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Activity of Cabazitaxel in Castration-resistant Prostate Cancer Progressing After Docetaxel and Next-generation Endocrine Agents
European Urology, Volume 66 Issue 1, September 2014, Pages 459-465
Cabazitaxel, abiraterone, and enzalutamide are survival-prolonging treatments in men with castration-resistant prostate cancer (CRPC) progressing following docetaxel chemotherapy. The sequential activity of these agents has not been studied and treatment sequencing remains a key dilemma for clinicians.
To describe the antitumour activity of cabazitaxel after docetaxel and next-generation endocrine agents.
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 whom had received prior enzalutamide.
Outcome measurements and statistical analysis
Changes in prostate-specific antigen (PSA) level were used to determine activity on abiraterone, enzalutamide, and cabazitaxel treatment. Radiologic tumour regressions according to Response Evaluation Criteria in Solid Tumors (RECIST) and symptomatic benefit were evaluated for cabazitaxel therapy.
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-naïve cohort (n = 18), likely reflecting biologic differences in this cohort. These data were obtained from a retrospective analysis.
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.
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.
Keywords: Castration-resistant prostate cancer, Cabazitaxel, Abiraterone, Enzalutamide, Treatment sequencing.
Cabazitaxel is one of six survival-prolonging therapies now available for men with metastatic castration-resistant prostate cancer (CRPC) , , , , , and . The randomised phase 3 TROPIC trial, performed in the postdocetaxel setting but in abiraterone- and enzalutamide-naïve patients, demonstrated that cabazitaxel therapy was associated with a median 2.8-mo improvement in survival compared to mitoxantrone, 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 , , , and . Preclinical and translational data have suggested that taxanes may, in part, act by interrupting tubulin-dependent androgen receptor (AR) translocation to the nucleus  . We have previously reported lower than expected activity with docetaxel when used after abiraterone, suggesting the possibility of cross-resistance between these agents  , 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 enzalutamide 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 participants 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  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 μg/l  . 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  . 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  . 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).
3.1. 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-naïve 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.
|Prior abiraterone with or without enzalutamide
(n = 37)
|Abiraterone-naïve (n = 22)|
(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)|
|Interval on abiraterone, mo, median||7.2||–||–|
|Interval on enzalutamide, mo, median||10.9 †||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)|
|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)|
|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)|
|Baseline laboratory values, median|
|– Haemoglobin, g/l (normal range: 130–170)||10.9 ‡||11.7||10.7|
|– ALP, U/l (normal range: 24–110)||150 ‡||214||165|
|– Albumin, g/l (normal range: 30–50)||34 ‡||35||33|
|– LDH, U/l (normal range: 98–192)||217 ‡||207||288|
|– PSA, μg/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)|
|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 for seven patients.
** NA for four patients.
† n = 5 patients.
‡ NA for three patients.
# NA for one patient.
§ NA in two patients.
∧ No CI data.
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.
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 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 treatment 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-naïve 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 of 10.8 mo (range: 5.2–14.6 mo). One patient (20%) had a ≥50% PSA decline while on enzalutamide therapy.
3.2.3. Response to cabazitaxel
Of these 37 patients, 15 (41%) had a ≥50% PSA decline while receiving cabazitaxel ( Table 2 ). A median of six cycles of cabazitaxel were delivered (four patients ongoing at the time of analysis). Of 20 patients with RECIST-evaluable disease, three (15%) achieved a confirmed partial response on treatment. Of 33 evaluable patients (no baseline pain in four patients), symptomatic benefit was observed in 9 (27%). As shown in Table 3 and Figure 1 , there was no correlation between a favourable biochemical response to abiraterone and response to subsequent cabazitaxel. Of 14 patients who had a ≥50% decline in PSA level while on abiraterone, four (29%) had a ≥50% decline in PSA on cabazitaxel treatment, whereas of the 23 patients with <50% decline while on abiraterone, 11 (49%) had a ≥50% PSA decline while on subsequent cabazitaxel treatment ( Table 4 ).
|Prior abiraterone with or without enzalutamide (n = 37)||Abiraterone-naïve (n = 22)|
|Prior enzalutamide (n = 4)||Enzalutamide-naïve (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.
|≥50% PSA decline, no. (%)||Comments||<50% PSA decline, no. (%)||Comments||≥50% PSA decline, no. (%)||<50% PSA decline, no. (%)||Comments|
|Discontinued due to PD (n = 12)||2 (17)||Plus 2 patients who received abiraterone before docetaxel||7 (58)||Plus 1 patient who received abiraterone before docetaxel||3 (25)||8 (67)
(Included all 3 pre-docetaxel abi patients)
|NA = 1|
|Discontinued without PD (n = 25)
(EOT = 16, toxicity = 7, NA = 2)
|9 (36)||Plus 1 patient who received abiraterone before docetaxel||15 (60)||–||12 (48)||12 (48)
(Included the pre-docetaxel abiraterone patient)
|NA = 1|
PSA = prostate-specific antigen; PD = progressive disease; NA = not available; EOT = end of treatment cycles.
|≥50% PSA decline, no. (%)||<50% PSA decline, no. (%)|
|≥50% PSA decline (n = 14)||4 (29)||10 (71)|
|<50% PSA decline (n = 23)||11 (49)||12 (52)|
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 nomogram.
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-naïve cohort
3.4.1. Response to docetaxel
In the patients treated with docetaxel followed by cabazitaxel (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.
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 16 patients evaluable for symptomatic benefit (no pain at 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.
We report significant antitumour activity with cabazitaxel in abiraterone- and enzalutamide-naïve 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  . 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  and  and has a low affinity for the adenosine triphosphate-dependent P-glycoprotein, a drug efflux pump associated with taxane resistance , , and . Since the AR amino-terminal domain has been reported to be critically important to tubulin binding  , 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 ineffective 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.
Currently, no consensus on treatment sequencing exists and, in the absence of predictive markers, all approved postdocetaxel 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.
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Prostate Cancer Targeted Therapy Group and Academic Urology Unit, Royal Marsden NHS Foundation Trust and Institute of Cancer Research, Sutton, Surrey, UK
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.
© 2013 European Association of Urology, Published by Elsevier B.V.