: de Bono, Attard.
Other (specify): None.
Financial disclosures: Gerhardt Attard certifies that all conflicts of
interest, including specific financial interests and relationships and
affiliations relevant to the subject matter or materials discussed in the
manuscript (eg, employment/affiliation, grants or funding, consultancies,
honoraria, stock ownership or options, expert testimony, royalties, or
patents filed, received, or pending), are the following: C. Pezaro received
honoraria from Sanofi-Aventis and travel support from Sanofi-Aventis and
Janssen-Cilag. D. Dearnaley received honoraria and consulting fees from
Amgen, Astellas, Takeda, and Succinct Healthcare. C. Parker received
honoraria from Sanofi-Aventis, Janssen-Cilag, Astellas, Bayer, BNIT, and
Takeda. J. de Bono received consulting fees from Ortho Biotech Oncology
Research and Development (a unit of Cougar Biotechnology), consulting
fees and travel support from Amgen, Astellas, AstraZeneca, Boehringer-
Ingelheim; Bristol-Myers Squibb, Dendreon, Enzon, Exelixis, Genentech,
GlaxoSmithKline, Medication, Merck, Novartis, Pfizer, Roche, Sanofi-
Aventis, Supergen, and Takeda; and grant support from AstraZeneca and
Genentech. G. Attard received consulting fees and travel support from
Janssen-Cilag, Veridex, Roche/Ventana, and Millennium Pharmaceuticals,
honoraria from Janssen-Cilag, Ipsen, Takeda, and Sanofi-Aventis; and grant
support from AstraZeneca and Genentech. G. Attard and D. Dearnaley are
on the ICR awards to inventors list of abiraterone acetate. The authors are
employees of the Section of Medicine that is supported by a Cancer
Research UK programme grant and an Experimental Cancer Medical
Centre grant from Cancer Research UK and the Department of Health
(Ref: C51/A7401). A. Omlin is recipient of a 2-yr bursary from the Swiss
Cancer League (No. BIL KLS-02592-02-2010). G. Attard is supported by a
Cancer Research UK Clinician Scientist Fellowship. G. Attard and J. de Bono
have received support from Prostate Cancer UK and the Prostate Cancer
Foundation.
Funding/Support and role of the sponsor: Abiraterone acetate was
developed at The Institute of Cancer Research, which, therefore, has a
commercial interest in the development of this agent. The authors
acknowledge National Health Service funding to the Royal Marsden
NIHR Biomedical Research Centre.
Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.eururo.2013.11.044.
References
[1] 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.
[2] Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy
for castration-resistant prostate cancer. N Engl J Med 2010;363:
411–22.
[3] De Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazi-
taxel or mitoxantrone for metastatic castration-resistant prostate
cancer progressing after docetaxel treatment: a randomised open-
label trial. Lancet 2010;376:1147–54.
 EUROPEAN UROLOGY 66 (2014) 459–465
[4] De Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased
survival in metastatic prostate cancer. N Engl J Med 2011;364:
1995–2005.
[5] Scher HI, Fizazi K, Saad F, et al. Increased survival with enzaluta-
mide in prostate cancer after chemotherapy. N Engl J Med 2012;
367:1187–97.
[6] Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223
and survival in metastatic prostate cancer. N Engl J Med 2013;369:
213–23.
[7] Loriot Y, Bianchini D, Ileana E, et al. Antitumour activity of abir-
aterone acetate against metastatic castration-resistant prostate
cancer progressing after docetaxel and enzalutamide (MDV3100).
Ann Oncol 2013;24:1807–12.
[8] Noonan KL, North S, Bitting RL, Armstrong AJ, Ellard SL, Chi KN.
Clinical activity of abiraterone acetate in patients with metastatic
castration-resistant prostate cancer progressing after enzaluta-
mide. Ann Oncol 2013;24:1802–7.
[9] Schrader AJ, Boegemann M, Ohlmann C-H, et al. Enzalutamide in
castration-resistant prostate cancer patients progressing after doc-
etaxel and abiraterone. Eur Urol 2014;65:30–6.
[10] Bianchini D, Lorente D, Rodriguez AV, et al. Antitumor activity of
enzalutamide (MDV3100) in patients with metastatic castration-
resistant prostate cancer (CRPC) pre-treated with docetaxel and
abiraterone. Eur J Cancer 2014;50:78–84.
[11] Darshan MS, Loftus MS, Thadani-Mulero M, et al. Taxane-induced
blockade to nuclear accumulation of the androgen receptor pre-
dicts clinical responses in metastatic prostate cancer. Cancer Res
2011;71:6019–29.
[12] Mezynski J, Pezaro C, Bianchini D, et al. Antitumour activity
of docetaxel following treatment with the CYP17A1 inhibitor
465
abiraterone: clinical evidence for cross-resistance? Ann Oncol
2012;23:2943–7.
[13] Scher HI, Halabi S, Tannock I, et al. Design and end points of
clinical trials for patients with progressive prostate cancer and
castrate levels of testosterone: recommendations of the Prostate
Cancer Clinical Trials Working Group. J Clin Oncol 2008;26:
1148–59.
[14] Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evalua-
tion criteria in solid tumours: revised RECIST guideline (version 1.1).
Eur J Cancer 2009;45:228–47.
[15] Armstrong AJ, Garrett-Mayer ES, Yang YC, de Wit R, Tannock IF,
Eisenberger M. A contemporary prognostic nomogram for men
with hormone-refractory metastatic prostate cancer: a TAX327
study analysis. Clin Cancer Res 2007;13:6396–403.
[16] Mita AC, Denis LJ, Rowinsky EK, et al. Phase I and pharmacokinetic
study of XRP6258 (RPR 116258A), a novel taxane, administered as a
1-hour infusion every 3 weeks in patients with advanced solid
tumors. Clin Cancer Res 2009;15:723–30.
[17] Vrignaud P, Semiond D, Lejeune P, et al. Preclinical antitumor
activity of cabazitaxel, a semisynthetic taxane active in taxane-
resistant tumors. Clin Cancer Res 2013;19:2973–83.
[18] Yap TA, Pezaro CJ, de Bono JS. Cabazitaxel in metastatic castration-
resistant prostate cancer. Expert Rev Anticancer Ther 2012;12:
1129–36.
[19] Mita AC, Figlin R, Mita MM. Cabazitaxel: more than a new taxane
for metastatic castrate-resistant prostate cancer? Clin Cancer Res
2012;18:6574–9.
[20] Zhu ML, Horbinski CM, Garzotto M, Qian DZ, Beer TM, Kyprianou N.
Tubulin-targeting chemotherapy impairs androgen receptor activity
in prostate cancer. Cancer Res 2010;70:7992–8002.