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RESEARCH ARTICLE
Indirect treatment comparison of cabazitaxel
for patients with metastatic castrate-resistant
prostate cancer who have been previously
treated with a docetaxel-containing regimen
Jon P. Fryzek
1
*, Heidi Reichert
1
, Nicholas Summers
2
*, Lindsay Townes
1
,
Robert Deuson
3
, Dominik D. Alexander
2
, Jackie Vanderpuye-Orgle
2
1EpidStat Institute, Ann Arbor, Michigan, United States of America, 2Precision Health Economics, Los
Angeles, California, United States of America, 3Medenomics, LLC, Moorpark, California, United States of
America
*jon@epidstat.com (JPF); nick.summers@pheconomics.com (NS)
Abstract
Background
The objective of this study was to conduct an indirect treatment comparison between caba-
zitaxel, abiraterone and enzalutamide to determine the clinical efficacy and safety of cabazi-
taxel relative to comparators in the treatment of patients with metastatic castrate-resistant
prostate cancer who progress on docetaxel-based therapies.
Methods
A systematic literature review was conducted to inform the network meta-analysis of cabazi-
taxel, abiraterone and enzalutamide. Due to a lack of head-to-head trials, studies with a
comparator arm of best supportive care were included in the analysis. Overall survival, pro-
gression-free survival, and adverse events were compared within both Bayesian and Fre-
quentist frameworks. The ratios for survival outcomes were estimated using hazard ratios
(HR), and the ratios for adverse events between groups were estimated using odds ratios
(ORs); uncertainty was reported as 95% confidence (Frequentist) and credible (Baysesian)
Intervals.
Results
Three of thirteen trials identified for abstraction were relevant for analyses. Median overall
survival was not statistically significantly different for abiraterone (HR = 1.04; 95% CI =
0.83–1.28) or enzalutamide (HR = 0.88; 95% CI = 0.69–1.11) when compared to cabazitaxel
in the Bayesian analysis. Anaemia (OR = 3.71; 95% CI = 1.01–10.44), diarrhoea (OR =
16.60; 95% CI = 1.41–75.31) and haematuria (OR = 3.88; 95% CI = 1.03–10.09) were more
likely to occur in the cabazitaxel group than the abiraterone group, while pyrexia risk was
higher in cabazitaxel compared to enzalutamide (OR = 36.23; 95% CI = 1.14–206.40). Fre-
quentist analyses produced similar results.
PLOS ONE | https://doi.org/10.1371/journal.pone.0195790 April 11, 2018 1 / 15
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OPEN ACCESS
Citation: Fryzek JP, Reichert H, Summers N,
Townes L, Deuson R, Alexander DD, et al. (2018)
Indirect treatment comparison of cabazitaxel for
patients with metastatic castrate-resistant prostate
cancer who have been previously treated with a
docetaxel-containing regimen. PLoS ONE 13(4):
e0195790. https://doi.org/10.1371/journal.
pone.0195790
Editor: Ste
´phanie Filleur, Texas Technical
University Health Sciences Center, UNITED
STATES
Received: June 13, 2017
Accepted: March 29, 2018
Published: April 11, 2018
Copyright: ©2018 Fryzek et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
files.
Funding: This research was funded by Sanofi to
NS. Sanofi contributed to the study design and
reviewed the final version of the manuscript to
ensure that the descriptions of Sanofi products are
Conclusions
The scarcity of clinical studies and lack of a common comparator limited analyses. The
adverse event results must be interpreted with caution as many were based on small num-
bers. The results from this analysis indicate comparable survival outcomes and adverse
event profiles. As these pivotal studies may not reflect the contemporary treatment land-
scape and patient profiles, additional research, including head-to-head clinical trials and real
world observational studies, should be conducted to further elucidate the beneficial effects
of these therapies.
Introduction
Despite evolution in the treatment paradigm over the past decade, prostate cancer remains a
significant public health burden. According to the American Cancer Society’s estimates, in
2016, approximately 180,890 new cases of prostate cancer were diagnosed in the United States,
and about 26,120 men died of prostate cancer. It is estimated that 1 in 7 men will be diagnosed
with prostate cancer during his lifetime [1]. In the United Kingdom, approximately 47,300
incident cases of prostate cancer occurred in 2013, with an estimated 11,287 deaths from this
malignancy in 2014 [2].
Health Technology Assessment agencies often need to make new drug coverage decisions
despite incomplete data on the comparative safety and efficacy of available treatment options.
More often than not, newly approved drugs lack head-to-head comparison data from clinical
trials for all available treatment options, limiting comparators to one or two legacy treatments.
Due to concerns around adequate assessments of comparative effectiveness, global reimburse-
ment agencies such as the United Kingdom’s National Institute for Health and Care Excellence
(NICE), and more recently, major private payers in the United States, require alternative
approaches for assessing comparative risk and efficacy be performed [3].
The challenge of inadequate comparative efficacy and safety data is prevalent in clinical
studies of treatments for metastatic castrate-resistant prostate cancer (mCRPC). In particular,
as new therapies were approved for this difficult to treat population, no direct head-to-head
comparisons for novel therapies versus cabazitaxel have become available. Therefore, this
study was undertaken to assess the comparative effectiveness and safety of cabazitaxel in
patients with mCRPC who have been treated with docetaxel-based regimens relative to thera-
pies endorsed by the latest guidelines in the United Kingdom for this indication (e.g., abirater-
one and enzalutamide).
Materials and methods
This indirect treatment comparison follows the PRISMA extension statement for reporting of
systematic reviews incorporating network meta-analyses [4].
Eligibility criteria
Phase 2 or Phase 3 randomized controlled trials with any blinding status of adult (age 18 or
older) mCRPC patients previously treated with docetaxel-based regimens were included.
Indirect treatment comparison for cabazitaxel, abiraterone or enzalutamide among mCRPC patients
PLOS ONE | https://doi.org/10.1371/journal.pone.0195790 April 11, 2018 2 / 15
medically accurate, but did not take part in the
writing of the manuscript.
Competing interests: JPF, HR, LT, and DDA are
employees of EpidStat Institute, which is a
research institute that provides expert assistance
on the evaluation of complex health issues and on
the conduct and interpretation of epidemiological
studies to pharmaceutical and medical device
companies. NS is an employee of Precision Health
Economics (PHE), which provides consulting and
other research services to pharmaceutical, device,
governmental, and non-governmental
organizations. JV-O was an employee of PHE at the
time this manuscript was written. RD was a
consultant to PHE during the execution of this
study and is the Founder and President of
Medenomics LLC, a consultancy that provides
health economic and outcomes research services
to companies in the life sciences industry. The
study was sponsored by Sanofi. This does not alter
our adherence to PLOS ONE policies on sharing
data and materials. Meghan Gallagher, an
employee of Sanofi contributed to the study
design. Sanofi reviewed the final version of the
manuscript for medical accuracy, but did not take
part in the writing of the manuscript.
Systematic literature review
Results of the systematic literature review are available in a separate publication [5]. A formal
protocol is not available for the systematic review. Details on the eligibility criteria, informa-
tion sources or databases, key words and search strings utilized for the databases, study selec-
tion criteria, data collection process, and qualitative information and quantitative data
extracted are presented in the prior publication. Database searches of MEDLINE, Embase,
and Cochrane CENTRAL were conducted from January 1, 2010 to February 26, 2015 (see S1
Appendix for complete search strategies). Manual searches were conducted for abstracts
from multiple congresses held between January 1, 2011 and March 8, 2015 –American Soci-
ety of Clinical Oncology (ASCO); ASCO-Genitourinary; European Society for Medical
Oncology; American Urological Association; American Association for Cancer Research;
European Association of Urology; and Socie
´te
´Internationale d’Urologie. Two reviewers
screened articles for inclusion using a two-step process whereby article titles and abstracts
were screened, followed by full-text review. Any disputes about the abstracted data were
resolved through discussion between reviewers or consultation with a third reviewer. To be
eligible for inclusion, studies were required to have a population of patients with mCRPC
who had received a docetaxel-based regimen for any previous line of therapy, and who were
treated by one or more interventions of interest (cabazitaxel, abiraterone, enzalutamide,
mitoxantrone, ipilimumab, radium-223, sipuleucel-T, and estramustine). A pre-specified list
of relevant efficacy and safety outcomes, such as overall survival (OS), progression-free sur-
vival (PFS) data and adverse events (AE), were required to be reported. The PRISMA flow
diagram is illustrated in Fig 1.
Data from relevant articles were extracted in parallel by two independent reviewers, and
studies were critically examined using both a qualitative appraisal and a study grade. Both sets
of extracted data were compared and combined into a final data extraction table, which was
subsequently verified for the accuracy of all content by an independent third reviewer. In
instances where multiple publications were identified for the same trial, the novel data
reported in each publication were initially extracted separately and then grouped together to
create the most complete dataset for each study population while avoiding double counting of
the patients. Both qualitative study characteristics and quantitative data were extracted from
each study. This enabled us to perform a systematic and critical evaluation of study relevancy
and design homogeneity as described in the sections below. Variables abstracted included the
following: study acronym and authors, country, randomization, blinding, control, line of ther-
apy, age, sample size (%), length of follow-up, ECOG/WHO performance status, race, prior
therapy, OS rate, PFS rate, and grade 3 or 4 AEs.
Geometry of the network
In order to conduct the analyses, the first step was to synthesize the relevant studies by devel-
oping a map (network geometry) that details the specific direct comparisons, indirect compar-
isons, and comparisons of analytical interest across the trials. Before constructing a network, it
is critical to review each study’s characteristics, methodology, and analytical comparisons and
techniques in an effort to assemble a harmonized group of studies that could be evaluated col-
lectively in a meta-analytic framework. Only studies that do not present significant heteroge-
neity relative to the other studies were included in the final analysis. The network depicts each
drug in the analysis as a node, where the links between different nodes represent trials compar-
ing the connected agents.
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Risk of bias within individual studies
Studies were assessed by performing semi-quantitative evaluations, qualitative appraisals, and
study quality grading. Various components of the included studies were assessed for the possi-
ble introduction of bias using guidance adapted from the University of York’s Centre for
Reviews and Dissemination [6]. Examples of the evaluated study criteria include appropriate
patient randomization technique, double-blind study design and description of blinding meth-
ods, and adequate explanation of withdrawals and drop-outs. An overall qualitative study
appraisal was also conducted using the Jadad score [7]. Additional information can be found
in the systematic literature review manuscript [5].
Both a qualitative assessment and an analysis of statistical heterogeneity were used to deter-
mine the risk of bias during the study selection process. As indicated in the previous section, it
is of critical importance to systematically examine the qualitative study appraisals for potential
“design heterogeneity” or “conceptual heterogeneity” before it can be included in the quantita-
tive assessment. Design heterogeneity is evaluated by qualitatively examining the study specific
characteristics, such as the nature of the study population (e.g., age and gender), duration of
Fig 1. PRISMA trial flow diagram.
https://doi.org/10.1371/journal.pone.0195790.g001
Indirect treatment comparison for cabazitaxel, abiraterone or enzalutamide among mCRPC patients
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follow-up, drop-out rate, and the sample size among other important characteristics. To evalu-
ate statistical heterogeneity, statistical testing is performed to evaluate the magnitude and
degree of between-study variability. By conducting an in-depth review of these study parame-
ters, we were able to determine if there were substantial differences between the studies that
would prevent the combining of quantitative data.
Analytic methods
The outcomes of interest in these analyses included median OS, median PFS, and risk of vari-
ous AEs. The measure of association for OS and PFS was the hazard ratio (HR) with 95% Con-
fidence Intervals (95% CI) for Frequentist analyses and 95% Credible Intervals (also referred
to as 95% CI henceforth) for Bayesian analyses. The ratios of AEs between groups were esti-
mated using odds ratios (ORs) with 95% CIs. The monitoring scheme for PFS differed among
the included studies; therefore, these analyses should be considered exploratory. The conduct
of specific analyses was limited to the available data and to the scientific justification for
including similar studies together in a quantitative fashion. A network meta-analysis compar-
ing the effect of treatment with cabazitaxel to its comparators was performed within a Fre-
quentist and a Bayesian framework, offering two different methodological approaches to the
analyses [8]. These two analytical methodologies were utilized for the purpose of evaluating
the consistency of findings. To address possible heterogeneity between studies, fixed and ran-
dom effects models were used.
NICE recommends that vague or flat priors, such as N (0, 1002) be used for Bayesian analy-
ses if there are a minimal number of clinical trials with large numbers of subjects [9]. Given
that only one study for each drug of interest was identified in the systematic literature review,
only a single model was built. The Deviance Information Criterion (DIC) was used to assess
“goodness of fit” of the model. Statistical heterogeneity was measured with the I
2
statistic.
Frequentist analyses were conducted in Stata [10], and Bayesian analyses were performed
using WinBugs based on code supplied by Woods et al., 2010 [11].
Assessment of inconsistency
Inconsistency can be assessed using statistical methodology when the network geography con-
tains closed loops. However, we were not able to evaluate inconsistency because there is no
available literature that accommodates closed loops for these treatments.
Risk of bias across studies
Factors that may differ across studies and lead to bias include the characteristics of the patients
(e.g., age distribution), the way in which the outcomes are measured (e.g., HRs for OS vs. pro-
portions for disease free progression), the length of follow-up (e.g., comparable evaluations
based on variable lengths of patient follow-up), and the study timeframe.
Results
Study selection
The comprehensive literature search produced 935 studies that underwent initial screening.
After careful review for eligibility, 13 studies were fully abstracted from 31 publications. A flow
diagram of the studies included and excluded at each stage is provided in Fig 1.
Only three of the clinical trials (AFFIRM, COU-AA-301, and TROPIC) had similar com-
parator groups. Thus, the analyses focused on these trials. Results for the TROPIC study came
Indirect treatment comparison for cabazitaxel, abiraterone or enzalutamide among mCRPC patients
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from Joulain et al (2010) [12], results for AFFIRM were published by Scher et al (2012) [13],
and results for COU-AA-301 were reported by Fizazi (2012) [14].
Summary of network geometry
The treatment network was based on three clinical trials. For the drugs of interest, no direct
comparisons could be made. Therefore, all comparisons were made indirectly through their
relationship with a common comparator (Fig 2).
For these analyses, it was assumed that comparator patients in all three trials received best
supportive care. Furthermore, we assumed that the placebo used in the comparator group in
the AFFIRM trial had no relationship to any of our outcomes (OS, PFS, AEs). The COU-AA-
301 trial used prednisone to treat their comparator patients, while TROPIC used mitoxantrone
and prednisone. A recent study showed that survival patterns were similar for prednisone and
mitoxantrone/prednisone treated groups; although, AEs may be more abundant in the mitox-
antrone/prednisone group among mCRPC patients [15]. Therefore, the indirect treatment
comparison of cabazitaxel, abiraterone, and enzalutamide is anchored on best supportive care.
Study characteristics
Table 1 compares the characteristics for each study included in the indirect treatment compar-
isons. The studies are similar in terms of treatment line (pre-treated with docetaxel-based regi-
men), study years (range: 2007–2010), total patients (range: 755–1199), age (median range:
68–69) and ECOG score (0–1 range: 90%-93%).
Fig 2. Network geometry of published randomized studies. Direct comparisons = solid line/link between the nodes;
best supportive care varied by study: TROPIC = mitoxantrone + prednisone, COU-AA-301 = prednisone, and
AFFIRM = placebo.
https://doi.org/10.1371/journal.pone.0195790.g002
Indirect treatment comparison for cabazitaxel, abiraterone or enzalutamide among mCRPC patients
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Results of individual studies
Individual study results for median OS are reported in Table 2. Similar median lengths of
study follow-up were found for the TROPIC and COU-AA-301 studies (i.e., 623.96 days and
614.82 days, respectively). The median length of follow-up for the AFFIRM study was slightly
less at 428.29 days. The active arm of all studies had better median survival compared to best
supportive care.
Median PFS is reported in Table 3 along with the definitions used to measure PFS in each
study. These differences may contribute to the considerably shorter median length of follow-
up for the TROPIC study compared to COU-AA-301 and AFFIRM since TROPIC uses a
broader definition of the PFS endpoint. As with OS, PFS was statistically significantly longer in
the active arm compared to best supportive care in all three trials.
The proportion of individuals with AEs graded 3 or higher for each study is reported in
Table 4. Adverse events in the TROPIC trials were ascertained from the Sanofi internal report
[12] for all AEs except cardiac disorders and abnormalities in liver function tests (available on
clinicaltrials.gov for trial NCT00417079). All AEs identified in the COU-AA-301 trials were
published in Fizazi (2012) [14], while AEs from the AFFIRM trials were mainly identified
from clinicaltrials.gov for trial NCT00974311, except for diarrhoea, fatigue, cardiac disorder
and abnormalities in liver function tests, which were available in Scher (2012) [13]. The most
common AEs among cabazitaxel users were neutropenia (21.3%), febrile neutropenia (7.5%),
and diarrhoea (6.2%). The most common AEs among abiraterone were fatigue (9.5%),
Table 1. Baseline characteristics of the studies included in the indirect treatment comparison for cabazitaxel, abiraterone acetate and enzalutamide.
Author
(Year)
Acronym TX
Line
Study
Type
Treatment / Study
Years
Region Total
Patients
Age Race ECOG
Comparator
Joulain
(2010)
TROPIC 3 RCT Cabazitaxel + prednisone / 2007–2008 26
countries
755 75 yrs: 18%
median: 68
White:
83.5%
Asian: 7.5%
Black: 5%
Other: 3.5%
0–1: 93%
Mitoxantrone + prednisone
Fizazi (2012) COU-AA-
301
3 RCT Abiraterone acetate
+ prednisone /
2008–2009 13
countries
1195 75 yrs: 28%
median: 69
NR 0–1: 90%
2: 10%
Placebo + prednisone
Scher (2012) AFFIRM 3 RCT Enzalutamide / 2009–2010 15
countries
1199 75 yrs:
25.3%
median: 69
NR 0–1:
91.5%
2: 8.5%
Placebo
RCT = Randomized controlled trial; TX = Treatment
https://doi.org/10.1371/journal.pone.0195790.t001
Table 2. Hazard ratios (HR) and 95% Confidence Interval (CI) for overall survival (OS) for studies included in the indirect treatment comparison for cabazitaxel,
abiraterone acetate and enzalutamide.
Author (Year) Acronym Treatment / Comparator Length of follow-up
(median)
Median OS HR
(95% CI)
HR
p-value
Joulain (2010) TROPIC Cabazitaxel + prednisone / 623.96 days 0.72 (0.61–0.84) <0.0001
Mitoxantrone + prednisone
Fizazi (2012) COU-AA-301 Abiraterone acetate + prednisone / 614.82 days 0.74 (0.64–0.86) <0.0001
Placebo + prednisone
Scher (2012) AFFIRM Enzalutamide / 438.29 days 0.63 (0.53–0.75) <0.001
Placebo
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followed by anaemia (8%) and back pain (7.5%). For enzalutamide, fatigue (6%), anaemia
(2.63%), haematuria (1.5%), and bone pain (1.5%) were most common.
Indirect treatment comparison results
Overall survival. We used the TROPIC, COU-AA-301, and AFFIRM trials to compare
cabazitaxel with abiraterone and enzalutamide indirectly through a common comparator
using a Bayesian fixed effects model. No statistically significant difference in median OS for
patients treated with abiraterone was observed when compared with patients treated with
cabazitaxel (HR = 1.04; 95% CI = 0.83–1.28). While patients on enzalutamide had a better
median OS compared to cabazitaxel, this difference was not statistically significant (HR = 0.88;
95% CI = 0.69–1.11) (Table 5). For this analysis, statistical heterogeneity was not significant
(I
2
3.1% (0%-89.9%)) and the DIC was low (DIC = 5.93).
Progression-free survival. We compared the median PFS of patients on abiraterone to
patients on cabazitaxel indirectly through a common comparator using a Bayesian fixed effects
model. Data from the AFFIRM trial was excluded because the confidence interval for PFS did
not overlap the confidence interval of the two other trials, indicating heterogeneity. PFS was
modestly lower for abiraterone than cabazitaxel, but the difference was not statistically signifi-
cant (HR = 0.88; 95% CI = 0.72–1.07) (Table 5).
Adverse events. The results for the AEs must be interpreted with caution as many of these
outcomes were based on very few events resulting in unstable risk estimates. Of some of the
more frequently reported AEs in the 3 included trials (e.g., fatigue, anaemia, back pain, diar-
rhoea), only anaemia (OR = 3.71; 95% CI = 1.01–10.44) and diarrhoea (OR = 16.60; 95%
CI = 1.41–75.31) were statistically significantly more likely to occur in the cabazitaxel group
compared to abiraterone (Table 6). In addition, the indirect treatment comparison showed
haematuria (OR = 3.88; 95% CI = 1.03–10.09) and pyrexia (OR = 36.23; 95% CI = 1.14–
206.40) were higher among those receiving cabazitaxel compared to those receiving abirater-
one and enzalutamide, respectively. None of the other AEs were statistically significantly dif-
ferent for the three groups.
Risk of bias across studies
Based on our assessment of design heterogeneity, we did not identify potential sources of qual-
itative variability or bias that would preclude the combination of quantitative data across stud-
ies. Because only a few studies were deemed relevant for the quantitative meta-analysis, we
Table 3. Hazard ratios (HR) and 95% Confidence Interval (CI) for progression-free survival (PFS) for studies included in the indirect treatment comparison for
cabazitaxel, abiraterone acetate and enzalutamide.
Study Treatment Length of follow-
up (median)
Median PFS HR
(95% CI; p-value)
Description of PFS Endpoint
TROPIC Cabazitaxel
+ prednisone
85 days 0.75 (0.65–0.87;
<0.0001)
The earliest progression in tumor, PSA or pain or death
Mitoxantrone
+ prednisone
43 days
COU-AA-
301
Abiraterone acetate
+ prednisone
170.45 days 0.66 (0.58–0.76;
<0.0001)
Soft-tissue disease progression by modified Response Evaluation Criteria In Solid
Tumors (RECIST) criteria
Placebo + prednisone 109.57 days
AFFIRM Enzalutamide 252.63 days 0.40 (0.35–0.47;
<0.001)
Progression of soft-tissue disease according to RECIST, version 1.1, progression of
osseous disease according to bone scans showing two or more new lesions per
PCWG2, and death from any cause.
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Table 4. Percent grade 3 and above adverse events (AEs) for cabazitaxel, abiraterone acetate and enzalutamide and their comparators.
CABAZITAXEL (TROPIC)
Adverse Event Author (year) Follow-up Cabazitaxel % with AE Comparator % with AE
Abdominal pain TROPIC (2010) max: 3 yrs / med: 20.5 mos 1.9% 0%
Abnormalities in liver function tests NCT00417079 (2011) max: 2 yrs 0.3% 0%
Anaemia TROPIC (2010) max: 3 yrs / med: 20.5 mos 3.5% 1.3%
Arthralgia TROPIC (2010) max: 3 yrs / med: 20.5 mos 1.1% 1.1%
Asthenia TROPIC (2010) max: 3 yrs / med: 20.5 mos 4.6% 2.4%
Back pain TROPIC (2010) max: 3 yrs / med: 20.5 mos 3.8% 3%
Bone pain TROPIC (2010) max: 3 yrs / med: 20.5 mos 0.8% 2.4%
Cardiac disorders NCT00417079 (2011) max: 2 yrs 1.89% 0.81%
Constipation TROPIC (2010) max: 3 yrs / med: 20.5 mos 1.1% 0.5%
Diarrhoea TROPIC (2010) max: 3 yrs / med: 20.5 mos 6.2% 0.3%
Dyspnoea TROPIC (2010) max: 3 yrs / med: 20.5 mos 1.3% 0.8%
Fatigue TROPIC (2010) max: 3 yrs / med: 20.5 mos 4.9% 3%
Febrile neutropenia TROPIC (2010) max: 3 yrs / med: 20.5 mos 7.5% 1.3%
Haematuria TROPIC (2010) max: 3 yrs / med: 20.5 mos 1.9% 0.5%
Nausea TROPIC (2010) max: 3 yrs / med: 20.5 mos 1.9% 0.3%
Neutropenia TROPIC (2010) max: 3 yrs / med: 20.5 mos 21.3% 7%
Pain TROPIC (2010) max: 3 yrs / med: 20.5 mos 1.1% 1.9%
Pain in extremity TROPIC (2010) max: 3 yrs / med: 20.5 mos 1.6% 1.1%
Pyrexia TROPIC (2010) max: 3 yrs / med: 20.5 mos 1.1% 0.3%
Thrombocytopenia TROPIC (2010) max: 3 yrs / med: 20.5 mos 2.4% 0.3%
Urinary-tract infection TROPIC (2010) max: 3 yrs / med: 20.5 mos 1.1% 0.8%
Vomiting TROPIC (2010) max: 3 yrs / med: 20.5 mos 1.9% 0%
ABIRATERONE (COU-AA-301)
Adverse Event Author (year) Follow-up Abiraterone % with AE Comparator % with AE
Abdominal pain Fizazi (2012) max: 2 yrs / med: 20.2 mos 2% 2%
Abnormalities in liver function tests Fizazi (2012) max: 2 yrs / med: 20.2 mos 4.5% 3.5%
Anaemia Fizazi (2012) max: 2 yrs / med: 20.2 mos 8% 9%
Arthralgia Fizazi (2012) max: 2 yrs / med: 20.2 mos 5% 4%
Asthenia Fizazi (2012) max: 2 yrs / med: 20.2 mos 3% 2.5%
Back pain Fizazi (2012) max: 2 yrs / med: 20.2 mos 7.5% 10.5%
Bone pain Fizazi (2012) max: 2 yrs / med: 20.2 mos 6.5% 8%
Cardiac disorders Fizazi (2012) max: 2 yrs / med: 20.2 mos 5% 2.5%
Constipation Fizazi (2012) max: 2 yrs / med: 20.2 mos 1% 1%
Diarrhoea Fizazi (2012) max: 2 yrs / med: 20.2 mos 1.5% 1%
Dyspnoea Fizazi (2012) max: 2 yrs / med: 20.2 mos 2.5% 2.5%
Fatigue Fizazi (2012) max: 2 yrs / med: 20.2 mos 9.5% 10.5%
Febrile neutropenia Fizazi (2012) max: 2 yrs / med: 20.2 mos 0.5% 0%
Haematuria Fizazi (2012) max: 2 yrs / med: 20.2 mos 2% 2%
Nausea Fizazi (2012) max: 2 yrs / med: 20.2 mos 2.5% 3%
Neutropenia Fizazi (2012) max: 2 yrs / med: 20.2 mos 0.5% 0.5%
Pain Fizazi (2012) max: 2 yrs / med: 20.2 mos 0.5% 2.5%
Pain in extremity Fizazi (2012) max: 2 yrs / med: 20.2 mos 3.5% 5%
Pyrexia Fizazi (2012) max: 2 yrs /med: 20.2 mos 0.5% 1%
Thrombocytopenia Fizazi (2012) max: 2 yrs / med: 20.2 mos 1.5% 1%
Urinary-tract infection Fizazi (2012) max: 2 yrs / med: 20.2 mos 2% 0.5%
(Continued)
Indirect treatment comparison for cabazitaxel, abiraterone or enzalutamide among mCRPC patients
PLOS ONE | https://doi.org/10.1371/journal.pone.0195790 April 11, 2018 9 / 15
were able to efficiently compare and contrast the study design and characteristics between
studies. Specifically, for OS, important study characteristics, such as age, ECOG score, and
length of follow-up were relatively similar between studies. The TROPIC study had an
expanded definition for a progression-free endpoint, which may have shortened PFS com-
pared to AFFIRM or COU-AA-301. A broad overview of comparisons of the three trials is in
Table 7.
Table 4. (Continued)
Vomiting Fizazi (2012) max: 2 yrs / med: 20.2 mos 3.5% 3%
ENZALUTAMIDE (AFFIRM)
Adverse Event Author (year) Follow-up Enzalutamide % with AE Comparator % with AE
Abdominal pain NCT00974311 (2014) max: 3 yrs 0.13% 0.5%
Abnormalities in liver function tests Scher (2012) max: 2 yrs / med: 14.4 mos 0.5% 0.5%
Anaemia NCT00974311 (2014) max: 3 yrs 2.63% 3.01%
Arthralgia NCT00974311 (2014) max: 3 yrs 0.38% 0.25%
Asthenia NCT00974311 (2014) max: 3 yrs 0.38% 0.75%
Back pain NCT00974311 (2014) max: 3 yrs 1.38% 1.75%
Bone pain NCT00974311 (2014) max: 3 yrs 1.5% 1%
Cardiac disorders Scher (2012) max: 2 yrs / med: 14.4 mos 1% 2%
Constipation NCT00974311 (2014) max: 3 yrs 0.63% 0.75%
Diarrhoea Scher (2012) max: 2 yrs / med: 14.4 mos 1.0% 0.5%
Dyspnoea NCT00974311 (2014) max: 3 yrs 0.13% 0.25%
Fatigue Scher (2012) max: 2 yrs / med: 14.4 mos 6.0% 7%
Febrile neutropenia Not Available
Haematuria NCT00974311 (2014) max: 3 yrs 1.50% 1.25%
Nausea NCT00974311 (2014) max: 3 yrs 0.63% 0.75%
Neutropenia Not Available
Pain NCT00974311 (2014) max: 3 yrs 0.63% 0.25%
Pain in extremity NCT00974311 (2014) max: 3 yrs 0.38% 0.5%
Pyrexia NCT00974311 (2014) max: 3 yrs 0.25% 1.25%
Thrombocytopenia NCT00974311 (2014) max: 3 yrs 0.13% 0%
Urinary-tract infection NCT00974311 (2014) max: 3 yrs 0.88% 1.25%
Vomiting NCT00974311 (2014) max: 3 yrs 0.25% 2.01%
https://doi.org/10.1371/journal.pone.0195790.t004
Table 5. Median overall survival and progression-free survival hazard ratios (HRs) and 95% Credible Intervals
for cabazitaxel, abiraterone and enzalutamide using Bayesian fixed effects modeling.
Hazard Ratio 95% Credible Interval
Overall Survival
Cabazitaxel vs comparator 0.72 0.61–0.85
Abiraterone vs comparator 0.74 0.64–0.86
Enzalutamide vs comparator 0.63 0.53–0.75
Abiraterone vs Cabazitaxel 1.04 0.83–1.28
Enzalutamide vs Cabazitaxel 0.88 0.69–1.11
Enzalutamide vs Abiraterone 0.86 0.68–1.07
Progression-Free Survival
Cabazitaxel vs comparator 0.75 0.65–0.87
Abiraterone vs comparator 0.66 0.58–0.76
Abiraterone vs Cabazitaxel 0.88 0.72–1.07
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Additional analyses
We repeated analyses using a Frequentist model, a Bayesian fixed effects model, and a Bayesian
random effects model to understand the robustness of the results for overall survival. It should
be noted that the posterior distributions of the Bayesian random effects model are skewed, and
thus in the presence of skewed distributions, the median was used for inference. The three
approaches produced similar findings (Table 8).
Table 6. Odds ratios and 95% Credible Intervals for grade 3 and above adverse events.
Adverse Event Cabazitaxel vs AbirateroneCabazitaxel vs Enzalutamide
Odds Ratios 95% Credible Intervals Odds Ratios 95% Credible Intervals
Anaemia 3.71 1.01–10.44 3.99 0.89–12.24
Arthralgia 1.07 0.16–3.79 2.68 0.10–13.86
Asthenia 2.01 0.55–5.27 6.99 0.63–29.56
Back pain 2.04 0.76–4.50 1.95 0.44–5.54
Bone pain 0.48 0.07–1.45 0.27 0.56–1.03
Cardiac disorders 1.74 0.26–6.58 8.04 0.95–32.86
Constipation 4.28 0.24–21.05 5.63 0.24–29.43
Diarrhoea 16.60 1.41–75.31 11.44 0.55–56.73
Dyspnoea 2.59 0.32–10.13 72.84 0.09–178.30
Fatigue 2.01 0.79–4.33 2.13 0.79–4.76
Haematuria 3.88 1.03–10.09 0.81 0.16–2.43
Nausea 3.05 0.83–7.79 0.17 0.04–0.47
Neutropenia 5.14 0.42–19.98 NA NA
Pain 4.49 0.50–17.75 0.69 0.04–3.09
Pain in extremity 3.00 0.54–10.08 2.11 0.03–11.74
Pyrexia 9.92 0.46–52.19 36.23 1.14–206.40
Thrombocytopenia 6.61 0.48–31.99 NA NA
Urinary-tract infection 0.53 0.03–2.48 3.32 0.26–14.83
Note: all omitted AEs had a least one cell with 0 observations
Referent (or comparison) group
https://doi.org/10.1371/journal.pone.0195790.t006
Table 7. Comparison of age, ECOG score, and lengths of follow-up for overall survival (OS) and progression-free survival (PFS) for clinical trials used in the indi-
rect treatment comparison.
Study Total
Patients
Age ECOG Length of OS
follow-up
(median)
Length of PFS
follow-up (median)
Description of PFS
TROPIC 755 75 yrs: 18%;
median: 68
0–1: 93% 623.96 days Treatment: 85 days The earliest progression in tumor, PSA or pain or death
Comparator: 43
days
COU-AA-
301
1195 Treatment: 75 yrs:
25%; median: 69
Treatment: 0–1:
91%; 2: 9%
614.82 days Treatment: 170.45
days
Soft-tissue disease progression by modified Response
Evaluation Criteria In Solid Tumors (RECIST) criteria
Comparator: 75
yrs: 26%; median: 69
Comparator: 0–1:
92%; 2: 8%
Comparator: 109.57
days
AFFIRM 1199 Treatment: 75 yrs:
24.9%
0–1: 91.5%; 2:
8.5%
438.29 days Treatment: 252.63
days
Progression of soft-tissue disease according to RECIST,
version 1.1, progression of osseous disease according to
bone scans showing two or more new lesions per
PCWG2, and death from any cause.
Comparator: 75
yrs: 26.1%
Comparator: 88.27
day
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Discussion
Summary of evidence
Median OS was similar for cabazitaxel, abiraterone and enzalutamide. While median PFS was
modestly lower for abiraterone than cabazitaxel, the results of the exploratory analysis were
not statistically significant. Anaemia, diarrhoea and haematuria were statistically significantly
more likely to occur in the cabazitaxel group compared to abiraterone, while only pyrexia was
higher among those receiving cabazitaxel compared to those receiving enzalutamide. None of
the other AEs were statistically significantly different for the three groups.
Comparison to past studies
Four studies have conducted indirect treatment comparisons between abiraterone and enzalu-
tamide for overall survival [16–19], but these did not consider cabazitaxel in the analysis. Two
of the past studies [18,19] supported our findings for the indirect estimate of OS between abir-
aterone and enzalutamide (HR = 0.86; 95% CI 0.68–1.07). In modest contrast, an HR of 0.97
(95% CI = 0.75–1.25) for OS was reported in a study by Brodszky [16]. It appears that this
study included an interim report [20] and a final report [14] from the COU-AA-301 trial for
abiraterone in their indirect treatment comparisons which may have skewed their results. One
study [17] compared mean survival for the two groups and found that the mean survival for
enzalutamide (38.7 months; 95% CI = 36.4–40.7) was greater than the mean survival for abira-
terone (34.6 months; 95% CI = 31.8–37.8). However, the mean survival time is not informative
for understanding the efficacy of a drug on survival as all of the deaths in the study population
would have to be observed before a valid mean survival time could be calculated. Indirect
Table 8. Hazard ratios and 95% Credible Intervals for indirect treatment comparisons between cabazitaxel, abira-
terone and enzalutamide using Bayesian fixed and random effects and Frequentist fixed effects modeling.
Approach Hazard Ratio 95% Credible Interval
Bayesian Fixed Effects
Cabazitaxel vs comparator 0.72 0.61–0.85
Abiraterone vs comparator 0.74 0.64–0.86
Enzalutamide vs comparator 0.63 0.53–0.75
Abiraterone vs Cabazitaxel 1.04 0.83–1.28
Enzalutamide vs Cabazitaxel 0.88 0.69–1.11
Enzalutamide vs Abiraterone 0.86 0.68–1.07
Bayesian Random Effects
Cabazitaxel vs comparator 0.71 0.21–2.43
Abiraterone vs comparator 0.74 0.22–2.50
Enzalutamide vs comparator 0.62 0.19–2.16
Abiraterone vs Cabazitaxel 1.03 0.29–3.60
Enzalutamide vs Cabazitaxel 0.87 0.25–3.14
Enzalutamide vs Abiraterone 0.85 0.24–3.05
Frequentist Fixed Effects
Cabazitaxel vs comparator 0.72 0.61–0.84
Abiraterone vs comparator 0.74 0.64–0.86
Enzalutamide vs comparator 0.63 0.53–0.75
Abiraterone vs Cabazitaxel 1.03 0.83–1.28
Enzalutamide vs Cabazitaxel 0.88 0.69–1.11
Enzalutamide vs Abiraterone 0.85 0.68–1.07
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Indirect treatment comparison for cabazitaxel, abiraterone or enzalutamide among mCRPC patients
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estimates of median radiographic PFS for abiraterone and enzalutamide were similar (both
calculated an indirect HR = 0.61; 95% CI = 0.50–0.74) in two studies [18,19] while a third
study compared means of radiographic PFS [17]. We did not include enzalutamide in our
indirect treatment comparison analysis of PFS as the AFFIRM trial introduced heterogeneity
into the model. While three of the studies [16,18,19] also evaluated AEs, to our knowledge,
our study was the first to formally compare these outcomes for abiraterone, enzalutamide and
cabazitaxel.
Limitations
The main limitation of these analyses is the lack of a specified common comparator. While evi-
dence exists showing that survival among prostate cancer patients taking mitoxantrone/pred-
nisone and prednisone alone is similar [15], there is no evidence to support that PFS is similar
in these groups. The PFS analyses should be considered exploratory as the studies did not have
a consistent definition for PFS. The results for the analysis of AEs must be interpreted with
caution as well since patients treated with mitoxantrone/prednisone may experience different
rates of safety outcomes than those treated with prednisone alone [15]. Additionally, many of
the specific AEs were based on very small numbers resulting in unstable risk estimates, and fol-
low-up time varied between studies. The scarcity of clinical studies also limited the types and
numbers of analyses that could be performed, and brings with it the inability to conduct or
rely on the findings of the underlying tests of publication bias and study heterogeneity.
In order to conduct an indirect treatment comparison, treatments are compared through
their comparators. Given this, we were only able to identify three registrational trials con-
ducted pre-marketing to include in our study. In essence, the comparative assessment method-
ology was limited to randomized controlled trial-defined data reporting under circumstances
that do not reflect current therapeutic sequencing and utilization patterns that are based on
additional scientific evidence generated from post-marketing trials and observational studies.
The addition of new studies may change findings reported here.
Conclusions
In this analysis of pivotal clinical trial data, cabazitaxel, abiraterone and enzalutamide had sim-
ilar survival outcomes and AE profiles. To the best of our knowledge, this is the first indirect
treatment comparison including these 3 agents evaluating both efficacy and safety outcomes.
Data from future trials should be incorporated into this study framework to garner additional
information about the relative performance of these drugs.
Supporting information
S1 Table. PRISMA checklist.
(DOCX)
S1 Appendix. Complete search strategy.
(DOCX)
Author Contributions
Conceptualization: Jon P. Fryzek, Nicholas Summers, Robert Deuson, Dominik D. Alexan-
der, Jackie Vanderpuye-Orgle.
Data curation: Heidi Reichert, Nicholas Summers, Lindsay Townes.
Formal analysis: Jon P. Fryzek, Heidi Reichert, Lindsay Townes, Dominik D. Alexander.
Indirect treatment comparison for cabazitaxel, abiraterone or enzalutamide among mCRPC patients
PLOS ONE | https://doi.org/10.1371/journal.pone.0195790 April 11, 2018 13 / 15
Funding acquisition: Nicholas Summers, Jackie Vanderpuye-Orgle.
Investigation: Heidi Reichert, Nicholas Summers, Lindsay Townes.
Methodology: Jon P. Fryzek, Heidi Reichert, Lindsay Townes, Robert Deuson, Dominik D.
Alexander, Jackie Vanderpuye-Orgle.
Project administration: Nicholas Summers.
Software: Jon P. Fryzek, Heidi Reichert, Lindsay Townes, Dominik D. Alexander.
Supervision: Jon P. Fryzek, Nicholas Summers, Jackie Vanderpuye-Orgle.
Validation: Jon P. Fryzek, Dominik D. Alexander.
Visualization: Jon P. Fryzek, Heidi Reichert, Nicholas Summers, Lindsay Townes, Robert
Deuson, Dominik D. Alexander, Jackie Vanderpuye-Orgle.
Writing – original draft: Jon P. Fryzek, Heidi Reichert, Lindsay Townes, Robert Deuson,
Dominik D. Alexander.
Writing – review & editing: Jon P. Fryzek, Heidi Reichert, Nicholas Summers, Lindsay
Townes, Robert Deuson, Dominik D. Alexander, Jackie Vanderpuye-Orgle.
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