Platinum Priority – Prostate Cancer
Editorial by Bertrand Tombal on pp. 236–237 of this issue

Cabazitaxel Remains Active in Patients Progressing After Docetaxel Followed by Novel Androgen Receptor Pathway Targeted Therapies

By: Nader Al Nakouzi a , Sylvestre Le Moulec b , Laurence Albigès c , Chris Wang a , Philippe Beuzeboc d , Marine Gross-Goupil e , Thibault de La Motte Rouge f , Aline Guillot g , Dorota Gajda h , Christophe Massard c , Martin Gleave a , Karim Fizazi c and Yohann Loriot c

European Urology, Volume 68 Issue 2, August 2015, Pages 228-235

Published online: 28 August 2015

Keywords: Prostate cancer, Metastatic, Cabazitaxel, Abiraterone

Abstract Full Text Full Text PDF (1,5 MB) Patient Summary



Cabazitaxel, abiraterone acetate (AA), and enzalutamide have been approved for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) following docetaxel chemotherapy. Whether taxanes and next-generation androgen receptor (AR) axis inhibitors are cross-resistant or not is a subject of debate.


To evaluate the antitumour activity of cabazitaxel in mCRPC pretreated with abiraterone or enzalutamide.

Design, setting, and participants

The antitumour activity of cabazitaxel was assessed in patients with mCRPC and progressive disease after treatment with docetaxel and AA. In parallel, cabazitaxel antitumour activity was studied in enzalutamide-resistant models.

Outcome measurements and statistical analysis

Changes in prostate-specific antigen (PSA) levels and progression-free survival were used to determine the activity of cabazitaxel treatment. Cell proliferation, immunofluorescence, and AR transactivation assay were used in enzalutamide-resistant models.

Results and limitations

A total of 79 patients who had progressive mCRPC after docetaxel (median: 8 cycles; range: 4–12 mo), and AA (median: 4.8 mo; range:1–55 mo) received cabazitaxel 25 mg/m2 every 3 weeks (median: 6 cycles; range:1–15 cycles). A PSA decline ≥30% was achieved in 48 patients (62%; 95% confidence interval [CI], 51–73), and a decline ≥50% was achieved in 28 patients (35%; 95% CI, 25–47). The median progression-free survival and overall survival were 4.4 and 10.9 mo, respectively. In vitro, cabazitaxel decreased cell viability in both enzalutamide-sensitive and enzalutamide-resistant prostate cancer cells within the same range of concentrations. PC3, an AR-negative cell line, exhibited similar sensitivity to cabazitaxel.


Cabazitaxel and AR-pathway inhibitors are not cross-resistant. Preclinical data suggest that cabazitaxel activity does not act mainly through AR axis inhibition.

Patient summary

The antitumour activity of cabazitaxel, a chemotherapy agent, was studied in prostate cancer resistant to conventional hormonal therapy and to more recent endocrine therapies (abiraterone or enzalutamide). Cabazitaxel retained anticancer activity in more than half of the cases.

Take Home Message

The aim of our study was to evaluate the antitumour activity of cabazitaxel after abiraterone or enzalutamide. Cabazitaxel retains clinical activity in patients with castration-resistant prostate cancer pretreated with docetaxel and abiraterone. Preclinical data suggest that cabazitaxel activity does not act mainly through androgen receptor axis inhibition.

Keywords: Prostate cancer, Metastatic, Cabazitaxel, Abiraterone.

1. Introduction

Greater understanding of the biology of metastatic castration-resistant prostate cancer (mCRPC) over the last decade has led to multiple agents being added to the therapeutic armamentarium [1]. Resistance to castration involves androgen receptor (AR) modifications and extratesticular ligand biosynthesis, and, at least in some cases, non–AR axis-related mechanisms of activated cell proliferation [1] and [2]. In patients with mCRPC, two AR axis inhibitors have improved overall survival (OS): abiraterone, a CYP17 inhibitor [3], [4], and [5], and enzalutamide, an AR inhibitor [6]. Cabazitaxel, a second-generation taxane [7], radium-223, [8], and sipuleucel-T [9] have also improved OS in patients with mCRPC raising the question of how these agents should be used to achieve optimal medical management.

Some evidence suggests cross-resistance between these agents. Retrospectives analyses provide data that enzalutamide has limited activity in patients progressing after abiraterone with similar data regarding reverse sequential administration of enzalutamide followed by abiraterone [10], [11], [12], and [13]. The issue of cross-resistance between taxanes and AR-targeted agents was brought to the fore following preclinical and clinical data showing that taxanes may also interfere with AR itself [14], [15], and [16]. A retrospective study of docetaxel in 35 abiraterone-pretreated mCRPC patients showed that abiraterone-refractory patients were unlikely to respond to subsequent docetaxel-based chemotherapy [17]. However, subanalyses from the AFFIRM study demonstrated the efficacy of enzalutamide despite previous docetaxel exposure, suggesting that cross-resistance may not occur between the two drugs [18].

Because cabazitaxel has been approved for the treatment of docetaxel-pretreated CRPC patients and is currently being investigated in chemotherapy-naive mCRPC patients, our aim was to determine whether cabazitaxel efficacy may be affected by AR-pathway inhibitors.

2. Methods

2.1. Patients

Using systematic chart reviews, we identified the records of all patients with mCRPC previously treated with docetaxel and abiraterone (sometimes followed by enzalutamide) and receiving cabazitaxel as third-line therapy in five institutions in France. All patients were required to have castrate levels of testosterone, and castration was maintained with luteinising hormone-releasing hormone agonists during subsequent therapies. The following data were collected for all patients from the medical record history: age, site and number of metastases, Eastern Cooperative Oncology Group performance status, and previous treatments. Initiation of treatment with cabazitaxel followed standard clinical practice guidelines including adequate haematology and biochemistry requirements. Cabazitaxel was given intravenously 25 mg/m2 every 3 wk combined with 10 mg prednisone daily. Prostate-specific antigen (PSA) response was evaluated every 4 wk and assessed using Prostate Cancer Working Group 2 criteria [19]. Progression-free survival (PFS) was defined as the time from the date of the initiation of cabazitaxel to the first documentation of disease progression (PSA or radiographic) or to death from any causes, whichever occurred first. OS was measured from the date of the initiation of cabazitaxel to the date of death or of the last follow-up.

2.2. Cell lines

LNCaP cells were provided by Dr. Leland W.K. Chung (Cedar Sinai, Los Angeles, CA, USA). We tested and authenticated the cell lines by whole-genome and whole-transcriptome sequencing on the Illumina Genome Analyzer IIx platform in July 2009. They were maintained in RPMI-1640 supplemented with 5% foetal bovine serum (Invitrogen Life Technologies). LNCaP-CRPC xenografts and enza-R cells were obtained as previously described [20]. Details on MR49C, MR49F, and cabazitaxel-resistant 22RV1 cells are provided in the Supplement [21].

2.3. Reagents

The synthetic androgen R1881 was from PerkinElmer, cabazitaxel was supplied by Pfizer Inc., and customised synthetic enzalutamide and abiraterone were purchased from Shanghai Haoyuan Chemexpress. AR and PSA antibodies were purchased from Santa Cruz Biotechnology and the vinculin antibody from Sigma Chemical Co. Details on AR small interfering RNA are provided in the Supplement.

2.4. In vitro assays

The impact of AR expression on the efficacy of cabazitaxel was assessed by using AR transactivation, cell proliferation assays, and immunofluorescence as well as Western blot analyses. Details on these in vitro experiments are provided in the Supplement [22].

2.5. Statistical analyses

For in vitro experiments, data were analysed statistically using a one-way analysis of variance test, and a p < 0.05 was considered significant. The Student t test (two sided) was used to evaluate statistically significant differences in all experiments. For clinical data, baseline was defined as the date of cabazitaxel initiation. Continuous baseline characteristics were expressed as median, range (minimum-maximum), and interquartile range; the number and percentage of patients were provided for categorical variables. Response was defined using the PSA criterion: Patients with a decrease in PSA >50% were considered responders. The proportion of patients with PSA response >50% and its 95% Clopper-Pearson exact confidence interval (CI) were provided. Distributions of continuous variables in responders and in nonresponders were compared using a nonparametric Mann-Whitney test. The PFS and OS were estimated using the Kaplan-Meier method with Rothman's 95% CI and compared across the groups using the log-rank test. All analyses were done using SAS software v.9.3 (Cary, NC, USA).

3. Results

3.1. Cabazitaxel retains clinical activity in abiraterone-pretreated patients

To investigate the activity of cabazitaxel in patients pretreated with AR-pathway inhibitors, we retrospectively collected clinical data from 79 patients previously treated with docetaxel and abiraterone, and subsequently treated with cabazitaxel between September 2011 and April 2013. Table 1 shows the patient characteristics. All patients treated with third-line cabazitaxel had received first-line chemotherapy with docetaxel (median: 8 cycles; range: 3–15 cycles) and then abiraterone in the post-docetaxel setting (median: 4.8 mo; range: 1–18 mo). Six patients (8%) experienced disease progression on enzalutamide.

Table 1

Patient characteristics (n = 79)

Patient characteristicsNo. of patients (%)
Age, yr
 Quartiles: P25–P7562–75
ECOG PS score
 0–147 (59)
 ≥230 (38)
 Missing2 (3)
 No15 (20)
 Yes62 (79)
 Missing1 (1)
Bone metastasis
 No23 (29)
 Yes56 (71)
Visceral metastasis
 No68 (86)
 Yes11 (14)
PSA, ng/ml
 Quartiles: P25–P75190–1125
Haemoglobin, g/dl
 Quartiles: P25–P759–11
ALP, units/l
 Quartiles: P25–P7595–484
LDH, unit/l
 Quartiles: P25–P75206–526
Albumin, g/l
 Quartiles: P25–P7529–33

ALP = alkaline phosphatase; ECOG PS = Eastern Cooperative Oncology Group performance status; LDH = lactate dehydrogenase; PSA = prostate-specific antigen.

All patients received the first cycle of cabazitaxel at the planned dose of 25 mg/m2 every 3 wk. The median number of cabazitaxel cycles was 6 (range: 1–15 cycles), over a median duration of 4 mo (range: 1–10 mo). Overall, 28 patients (35%; 95% CI, 25–47) had ≥50% PSA decline. A PSA decline >30% was achieved in 48 patients (62%; 95% CI, 51–73). To compare the observed proportion to the one from the TROPIC study, a binomial proportion was performed to test the null hypothesis (H0: p = 39.2%). The comparison of the observed proportion of PSA responders (35%; 95% CI, 25–45 in a PSA decline >50%) to the proportion of PSA responders of 39.2% observed in the TROPIC study was not significantly different in our study.

Figure 1A shows a waterfall plot of PSA declines. No correlation was found between PSA declines on cabazitaxel and the median duration of docetaxel or abiraterone acetate therapies (Table 2). The median OS and PFS was 10.9 mo (95% CI, 8–14) and 4.4 mo (95% CI, 3.5–5.2), respectively (Fig. 1B and 1C). In PSA responders at the >50% level, the median OS and PFS were 14.3 mo (95% CI, 9–16.4) and 5.8 mo (95% CI, 4.6–8.7), respectively. In PSA responders at the >30% level, the median OS and PFS were 14.3 mo (95% CI, 8.1–6.4) and 4.8 mo (95% CI, 4.1–6.8), respectively.


Fig. 1

Waterfall plots of maximal prostate-specific antigen (PSA) changes on cabazitaxel therapy. (A) Response for each patient is plotted (n = 79); (B) overall survival of patients treated with cabazitaxel; (C) progression-free survival (PFS) of patients treated with cabazitaxel.

Table 2

History of cabazitaxel, docetaxel, and abiraterone and changes in prostate-specific antigen levels over time in cabazitaxel-sensitive* and cabazitaxel-insensitive patients (n = 79)

PSA response
No PSA responsePSA response
No. of patients5128
Baseline PSA
 Quartiles: P25–P75165–502220–1694
No. of cabazitaxel cycles
No. of docetaxel cycles
No. of abiraterone cycles

* Defined as a decline in PSA of 50%.

PSA = prostate-specific antigen.

3.2. No preclinical evidence for cross-resistance between AR axis inhibitors

To investigate the impact of AR on cabazitaxel efficacy, we used a preclinical model of enzalutamide resistance because enzalutamide was shown to efficiently inhibit the AR in mCRPC [6]. Third-generation transplanted enzalutamide-resistant xenograft tumours, obtained as described in the Methods section, were harvested, and single-cell suspensions were grown in culture under the constant pressure of 10 μmol/l enzalutamide to generate enzalutamide-resistant MR49F and MR49C cells. Enza-R cells continued to express both AR and PSA protein, which was not affected by enzalutamide treatment [20]. We showed that cabazitaxel was able to decrease cell viability in both enza-S cells and enza-R cells within the same range of concentration (Fig. 2A). By contrast, enza-R cells were less sensitive to abiraterone compared with mCRPC parental cells, indicating that the cross-resistance between AR axis inhibitors may occur (Supplemental Fig. 1). AR and PSA were differentially expressed across the cell lines exposed to cabazitaxel at the half maximal inhibitory concentration (IC50) (Fig. 2B). The AR-negative cell line PC3 exhibited similar sensitivity to cabazitaxel. Conversely, the cabazitaxel-resistant 22RV1 cells still exhibited sensitivity to both enzalutamide and abiraterone as compared with the parental cells (Fig. 2C). Taken together, these data provide no evidence for cross-resistance between the AR axis inhibitors and cabazitaxel.


Fig. 2

(A) LNCaP, PC3, enza-R MR49C, and CRPC-V16D cells were exposed to increasing concentrations of cabazitaxel (Caba) for 48 h, and half maximal inhibitory concentration (IC50) was determined using WST-1 cell survival assay. (B) Whole cell extracts of CRPC-V16D and enza-R cells were subjected to immunoblotting after a 48-h exposure to 0, 2.5, or 10 nmol/l Caba with specific antibodies for androgen receptor (AR), prostate-specific antigen (PSA), or vinculin (Vinc) (loading control). (C) Parental and resistant 22RV1 cell lines were exposed to increasing concentrations of Caba, enzalutamide (ENZ), or abiraterone (Abi) for 48 h, and IC50 ranges were determined using WST1 assay and GraphPad Prism for analysis.

3.3. Cabazitaxel activity does not act mainly through AR pathway inhibition

Some previous studies reported that taxanes were able to impede AR translocation into the nucleus, suggesting that taxanes act in mCRPC patients, at least in part, by inhibiting AR nuclear transport and signalling [15] and [16]. Given the lack of cross-resistance between AR axis inhibitors and cabazitaxel, we first hypothesised that cabazitaxel was more potent than docetaxel at blocking the AR trafficking to the nucleus. To address this question, we compared side-by-side docetaxel and cabazitaxel to block AR transcriptional activity in a luciferase reporter assay in both enza-S and enza-R cells. As shown in Figure 3A, we did not find any significant difference between the two agents in the level of inhibition of AR transcriptional activity in prostate cancer cells exposed to R1881 (except for MR49C cells).


Fig. 3

(A) Enza-R (MR49C and MR49F) and enza-S cells (CRPC-V16D) (2.5 × 105) were plated on six-well plates and transfected with probasin luciferase reporter along with Renilla plasmid and then treated with cabazitaxel (Caba) or docetaxel (Doce) for 12 h before exposure to R1881 (1 nmol/l) for 4 h. All experiments were carried out in triplicate wells and repeated three times. (B) Inhibition of androgen receptor (AR) expression in CRPC-V16D and Enz-R49C cells after a 48-h transfection with small interfering RNA (siRNA) targeting AR (siAR). Cells transfected with a nontargeted siRNA (siSCR) were used as control. Western blot analysis was performed using specific antibodies for AR or vinculin. Half maximal inhibitory concentration ranges were calculated comparing AR-depleted cells (siAR) with control (siSCR). These data are representative of three independent experiments.

To address the alternative hypothesis of whether or not the activity of cabazitaxel is mediated by AR modulation, we assessed the efficacy of cabazitaxel on both enza-S and enza-R cells upon AR silencing. The IC50 value was not affected by AR downregulation, suggesting that cabazitaxel kills cells mainly via AR-independent mechanisms (Fig. 3B). We next sought to investigate, using a luciferase reporter assay, whether or not cabazitaxel was able to inhibit AR transcriptional activity in a clinically relevant model in which AR is localised in the nucleus before cabazitaxel treatment. Whereas cabazitaxel was able to block AR transcriptional activity when it was given before R1881 exposure (Fig. 3A), AR transcriptional activity was not inhibited in reverse sequence administration of R1881 before cabazitaxel exposure (Fig. 4A). Consistent with these data, there was no significant impact of cabazitaxel on AR localisation. Enza-S and enza-R cells were treated with cabazitaxel before or after adding R1881 (Fig. 4B) and analysed for evidence of R1881-induced AR nuclear accumulation by confocal microscopy. Cabazitaxel did not induce a significant decrease in AR nuclear accumulation, neither at baseline nor following R1881 treatment. When cells were treated with cabazitaxel before exposure to R1881, some cellular features suggestive of mitotic catastrophe (MC) were observed along with cytoplasmic localisation of AR (Fig. 4B). Thus our data suggest that the cytoplasmic localisation of AR upon cabazitaxel exposure is mostly due to cell-cycle arrest rather than a direct effect on AR itself.


Fig. 4

(A) Enza-R and enza-S cells (2.5 × 105) were plated on six-well plates and transfected with probasin luciferase reporter along with Renilla plasmid as in Figure 3A and then exposed to R1881 (1 nmol/l) for 4 h before being treated with cabazitaxel (caba) for 12 h. All experiments were carried out in triplicate wells and repeated three times. (B) CRPC-V16D cells were treated with cabazitaxel (10 nmol/l), R1881 (1 nmol/l), caba then R1881 or reverse sequence (R1881 then caba). Androgen receptor (AR) localisation was assessed by immunofluorescence as described in the Methods section. Cellular features of mitotic catastrophe (multiple nuclei cells) are shown by arrows.

4. Discussion

In this study, we provided evidence for anticancer activity of cabazitaxel in mCRPC patients pretreated with docetaxel and abiraterone. PSA responses were found in a large proportion of 79 patients with mCRPC progressing after docetaxel and abiraterone. Preclinical data suggest that cabazitaxel-induced inhibition of AR nuclear translocation is a late event resulting from MC. Furthermore, we found no difference between cabazitaxel and docetaxel in their ability to inhibit AR-induced PSA gene transactivation. Taken together, the clinical data from abiraterone-pretreated patients and preclinical data in enzalutamide-resistant cells suggest limited or an absence of cross-resistance between cabazitaxel and AR-pathway inhibitors, thus further supporting the role of cabazitaxel in prostate cancer [23].

Recent retrospective studies suggested a degree of cross-resistance between the new approved agents in mCRPC. We and others reported limited activity of abiraterone in enzalutamide-pretreated patients [10] and [11]. Two recent studies also reported similar data regarding reverse sequential administration of enzalutamide followed by abiraterone [12] and [13]. Our preclinical data confirmed the existence of cross-resistance between AR axis inhibitors supporting the validity of our preclinical model (Supplemental Fig. 1). Previous reports suggested that taxanes inhibit ligand-induced AR nuclear translocation and downstream transcriptional activation of AR target genes [14], [15], and [16]. However, clinical extrapolation of these studies was compromised by the use of paclitaxel, a nonapproved agent in mCRPC, and/or a dose far higher than the IC50 value (2–10 nmol/l) [24] and [25]. Taxane-induced inhibition of AR trafficking into the nucleus may be seen as a result of MC occurring within the first 24 h of exposure to taxanes and not a direct AR-targeting effect. Unlike apoptosis or senescence, the likely mechanism for taxane-induced MC involves the disruption of mitotic cell division by the drug's inhibition of the dynamic reorganisation of microtubules. MC is an onco-suppressive pathway that precedes cell death or senescence with cells frequently exhibiting gross nuclear alterations (e.g., micro- and multinucleation) after aberrant mitosis. MC is initiated during the M phase of the cell cycle by perturbations of the mitotic apparatus (ie, chromosomes and the complex machinery that ensure their faithful segregation) [26]. To our knowledge no hormone therapy was reported to induce MC, and in our experiments abiraterone and enzalutamide did not induce MC. At the dosages and time points examined in this study, after cabazitaxel treatment, MC was the predominant mechanism of cell death observed in all three cell lines, with a lesser contribution by other modes of death. These data suggest that the effect of cabazitaxel on AR translocation should be mostly viewed as a consequence of MC induction and not as a direct interaction between cabazitaxel and AR itself. The lack of an impact of AR silencing on cabazitaxel efficacy along with cabazitaxel activity in AR-negative PC3 prostate and other cancer types support this hypothesis.

A recent preclinical study reported limited activity of docetaxel and cabazitaxel against the AR-targeted resistant PC346 prostate cancer cell line, compared with the nonresistant cell line, suggesting evidence for in vitro cross-resistance [27]. In an experiment using the hep3B hepatocarcinoma cell line, docetaxel and cabazitaxel were shown to inhibit AR nuclear translocation. However, hep3B cells were treated at a dose of 1 μmol/l for 48 h that was reported to induce massive cell death by apoptosis in hep3B cells, making it difficult to interpret the experiments. We speculate that the duration of exposure to taxanes was too short (4 h) to assess the mitosis-dependent cellular effects of both agents on AR translocation in PC346 prostate cancer cells (doubling time: 3–4 d) [28].

Our clinical data in 79 patients demonstrated that cabazitaxel still exerts activity after abiraterone and docetaxel therapy, thus arguing against complete cross-resistance between AR-targeted agents and cabazitaxel. Our study showed that in the 79 patients progressing on docetaxel and abiraterone, cabazitaxel resulted in a PSA decline >50% in 35% of patients. These results are similar to those reported in the phase 3 TROPIC study of cabazitaxel in patients with mCRPC who progressed during or after treatment with docetaxel, suggesting that complete cross-resistance between cabazitaxel and abiraterone does not occur [7]. OS and PFS in our cohort were lower compared with TROPIC, probably because the patients enrolled in our retrospective study were not fit enough to be enrolled into clinical trials and had a poor prognosis. To our knowledge, no data are available for abiraterone-pretreated patients with other chemotherapy regimens like mitoxantrone/prednisone or carboplatin/etoposide [29]. A single-institution study recently reported the antitumour activity of docetaxel in a retrospective cohort of 35 abiraterone-pretreated patients, with a PSA decline ≥50% in only 26% of patients and a median OS of 12.5 mo [17]. However, recent subanalyses of the AFFIRM study did not demonstrate any association between the duration of docetaxel therapy and the efficacy of enzalutamide [18]. No study assessing the potential cross-resistance between enzalutamide and taxanes has been reported so far. Well-designed prospective studies to accurately address the question of cross-resistance are needed.

5. Conclusions

Cabazitaxel remains active in patients progressing after docetaxel followed by novel AR-pathway targeted therapies. Even our preclinical data suggest that cabazitaxel activity is not mainly mediated through direct AR inhibition, AR is still relevant in the abiraterone and enzalutamide resistance setting because PSA is often increasing when the patient develops resistance to abiraterone or enzalutamide, paving the way to a combination of cabazitaxel and AR-pathway inhibitors.

Author contributions: Yohann Loriot 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: Loriot, Massard, Al Nakouzi, Le Moulec.

Acquisition of data: Loriot, Massard, Al Nakouzi, Le Moulec, Beuzeboc, Gross-Goupil, de La Motte Rouge, Guillot.

Analysis and interpretation of data: Loriot, Al Nakouzi, Massard, Gajda.

Drafting of the manuscript: Loriot, Al Nakouzi, Massard.

Critical revision of the manuscript for important intellectual content: Al Nakouzi, Le Moulec, Albigès, Wang, Beuzeboc, Gross-Goupil, de La Motte Rouge, Guillot, Gajda, Massard, Gleave, Fizazi, Loriot.

Statistical analysis: Loriot, Massard, Al Nakouzi, Gajda.

Obtaining funding: Loriot, Massard.

Administrative, technical, or material support: Loriot, Massard, Al Nakouzi.

Supervision: Loriot, Massard.

Other (specify): None.

Financial disclosures: Yohann Loriot 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: Sylvestre Le Moulec receives honoraria and consulting fees from Sanofi-Aventis, Bayer, and Astellas. Laurence Albigès receives honoraria from Sanofi-Aventis. Philippe Beuzeboc, Marine Gross-Goupil, Thibault de La Motte Rouge, Christophe Massard, Karim Fizazi, and Yohann Loriot receive honoraria and consulting fees from Sanofi-Aventis, Jansen-Cilag and Astellas. Aline Guillot receives honoraria and consulting fees from Sanofi-Aventis, Jansen-Cilag, and Pfizer. Nader Al Nakouzi, Chris Wang, Martin Gleave, and Dorota Gajda have nothing to disclose.

Funding/Support and role of the sponsor: None.

Acknowledgments: We thank Lorna Saint Ange for editing.

Appendix A. Supplementary data


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a Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada

b Department of Medical Oncology, Val de Grâce Hospital, Paris, France

c Department of Cancer Medicine, Gustave Roussy, Cancer Campus, Grand Paris, University of Paris-Sud, and INSERM U981, Villejuif, France

d Department of Medical Oncology, Institut Curie, Paris, France

e Department of Medical Oncology, CHU de Bordeaux, Bordeaux, France

f Pitié-Salpetrière Hospital, Paris, France

g Institut de Cancérologie de la Loire, Saint-Etienne, France

h Biostatistics and Epidemiology unit, Institut Gustave Roussy, Cancer Campus, Grand Paris, Villejuif, France

Corresponding authors. Department of Cancer Medicine, Institut Gustave Roussy, Cancer Campus, Grand Paris, University of Paris-Sud, and INSERM U981, 114 rue Edouard Vaillant, 94800 Villejuif, France.

These authors contributed equally to this work.

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