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The influence of prior novel androgen receptor targeted therapy on the efficacy of cabazitaxel in men with metastatic castration-resistant prostate cancer
European Journal of Cancer, Volume 51, Issue 17, November 2015, Pages 2562 - 2569
The treatment armamentarium for metastatic castration-resistant prostate cancer (mCRPC) has expanded with the introduction of several new therapies. In this treatment continuum, it is unclear whether the efficacy of cabazitaxel is affected by prior novel androgen receptor targeted therapies (ART) such as abiraterone and enzalutamide. In this study, we investigated the influence of prior ART on the efficacy of cabazitaxel in men with mCRPC.
Patients and methods
Data from an ongoing multicentre, phase II trial were used comprising 114 men with mCRPC treated with cabazitaxel in the post-docetaxel setting. The primary endpoints of the current analysis were prostate-specific antigen (PSA) response (⩾50%), and overall survival (OS). Univariate and multivariable analyses were conducted to investigate the influence of prior ART on the efficacy of cabazitaxel.
From the 114 patients included in this analysis, 44 men received prior ART and 70 men did not receive prior ART before treatment with cabazitaxel. PSA response rates while on cabazitaxel treatment were similar in patients with and without prior ART (34% versus 40%, respectively, P = 0.53). Likewise, median OS was not significantly different between men with and without prior ART (13.0 versus 14.0 months, respectively, logrank P = 0.65). In multivariable analysis, the only variables significantly associated with OS were performance status, serum albumin and alkaline phosphatase.
Our study showed that prior treatment with ART may not influence the efficacy of cabazitaxel in men with mCRPC. With emerging evidence of cross-resistance in the treatment of mCRPC, cabazitaxel provides a good treatment option irrespective of prior ART.
Keywords: Abiraterone, Cabazitaxel, Enzalutamide, Metastatic castration-resistant prostate cancer, Taxanes.
The treatment armamentarium for metastatic castration-resistant prostate cancer (mCRPC) has changed considerably over the past few years, with the introduction of several new drugs that provide substantial survival benefits , , , , , and . Cabazitaxel, abiraterone, enzalutamide and radium-223 all demonstrated to prolong life in the post-docetaxel setting and subsequently became approved for the treatment of this disease. Moreover, the novel androgen receptor (AR)-targeted therapies abiraterone and enzalutamide have shown survival improvement when used in chemotherapy-naïve mCRPC  and . These advances also come with new challenges. Although there are emerging biomarkers such as the androgen receptor splice variant AR-V7 , no established biomarkers for treatment selection exist at the current time and the optimal treatment sequence in mCRPC is still undetermined.
Retrospective studies suggested that overall survival benefit obtained by the new therapies cannot be added up, as cross-resistance between docetaxel and AR-targeted agents has been observed , , and . Reduced efficacy of docetaxel was observed in men with mCRPC who had previously been treated with abiraterone, suggesting clinical cross-resistance , , and . In a post-hoc analysis of the COU-AA-302 study, a prostate-specific antigen (PSA) response rate of 45% was observed in patients treated with taxane chemotherapy after abiraterone . This was slightly higher as compared to previous reports of docetaxel in this setting, with PSA response rates ranging from 26% to 40% , , and . However, the observed response rates were lower as compared with a contemporary cohort of abiraterone-naïve patients treated with docetaxel (PSA response rate ⩾50%: 64%), which might support the hypothesis of cross-resistance .
Preclinical studies revealed that the AR may confer cross-resistance between enzalutamide and docetaxel in vivo, which is induced by an overlapping working mechanism on AR nuclear translocation  and . These findings are confirmed in clinical studies , and raise concern whether prior treatment with abiraterone or enzalutamide may affect the efficacy of subsequent cabazitaxel treatment. Emerging preclinical and retrospective clinical data suggested that cabazitaxel, in contrast to docetaxel, has sustained efficacy in men with mCRPC after prior abiraterone treatment  and . In two retrospective studies, cabazitaxel efficacy after abiraterone treatment was investigated and compared to the TROPIC trial of cabazitaxel in abiraterone-naïve patients as an historical control group , , and . These studies suggested retained efficacy of cabazitaxel after prior abiraterone, as the observed PSA response rates were similar when compared to the TROPIC trial. However, to date, the efficacy of cabazitaxel has never been directly compared between patients with and without prior abiraterone or enzalutamide, which limits clinical conclusions.
In the current study, we aimed to investigate the influence of prior novel AR-targeted therapy (ART) on the efficacy of cabazitaxel. For this purpose, we used data from a randomised phase II trial to directly compare clinical outcome and response to cabazitaxel in men with and without prior ART.
2. Patients and methods
2.1. Study population and data collection
CABARESC (Dutch Trial Registry number: NTR 2991, EudraCT number: 2011-003346-40) is an ongoing randomised, open-label, multicentre, phase II trial that was designed to investigate the effects of budesonide on cabazitaxel induced diarrhoea. The primary endpoint of the original study was the incidence of grade 2–4 diarrhoea. In order to detect a reduction of 15% in grade 2–4 diarrhoea a total sample size of 250 patients was planned for this study. Eligible men were randomised to either cabazitaxel (25 mg/m2) and prednisone (10 mg daily) plus oral budesonide (9 mg daily during 44 days), or standard cabazitaxel 25 mg/m2 plus prednisone (10 mg daily). It has been shown previously that budesonide does not affect the pharmacokinetics of cabazitaxel .
Full inclusion and exclusion criteria of the CABARESC trial are shown in the Supplementary materials and methods. In brief, patients were eligible if they had mCRPC with documented disease progression during or after treatment with docetaxel, as defined by rising PSA levels, appearance of new lesions or documented disease progression based on CT scan or bone scan. Cabazitaxel treatment was continued until disease progression, unacceptable toxicity, or until 10 cycles have been administered. Administration of G-CSF was allowed during the study. Patients were randomly assigned to the treatment groups through a centralised stratified randomisation process using the following stratification factors: centre, age (⩾65 versus <65 years) and previous radiotherapy (yes versus no). In this study, data were prospectively collected at baseline and for every cycle including: heamatology and biochemistry laboratory values, performance status, age, prior treatment with ART, duration of treatment with ART, PSA values (every 3 weeks) and survival status.
For the current unplanned analysis, we included patients who were randomised and went off-study between December 2011 and May 2014. As the CABARESC study is still recruiting, the primary endpoint of the original study (incidence of grade 2–4 diarrhoea) was not reported, and no data per arm were analysed. The CABARESC study was approved by the institutional review board at each participating centre. Written informed consent was obtained from all participants. The study protocol allowed for secondary analyses that do not involve the primary endpoint of the CABARESC study to be conducted before reporting of the original study.
2.2. Data collection and definitions
The primary objective of the current analysis was to explore the influence of prior ART on the efficacy of cabazitaxel in men with mCRPC. Primary endpoints of this analysis were the proportion of patients with a ⩾50% PSA response, and overall survival (OS). As a secondary endpoint, we investigated PSA progression-free survival (PSA–PFS). For the definition of PSA response and PSA–PFS, Prostate Cancer Working Group 2 (PCWG2) criteria were used . As recommended by the PCWG2, PSA response was defined as ⩾50% decline from baseline, and PSA progression as a 25% increase (and a minimum of 2 ng/ml) from baseline or nadir. In most cases this was confirmed by a second measurement; however confirmation was not routinely performed for all patients. A taxane induced PSA flare during the first 12 weeks of treatment was ignored . OS was defined by time from randomisation to death from any cause. Since bone scans and CT-scans were not performed according to regular intervals in the study protocol, we did not include radiological PFS in our analyses.
Descriptive statistics were used to compare baseline characteristics in the ART pretreated versus non-pretreated patients, with statistical evaluation using Fisher’s exact test for categorical variables and Kruskal–Wallis test for continuous variables. OS and PSA–PFS were calculated using the Kaplan–Meier method with statistical evaluation by the logrank test.
2.3. Model building and statistical considerations
We conducted univariate and multivariable Cox regression analyses including prior treatment with ART (yes/no) and duration of prior ART to investigate its effect on PSA response and OS of men treated with cabazitaxel. For this purpose, Cox proportional hazards models were constructed including established prognostic factors from the Halabi nomogram : baseline serum PSA, lactate dehydrogenase (LDH), albumin, alkaline phosphatase, haemoglobin, and performance status. The multivariable model was constructed using backward elimination at the 5% level. A log transformation was applied to variables with a non-normal distribution.
3.1. Baseline characteristics
In the CABARESC trial, 141 patients were randomised and went off-study between December 2011 and May 2014. Of these 141 patients, 27 men were excluded from analysis for the following reasons: five patients had missing PSA values at baseline, nine patients were randomised but never received cabazitaxel treatment due to rapid worsening of performance status or death, and 13 patients had received previous study treatment with orteronel (Fig. 1). Patients who received prior orteronel were excluded from this analysis since this is not a clinically approved regimen in the treatment of mCRPC. All patients had received prior docetaxel chemotherapy. Forty-four out of 114 patients (39%) had received prior ART in the post-docetaxel setting, of whom 39 had received abiraterone, three had received enzalutamide, and two had received both abiraterone and enzalutamide. The remaining 70 patients had received no prior ART before study treatment with cabazitaxel.
Baseline characteristics of men with and without prior ART are shown in Table 1. Known prognostic variables were evenly distributed among subgroups, except for a significantly lower albumin level in men with prior ART (Table 1). The median number of cabazitaxel cycles received was six in the ART group, and five for men without prior ART.
|Characteristic||Prior abiraterone or enzalutamide||No prior abiraterone or enzalutamide||P-value|
|Number of patients||44||70|
|Age, years, median (range)||69 (53–83)||68 (49–82)||0.093|
|WHO performance score n (%)|
|0||18 (41)||25 (36)||0.56|
|1||25 (57)||44 (63)|
|PSA, ng/ml, median (range)||210 (15–5000)||154 (12.5–4172)||0.25|
|LDH at baseline, median (range)||287 (90–724)||273 (38–1843)||0.83|
|Haemoglobin at baseline, mmol/L, median (range)||8 (6–10)||8 (5–9)||0.96|
|Alkaline phosphatase at baseline, IU/L, median (range)||124 (50–907)||126 (43–1023)||0.83|
|Albumin at baseline, g/L, median (range)||37 (26–46)||41 (25–49)||0.013|
|Duration of treatment with abiraterone/enzalutamide, months, median (range)||6.1 (0.9–22)||–|
PSA – prostate-specific antigen; LDH – lactate dehydrogenase; WHO – World Health Organisation.
3.2. The influence of prior novel AR-targeted therapy on the efficacy of cabazitaxel
PSA response rates (⩾50%) while on cabazitaxel treatment were similar in patients with and without prior ART (34% versus 40% respectively, P = 0.53). Waterfall plots of the maximum PSA change while on cabazitaxel treatment for men with and without prior ART are shown in Fig. 2. Likewise, median PSA–PFS was not significantly different between the two groups. Men who received prior ART had a median PSA–PFS of 4.8 months, versus 6.5 months for men without prior ART (logrank P = 0.32) (Fig. 3A). Median OS was similar for patients previously treated with ART versus patients who were not previously treated with ART, with a median OS of 13.0 versus 14.0 months respectively (logrank P = 0.65) (Fig. 3B).
3.3. Univariable and multivariable analyses for OS and PSA response
Factors significantly associated with OS in univariate analysis are shown in Table 2 and included performance status, alkaline phosphatase, albumin, haemoglobin and LDH at baseline. Prior ART and the duration of prior ART were not significantly associated with OS (hazard ratio (HR) = 1.14; 95%confidence interval (CI): 0.66–1.97, P = 0.65 and HR = 1.00; 95%CI: 0.92–1.09, P = 0.98, respectively). From the significant variables in univariate analysis, a multivariate model for OS was constructed (Table 2). The only variables significantly associated with OS in multivariable analysis were performance status, alkaline phosphatase and albumin at baseline. Univariate logistic regression analyses for PSA response (⩾50%) are shown in Supplementary Table 1. Prior ART or the duration of prior ART were not significantly associated with PSA response (OR = 0.78; 95%CI: 0.35–1.70, P = 0.53 and OR = 1.00; 95%CI: 0.88–1.13, P = 0.98, respectively). Baseline haemoglobin was the only variable that was significantly associated with PSA response.
|Hazard ratio (95% CI)||P-value||Hazard ratio (95% CI)||P-value|
|Age (⩾median)||1.01 (0.97–1.05)||0.71|
|WHO performance score (1 versus 0)||1.83 (1.01–3.32)||0.039||2.23 (1.06–4.69)||0.035|
|Haemoglobin at baseline||0.68 (0.53–0.88)||0.005||0.88 (0.63–1.24)||0.47|
|PSA at baseline||1.12 (0.92–1.37)||0.26|
|Alkaline phosphatase at baseline||1.84 (1.31–2.60)||<0.001||1.65 (1.06–2.57)||0.026|
|LDH at baseline||1.69 (1.02–2.81)||0.049||0.74 (0.42–1.29)||0.29|
|Albumin at baseline||0.90 (0.86–0.95)||<0.001||0.87 (0.81–0.92)||<0.001|
|Prior novel AR-targeted therapy (yes/no)||1.14 (0.66–1.97)||0.65|
|Duration of prior AR-targeted therapy||1.00 (0.92–1.09)||0.98|
PSA – prostate-specific antigen; LDH – lactate dehydrogenase; AR – androgen receptor; OS – overall survival; CI – confidence interval.
In this study, prior ART did not influence the efficacy of cabazitaxel in patients with mCRPC. PSA response rates, OS and PSA–PFS were similar in patients with and without prior ART. The only variables significantly associated with OS were performance status, alkaline phosphatase and albumin at baseline.
We used data from a prospective phase II trial to directly compare the efficacy of cabazitaxel in men who received prior ART versus men who did not receive prior ART. To date, only two retrospective studies have been published that investigated the response of patients treated with cabazitaxel after abiraterone, which were limited by the use of a historical control group  and . In our study, we aimed to overcome this limitation by directly comparing clinical outcome and response to treatment with cabazitaxel between patients with and without prior ART, within the same study population. Our results strengthen the conclusions of the two previous studies  and  and confirm activity and lack of cross-resistance for cabazitaxel after prior ART in men with mCRPC.
Our observed PSA response rates in ART pretreated men (36%) are in line with those reported by Pezaro et al. and Al Nakouzi et al., which ranged from 40% to 45%  and . These findings are concordant with the TROPIC trial of cabazitaxel in ART-naïve men and with the ART-naïve patients in the current analysis, demonstrating PSA response to cabazitaxel in both second- and third line treatment for mCRPC . The only variable that was significantly associated with lower PSA response rates was haemoglobin (<median), which might reflect the worse prognostic features of this patient subgroup.
Taken together, these findings suggest that there might be no cross-resistance between ART and cabazitaxel. This is especially of interest, since an increasing number of reports have suggested impaired efficacy of docetaxel after abiraterone, suggesting cross-resistance with ART for this taxane , , and . Clinical cross-resistance could be explained by preclinical data from our group that showed an overlapping working mechanism on AR-nuclear translocation for both abiraterone and enzalutamide, as well as docetaxel  and . Docetaxel inhibited tumour growth and AR signalling in enzalutamide-naïve tumours, but did not in enzalutamide-resistant tumours, demonstrating cross-resistance between enzalutamide and docetaxel in vivo. Interestingly, in this preclinical model, cross-resistance was not observed for cabazitaxel, that demonstrated sustained antitumour activity even in tumours previously treated with enzalutamide . In the current analysis we confirmed these preclinical findings, showing similar activity of cabazitaxel either when delivered before or after ART. An explanation for the lack of cross-resistance for cabazitaxel could be that cabazitaxel, in contrast to docetaxel, is less dependent on the AR for exerting its antitumour activity . Moreover, it has been shown that cabazitaxel suppresses microtubule dynamics more potently as compared with docetaxel, with higher intratumoural concentrations, and stronger cytotoxic effects  and .
The main strength of our study is the use of prospective trial data to directly compare the efficacy of cabazitaxel in patients who did and did not receive prior ART within the same study population. Thus far, this is the only study that directly compared the influence of prior ART (post-docetaxel) on the efficacy of cabazitaxel. As an inherent limitation, the original CABARESC study was not designed for the aim of the current unplanned analysis and had a different primary endpoint. As a result, this study might be underpowered to detect a potential significant difference between patients with and without prior ART. In addition, some parameters such as Gleason score and the duration of response to LHRH agonists/antagonists have not been captured in our database. However, it has been shown previously that tumour differentiation and the duration of response to prior LHRH agonists/antagonists do not affect clinical outcome of men treated with cabazitaxel .
In conclusion, our study showed that prior treatment with ART may not influence the efficacy of cabazitaxel in men with mCRPC. With emerging evidence of cross-resistance between the currently available therapies in mCRPC, cabazitaxel provides a good treatment option both before and after novel AR-targeted therapies in the post-docetaxel setting.
Conflict of interest statement
RdW has received consultancy and speaker honoraria from Sanofi, Janssen, and Millenium, and Research funding from Sanofi. RvS has received research funding and speakers honoraria from Sanofi. RM has received research funding from Sanofi. AB has served on the advisory board of Sanofi. All remaining authors have declared no conflicts of interest.
We thank the patients who have participated in the CABARESC study and the investigators who recruited them. The CABARESC trial was supported by a research grant from Sanofi. The sponsor had no role in the design, execution or interpretation of the study.
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a Department of Urology, Erasmus University Medical Center and Cancer Institute, Rotterdam, The Netherlands
b Department of Medical Oncology, Erasmus University Medical Center and Cancer Institute, Rotterdam, The Netherlands
c Department of Biostatistics, Erasmus University Medical Center and Cancer Institute, Rotterdam, The Netherlands
d Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
e Department of Internal Medicine, Tweesteden Hospital, Tilburg, The Netherlands
f Department of Internal Medicine, Reinier de Graaf Hospital, Delft, The Netherlands
g Department of Clinical Trial Center, Erasmus University Medical Center and Cancer Institute, Rotterdam, The Netherlands
h Department of Internal Medicine, St Franciscus Gasthuis and Prostate Cancer Center, Rotterdam, The Netherlands
⁎ Corresponding author at: Department of Urology, Erasmus University Medical Center, Dr. Molewaterplein 50, Be-331, 3015 GE Rotterdam, The Netherlands. Tel.: +31 107043381; fax: +31 107044661.
1 The first two authors contributed equally to this article.
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