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Efficacy of Enzalutamide Following Abiraterone Acetate in Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer Patients
EURURO-5717; No. of Pages 7 EUROPEAN UROLOGY XXX (2014) XXX–XXX
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Efficacy of Enzalutamide Following Abiraterone Acetate in Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer Patients Arun A. Azad, Bernhard J. Eigl, R. Nevin Murray, Christian Kollmannsberger, Kim N. Chi * Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
Article info
Abstract
Article history: Accepted June 23, 2014
Background: The activity of enzalutamide after prior treatment with both abiraterone acetate (abiraterone) and docetaxel has been examined in several retrospective studies. However, limited data are available on the efficacy of enzalutamide following abiraterone in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC). Objective: To compare the activity of enzalutamide after abiraterone in docetaxelexperienced and docetaxel-naive mCRPC patients. Design, setting, and participants: The British Columbia Cancer Agency Cancer Registry was searched for mCRPC patients who received enzalutamide after prior abiraterone. Clinicopathologic characteristics, confirmed prostate-specific antigen (PSA) response rates (PSA decline 50% confirmed 3 wk later), and survival data were collected. Outcome measurements and statistical analysis: Outcomes on enzalutamide were compared between docetaxel-experienced and docetaxel-naive patients using chisquare for PSA response and log-rank test for time to PSA progression and overall survival (OS). Univariate analysis was performed to identify variables associated with confirmed PSA response on enzalutamide, using either chi-square for categorical variables or logistic regression for continuous variables. Results and limitations: A total of 115 patients received enzalutamide after abiraterone: 68 had received prior docetaxel and 47 were docetaxel naive. Median time on enzalutamide was 4.1 mo. Confirmed PSA response rates (22% vs 26%; p = 0.8), median time to radiologic/clinical progression (4.6 mo vs 6.6 mo; p = 0.6), and median OS (10.6 mo vs 8.6 mo; p = 0.2) did not differ significantly between docetaxel-experienced and docetaxel-naive patients. No clinical variables (including prior response to abiraterone) were found to associate significantly with confirmed PSA response to enzalutamide. Conclusions: Antitumour activity of enzalutamide following abiraterone was limited in mCRPC patients irrespective of prior docetaxel use. Identifying clinical and molecular factors predictive of response to enzalutamide remains a high priority for future research. Patient summary: We looked at the effectiveness of enzalutamide after abiraterone acetate for treatment of advanced prostate cancer. We found that patients who had received docetaxel chemotherapy before abiraterone gained similar benefit from enzalutamide compared with patients who had not received docetaxel. These results suggest that earlier treatment with docetaxel does not have a large impact on the activity of enzalutamide after abiraterone. # 2014 Published by Elsevier B.V. on behalf of European Association of Urology.
Keywords: Enzalutamide Abiraterone acetate Abiraterone Docetaxel Castration-resistant prostate cancer
* Corresponding author. Department of Medical Oncology, British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, BC, V5Z 4E6, Canada. Tel.: +1 604 877 6000; Fax: +1 604 877 0585. E-mail address: [email protected] (K.N. Chi). http://dx.doi.org/10.1016/j.eururo.2014.06.045 0302-2838/# 2014 Published by Elsevier B.V. on behalf of European Association of Urology.
Please cite this article in press as: Azad AA, et al. Efficacy of Enzalutamide Following Abiraterone Acetate in Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer Patients. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.06.045
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1.
Introduction
and log-rank test for time to PSA progression and OS. Univariate analysis was performed to identify variables associated with
The therapeutic armamentarium for metastatic castrationresistant prostate cancer (mCRPC) has rapidly expanded in recent years with several novel agents demonstrating a benefit on overall survival (OS) [1]. Among these agents are the novel androgen receptor (AR)-targeted therapies abiraterone acetate (abiraterone) and enzalutamide that inhibit CYP17 and AR, respectively. Both abiraterone and enzalutamide are increasingly being used in chemotherapynaive mCRPC patients on the basis of positive data from the COU-AA-302 (abiraterone) and PREVAIL (enzalutamide) phase 3 studies [2,3]. Despite their efficacy, however, many questions regarding the use of abiraterone and enzalutamide remain unanswered including the optimal sequencing of treatment. Several prior studies have reported on outcomes in mCRPC patients treated with enzalutamide after abiraterone [4–9]. All but one of these studies [9] were restricted to patients previously treated with docetaxel, and currently little is known about the activity of enzalutamide following abiraterone in docetaxel-naive mCRPC patients. The aim of this study was to examine the activity of enzalutamide after abiraterone in mCRPC patients not previously treated with docetaxel chemotherapy and to compare outcomes with docetaxel-experienced patients. 2.
Methods
2.1.
Patient population
The British Columbia Cancer Agency (BCCA) consists of six distinct centres located throughout British Columbia, Canada. The Cancer Registry at BCCA was reviewed for mCRPC patients treated with enzalutamide following abiraterone. Patient demographics, prior treatments including docetaxel and abiraterone, clinicopathologic characteristics, and outcomes on postabiraterone enzalutamide (prostate-specific antigen [PSA] response and survival parameters) were documented from medical records of each patient. Patients who had previously received a minimum of one cycle of docetaxel were classified as docetaxel experienced; all other patients were classified as docetaxel naive. Research ethics board approval was obtained prior to commencing this study.
2.2.
Outcome measures
The primary objective of this study was to compare the efficacy of enzalutamide following abiraterone in docetaxel-experienced and docetaxel-naive patients. Data were collected for the following end points: confirmed PSA response rate (PSA decline 50% from baseline maintained 3 wk), time to progression, and OS (time from initiation of enzalutamide to death of any cause or censoring on March 31, 2014). Progression was defined as radiologic (Prostate Cancer Working Group 2 [PCWG2] criteria) or clinical (worsening disease-related symptoms requiring a change in antineoplastic therapy or a decrease in Eastern Cooperative Oncology Group performance status of two or more levels). Reasons for discontinuation of enzalutamide were recorded as follows: PSA progression (PCWG2
confirmed PSA response to enzalutamide, using either chi-square for categorical variables or logistic regression for continuous variables. Progression-free survival (PFS) and OS were calculated using KaplanMeier estimates.
3.
Results
3.1.
Patient population
A total of 115 patients were treated with enzalutamide following abiraterone: 68 had received at least one cycle of docetaxel previously (‘‘docetaxel experienced’’); the remaining 47 patients were docetaxel naive. Table 1 lists the patient characteristics at the initiation of enzalutamide. Docetaxelexperienced and docetaxel-naive patients were matched for all clinicopathologic characteristics with the exception of age and serum lactate dehydrogenase (LDH). 3.2.
Enzalutamide treatment
Median duration of enzalutamide treatment was 4.1 mo and did not significantly differ between docetaxel-experienced and docetaxel-naive patients (Table 2). Overall, 21% of patients (24 of 115) received enzalutamide 6 mo. Median time between cessation of abiraterone and initiation of enzalutamide was 21 d (interquartile range: 2–68). A total of 13% of patients (15 of 115) received another systemic agent between stopping abiraterone and starting enzalutamide. Seven of these 15 patients were docetaxel experienced and were rechallenged with docetaxel between abiraterone and enzalutamide. The remaining patients received BEZ235 (n = 2), PX-866 (n = 2), mitoxantrone (n = 1), and AZD2171 (n = 1); two patients were enrolled in the Study of Cabozantinib (XL184) versus Mitoxantrone Plus Prednisone in Men with Previously Treated Symptomatic Castrationresistant Prostate Cancer (COMET-2) trial (cabozantinib vs mitoxantrone). A total of 61% of patients (70 of 115) were on corticosteroids at the start of enzalutamide and 28% (32 of 115) remained on corticosteroids at the cessation of enzalutamide. Reasons for enzalutamide discontinuation (more than one could apply) were clinical progression (43%), PSA progression (25%), radiologic progression (10%), and toxicity (9%); 28% of patients (32 of 115) remained on treatment as of March 31, 2014. Among patients stopping enzalutamide due to toxicity (n = 10), four were docetaxel experienced and six were docetaxel naive. Postenzalutamide systemic treatment was administered to 25% (17 of 68) and 16% (7 of 45) of docetaxel-experienced and docetaxel-naive patients, respectively ( p = 0.3; chi-square).
criteria), radiologic progression (PCWG2 criteria), clinical progression, and toxicity. Patients who stopped enzalutamide due to toxicity were censored
3.3.
Prostate-specific antigen response
for time to progression analysis.
2.3.
Statistics
Outcomes on enzalutamide were compared between docetaxel-naive and docetaxel-experienced patients using chi-square for PSA response
Confirmed PSA declines 90%, 50%, and 30% were seen in 4% (5 of 115), 23% (27 of 115), and 35% (40 of 115) of patients, respectively. Waterfall plots of maximal PSA decrease on enzalutamide are presented in Figure 1A and
Please cite this article in press as: Azad AA, et al. Efficacy of Enzalutamide Following Abiraterone Acetate in Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer Patients. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.06.045
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Table 1 – Baseline characteristics at initiation of enzalutamide in metastatic castration-resistant prostate cancer patients previously treated with abiraterone acetate Characteristic
Age Median (IQR) Gleason score, n (%) 6–7 8–10 Unknown Disease sites, n (%) Bone Lymph node Visceral Prior therapy Docetaxel, n (%) No. of cycles, median (range) No PSA decline, n (%) PSA decline <50%, n (%) PSA decline 50%, n (%) Abiraterone, Treatment duration, mo, median (95% CI) No PSA decline, n (%) PSA decline <50%, n (%) PSA decline 50%, n (%) Other therapy*, n (%) Laboratory LDH, U/l, median (IQR) Elevated, 250, n (%) Normal, n (%) Unknown, n (%) ALP, U/l, median (IQR) Elevated (160), n (%) Normal, n (%) Unknown, n (%) Albumin, g/l, median (IQR) Low, <40, n (%) Normal, n (%) Unknown, n (%) Haemoglobin, g/l, median (IQR) Low (<100), n (%) Normal, n (%) Unknown, n (%)
Docetaxel naive (n = 47)
p
Test
<0.001
Mann-Whitney
All (n = 115)
Docetaxel experienced (n = 68)
72 (67–81)
70 (64–74)
81 (72–86)
39 (34) 65 (57) 11 (10)
21 (31) 39 (57) 8 (12)
18 (38) 26 (55) 3 (6)
0.5
Chi-square
107 (93) 40 (35) 17 (15)
64 (94) 24 (35) 13 (19)
43 (91) 16 (34) 4 (9)
0.6 0.9 0.1
Chi-square Chi-square Chi-square
7.36 (6.00–8.72) 20 (29) 15 (22) 33 (49) 18 (26)
7.89 (5.41–10.36) 9 (19) 15 (32) 23 (49) 8 (17)
0.5 0.3
Log-rank Chi-square
0.2
Chi-square
0.046
Mann-Whitney
0.3
Mann-Whitney
0.7
Mann-Whitney
0.2
Mann-Whitney
68 8 10 21 37
(59) (1–12) (15) (31) (54)
7.56 (6.45–8.67) 29 (25) 30 (26) 56 (49) 26 (23) 257 62 49 4 166 58 55 2 37 83 24 8 121 18 97 0
(204–351) (54) (43) (3) (107–316) (50) (48) (2) (34–40) (72) (21) (7) (108–129) (16) (84) (0)
246 30 35 3 178 37 29 2 37 49 16 3 121 10 58 0
(186–308) (44) (51) (4) (110–329) (54) (43) (3) (34–40) (72) (24) (4) (114–129) (15) (85) (0)
266 32 14 1 145 21 26 0 36 34 8 5 116 8 39 0
(233–354) (68) (30) (2) (92–263) (45) (55) (0) (33–40) (72) (17) (11) (106–129) (17) (83) (0)
ALP = alkaline phosphatase; CI = confidence interval; IQR = interquartile range; LDH = lactate dehydrogenase; PSA = prostate-specific antigen. Systemic agents excluding androgen deprivation therapy (luteinising hormone-releasing hormone antagonist/agonist, antiandrogens).
*
Table 2 – Outcomes with enzalutamide treatment in metastatic castration-resistant prostate cancer patients previously treated with abiraterone acetate Characteristic
PSA decline 50%, n (%) <50%, n (%) None, n (%) Time on treatment, mo, median Time to progression, mo*, median Overall survival, moy, median
All n = 115
Docetaxel experienced n = 68
Docetaxel naive n = 47
27 (23.5) 46 (40) 42 (36.5) 4.1 5.3 10.6
15 (22) 29 (42.6) 24 (35.3) 4.1 4.6 10.6
12 (25.5) 17 (36.2) 18 (38.3) 4.6 6.6 8.6
Difference (95% CI)
3.5 (12 to 19) 6.4 (12 to 23) 3 (14 to 21) NA NA NA
HR (95% CI)
p
Test
NA NA NA 1.09 (0.69–1.74) 0.87 (0.50–1.51) 1.58 (0.82–3.02)
0.8
Chi-square
0.7 0.6 0.2
Log-rank Log-rank Log-rank
CI = confidence interval, HR = hazard ratio; NA = not available; PSA = prostate-specific antigen. Radiologic and/or clinical progression. y From start of enzalutamide. *
stratified by prior treatment with docetaxel in Figure 1B. Notably, confirmed PSA response rates (PSA decline 50%) did not differ between docetaxel-experienced and docetaxel-naive patients (Table 2). Univariate analysis was also performed to identify any clinicopathologic factors
predictive of response to enzalutamide. As shown in Table 3, no factors significantly correlated with a confirmed PSA response to enzalutamide including response to prior abiraterone, duration of prior abiraterone, and corticosteroid treatment at commencement or cessation of enzalutamide.
Please cite this article in press as: Azad AA, et al. Efficacy of Enzalutamide Following Abiraterone Acetate in Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer Patients. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.06.045
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Fig. 1 – (A) Waterfall plot showing maximum prostate-specific antigen (PSA) decline in patients treated with enzalutamide following abiraterone; (B) maximal PSA decline after enzalutamide administration stratified by prior treatment with docetaxel.
Fig. 2 – Overall survival and progression-free survival from the start of enzalutamide stratified by prior treatment with docetaxel.
Treatment with another systemic agent between abiraterone and enzalutamide was also not significantly associated with PSA response on enzalutamide. Interestingly, however, no PSA responses to enzalutamide were observed in the seven docetaxel-experienced patients who were rechallenged with docetaxel after abiraterone. 3.4.
Survival
Accurate data on time to progression and OS were available in 108 and 115 patients (94% and 100%, respectively). Median time to progression and OS were 5.3 mo and 10.6 mo, respectively. Kaplan-Meier survival curves are shown in Figure 2. Median time to progression and median OS on enzalutamide were not significantly different between docetaxel-experienced and docetaxel-naive patients (Table 2). 4.
Discussion
In this retrospective study, we examined the antitumour activity of enzalutamide after abiraterone in mCRPC
patients. We found that the efficacy of enzalutamide was comparable in docetaxel-experienced and docetaxel-naive patients in terms of confirmed PSA response rates (22% vs 26%; p = 0.8), median time to radiologic/clinical progression (4.6 mo vs 6.6 mo; p = 0.6), and median OS (10.6 mo vs 8.6 mo; p = 0.2). These findings are somewhat surprising because we had anticipated that enzalutamide would be less efficacious in more heavily pretreated patients, that is, those who had also received prior docetaxel. The differences in baseline age and LDH between the cohorts, which were biased against the docetaxel-naive group, may have had an impact on our results, although age and LDH have not been shown differentially to affect the benefit of enzalutamide [10,11]. Population-based studies have shown that only a third of mCRPC patients receive docetaxel [12]. However, results from the recently presented Androgen Ablation Therapy with or Without Chemotherapy in Treating Patients with Metastatic Prostate Cancer (CHAARTED) trial [13] are likely to lead to an increase in docetaxel use in patients with highrisk metastatic castration-sensitive disease. Our results, which indicate that earlier treatment with docetaxel does not have a large impact on the activity of enzalutamide after
Please cite this article in press as: Azad AA, et al. Efficacy of Enzalutamide Following Abiraterone Acetate in Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer Patients. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.06.045
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Table 3 – Univariate analysis examining association between baseline clinicopathologic factors and confirmed prostate-specific antigen response rate (decline I50% maintained I3 wk) in patients treated with enzalutamide after abiraterone acetate Variable Docetaxel preabiraterone Yes No PSA decline 50% on docetaxel Yes No PSA decline 50% on abiraterone Yes No Gleason score 7 8–10 ECOG performance status 0–1 2 Lymph node metastases Absent Present Visceral metastases Absent Present On steroids at start of enzalutamide Yes No On steroids at end of enzalutamide Yes No Systemic treatment postabiraterone and pre-enzalutamide Yes No Duration of abiraterone (continuous) Age at start of enzalutamide (continuous) Time from start of ADT to start of enzalutamide (continuous) Serum LDH (continuous) Serum ALP (continuous) Serum albumin (continuous) Haemoglobin (continuous)
n
PSA RR, %
Difference (95% CI)
p
68 47
22.0 25.5
3.5 (12 to 19)
0.7
37 31
27.0 16.1
10.9 (9 to 29)
0.3
56 59
28.6 18.6
10.0 (6 to 25)
0.2
39 65
23 23
0 (16 to 18)
1.0
67 47
25.4 21.3
4.1 (12 to 19)
0.6
75 40
26.7 17.5
9.2 (8 to 23)
0.3
98 17
24.5 17.6
6.9 (18 to 22)
0.5
70 45
20 28.9
8.9 (7 to 25)
0.3
32 83
18.8 25.3
6.5 (12 to 21)
0.5
15 100 115 115 114 112 114 111 115
13.3 25 NA NA NA NA NA NA NA
11.7 (14 to 25)
0.3
NA NA NA NA NA NA NA
0.3 0.9 0.5 0.7 0.9 0.1 0.4
ADT = androgen deprivation therapy; ALP = alkaline phosphatase; CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; LDH = lactate dehydrogenase; NA = not available; PSA = prostate-specific antigen; RR = response rate.
abiraterone, may therefore be of increasing relevance to the management of patients with metastatic prostate cancer. The findings of this study point to a common mechanism of resistance to enzalutamide in docetaxel-experienced and -naive patients. Resistance mechanisms to enzalutamide include induction of AR splice variants [14], an activating point mutation in the AR (F876L) [15,16], upregulation of the stress-activated chaperone protein clusterin [17], enhanced protein kinase C/Twist1 signalling [18], and activation of the glucocorticoid receptor [19]. These factors do not overlap with known mechanisms of docetaxel resistance [20], although it has been postulated that crossresistance may develop between docetaxel, enzalutamide, and abiraterone because all of these agents are known to modulate AR nuclear translocation [21]. The similar efficacy of enzalutamide regardless of prior docetaxel use in our study suggests that cross-resistance between abiraterone and enzalutamide emerges independently of docetaxel. The PSA response rate to enzalutamide in our cohort was 23%, median time to progression was 5.3 mo, and median OS was 10.6 mo. These results are broadly in keeping with earlier studies that reported PSA response rates of
13–29%, median PFS of 2.9–4.0 mo, and median OS of 7.3– 7.5 mo in mCRPC patients treated with enzalutamide after abiraterone [4–9]. In our chemotherapy-naive cohort, PSA declines 50% and 30% were seen in 23% and 35% of patients, respectively. These findings are also comparable with the only prior study to include chemotherapy-naive patients [9], which reported PSA declines 30% in 40% of patients. Collectively, these data indicate that enzalutamide has relatively modest activity when used after abiraterone. Abiraterone is also reported to have limited efficacy after prior treatment with enzalutamide [22,23]. This lends weight to the possibility of a common mechanism of resistance between enzalutamide and abiraterone. In support of this, a recent report linked detection of the AR-V7 splice variant with primary and acquired resistance to both enzalutamide and abiraterone [24]. Despite its limited overall activity, enzalutamide did confer longer-term benefit for a subset of patients in our study with 21% of patients remaining on treatment for at least 6 mo. However, predicting which patients will benefit from treatment with enzalutamide remains a major challenge. We could not find any clinicopathologic factors
Please cite this article in press as: Azad AA, et al. Efficacy of Enzalutamide Following Abiraterone Acetate in Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer Patients. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.06.045
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that predicted a PSA decline 50% on enzalutamide. Although prior PSA decline 50% on abiraterone has been linked to subsequent response to enzalutamide [8,9], we and other investigators [4,5] have not corroborated these findings. Gleason score has also been implicated as a predictor for enzalutamide response following abiraterone [4]; however, we did not find this to be the case. Similarly, although coadministration of corticosteroids was found to be associated with inferior survival parameters in a post hoc analysis of the Safety and Efficacy Study of MDV3100 in the Patients with Castration-resistant Prostate Cancer Who Have Been Previously Treated with Docetaxel-based Chemotherapy (AFFIRM) trial [25], we did not observe lower PSA response rates in patients receiving corticosteroids at the initiation of enzalutamide. Participation in clinical trials has also been linked to improved outcomes with systemic therapy in mCRPC patients [26]. However, this was not relevant to our study because no patients received enzalutamide in the context of a clinical trial. The absence of predictive clinicopathologic factors for enzalutamide efficacy illustrates the need for further translational studies to identify novel predictive biomarkers. Pretreatment measurement of serum androgens [27] and enumeration of circulating tumour cells (CTCs) [28–30] are avenues of interest, having been identified as prognostic factors in mCRPC patients receiving systemic therapy. Correlating outcomes on enzalutamide with genomic aberrations (eg, AR amplification, AR mutations, and TMPRSS2-ERG rearrangement) detectable in tumour biopsies, CTCs, and/or circulating tumour DNA would also be of significant interest. We acknowledge that this study has several limitations. The limited cohort size means our data must be interpreted with due caution and require validation in larger, prospective series. Other limitations of this study include its retrospective design, its restriction to a single province in Canada, and the relatively short follow-up period. We also could not assess radiologic response to treatment because imaging was not consistently performed, and postenzalutamide treatment may have confounded assessment of OS.
Author contributions: Kim N. Chi 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: Chi, Eigl, Azad. Acquisition of data: Chi, Eigl, Azad, Kollmannsberger, Murray. Analysis and interpretation of data: Kollmannsberger, Chi, Eigl, Azad. Drafting of the manuscript: Chi, Eigl, Azad, Kollmannsberger, Murray. Critical revision of the manuscript for important intellectual content: Chi, Eigl, Azad, Kollmannsberger, Murray. Statistical analysis: Azad. Obtaining funding: None. Administrative, technical, or material support: Chi, Eigl, Azad. Supervision: Chi, Eigl. Other (specify): None. Financial disclosures: Kim N. Chi 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: Kim N. Chi receives research funding from OncoGenex Technologies Inc., Astellas, Janssen, and Novartis, and is a consultant for Janssen, Astellas, Amgen, Bayer, Millennium, Novartis, and Sanofi. Bernhard J. Eigl has received an unrestricted educational grant from Janssen. Arun A. Azad receives research funding from Astellas. Funding/Support and role of the sponsor: None.
References [1] Heidenreich A, Pfister D, Merseburger A, Bartsch G. Castrationresistant prostate cancer: where we stand in 2013 and what urologists should know. Eur Urol 2013;64:260–5. [2] Beer TM, Armstrong AJ, Sternberg CN, et al. Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mCRPC): results of phase III PREVAIL study [abstract LBA1^]. J Clin Oncol 2014;32 (Suppl 4). [3] Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013;368:138–48. [4] Schrader AJ, Boegemann M, Ohlmann CH, et al. Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and abiraterone. Eur Urol 2014;65:30–6. [5] Bianchini D, Lorente D, Rodriguez-Vida A, et al. Antitumour activity
5.
Conclusions
We found that the antitumour efficacy of enzalutamide following abiraterone is similar in docetaxel-experienced and docetaxel-naive mCRPC patients. Our data suggest that therapeutic resistance to enzalutamide is not linked to prior treatment with docetaxel. Notably, enzalutamide had limited overall activity after abiraterone with or without prior docetaxel. This illustrates the importance of conducting clinical trials examining novel therapeutic approaches in patients progressing on abiraterone. Nevertheless, a subset of patients did attain relatively durable benefit from treatment with enzalutamide following abiraterone, and developing robust predictive biomarkers to identify these patients is paramount. In turn, this would optimise the use of enzalutamide and potentially lead to improved clinical outcomes for patients with mCRPC.
of enzalutamide (MDV3100) in patients with metastatic castrationresistant prostate cancer (CRPC) pre-treated with docetaxel and abiraterone. Eur J Cancer 2014;50:78–84. [6] Thomsen FB, Roder MA, Rathenborg P, Brasso K, Borre M, Iversen P. Enzalutamide treatment in patients with metastatic castrationresistant prostate cancer progressing after chemotherapy and abiraterone acetate. Scand J Urol 2014;48:268–75. [7] Schmid SC, Geith A, Boker A, et al. Enzalutamide after docetaxel and abiraterone therapy in metastatic castration-resistant prostate cancer. Adv Ther 2014;31:234–41. [8] Badrising S, van der Noort V, van Oort IM, et al. Clinical activity and tolerability of enzalutamide (MDV3100) in patients with metastatic, castration-resistant prostate cancer who progress after docetaxel and abiraterone treatment. Cancer 2014;120:968–75. [9] Cheng HH, Nadal R, Gulati R, et al. The effect of prior abiraterone (Abi) use on the activity of enzalutamide (Enza) in men with mCRPC [abstract 18]. J Clin Oncol 2014;32 (Suppl 4). [10] Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012;367:1187–97.
Please cite this article in press as: Azad AA, et al. Efficacy of Enzalutamide Following Abiraterone Acetate in Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer Patients. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.06.045
EURURO-5717; No. of Pages 7 EUROPEAN UROLOGY XXX (2014) XXX–XXX
7
[11] Sternberg CN, de Bono JS, Chi KN, et al. Improved outcomes
[21] van Soest RJ, van Royen ME, de Morree ES, et al. Cross-resistance
in elderly patients with metastatic castration-resistant prostate
between taxanes and new hormonal agents abiraterone and enza-
cancer treated with the androgen receptor inhibitor enzaluta-
lutamide may affect drug sequence choices in metastatic castra-
mide: results from the phase III AFFIRM trial. Ann Oncol 2014;
tion-resistant prostate cancer. Eur J Cancer 2013;49:3821–30.
25:429–34.
[22] Noonan KL, North S, Bitting RL, Armstrong AJ, Ellard SL, Chi KN.
[12] Zielinski RR, Tyldesley S, Chi KN. Population-based impact on
Clinical activity of abiraterone acetate in patients with metastatic
overall survival (OS) after the introduction of docetaxel as standard
castration-resistant prostate cancer progressing after enzaluta-
therapy for metastatic castration resistant prostate cancer (CRPC) [abstract 77]. J Clin Oncol 2013;31 (Suppl 6). [13] NIH-funded study shows increased survival in men with metastatic
mide. Ann Oncol 2013;24:1802–7. [23] Loriot Y, Bianchini D, Ileana E, et al. Antitumour activity of abiraterone acetate against metastatic castration-resistant prostate cancer pro-
prostate cancer who receive chemotherapy when starting hormone
gressing after docetaxel and enzalutamide (MDV3100). Ann Oncol
therapy [news release]. National Cancer Institute Web site. http://
2013;24:1807–12.
www.nih.gov/news/health/dec2013/nci-05.htm.
[24] Antonarakis ES, Lu C, Wang H, et al. Androgen receptor splice
[14] Cao B, Qi Y, Zhang G, et al. Androgen receptor splice variants
variant, AR-V7, and resistance to enzalutamide and abiraterone
activating the full-length receptor in mediating resistance to an-
in men with metastatic castration-resistant prostate cancer
drogen-directed therapy. Oncotarget 2014;30:1646–56.
(mCRPC) [abstract 5001]. J Clin Oncol 2014; 32:5s(Suppl).
[15] Joseph JD, Lu N, Qian J, et al. A clinically relevant androgen receptor
[25] Scher HI, Fizazi K, Saad F, et al. Impact of on-study corticosteroid
mutation confers resistance to second-generation antiandrogens
use on efficacy and safety in the phase III AFFIRM study of enza-
enzalutamide and ARN-509. Cancer Discov 2013;3:1020–9. [16] Korpal M, Korn JM, Gao X, et al. An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide). Cancer Discov 2013;3:1030–43. [17] Matsumoto H, Yamamoto Y, Shiota M, et al. Cotargeting androgen
lutamide (ENZA), an androgen receptor inhibitor [abstract 6]. J Clin Oncol 2013;31 (Suppl 6). [26] Goyal J, Nuhn P, Huang P, et al. The effect of clinical trial participation versus non-participation on overall survival in men receiving first-line docetaxel-containing chemotherapy for metastatic cas-
receptor and clusterin delays castrate-resistant prostate cancer
tration-resistant prostate cancer. BJU Int 2012;110:E575–82.
progression by inhibiting adaptive stress response and AR stability.
[27] Ryan CJ, Molina A, Li J, et al. Serum androgens as prognostic biomarkers
Cancer Res 2013;73:5206–17. [18] Shiota M, Yokomizo A, Takeuchi A, et al. Inhibition of protein kinase C/ Twist1 signaling augments anticancer effects of androgen deprivation
in castration-resistant prostate cancer: results from an analysis of a randomized phase III trial. J Clin Oncol 2013;31:2791–8. [28] de Bono JS, Scher HI, Montgomery RB, et al. Circulating tumor cells
and enzalutamide in prostate cancer. Clin Cancer Res 2014;20:
predict survival benefit from treatment in metastatic castration-
951–61.
resistant prostate cancer. Clin Cancer Res 2008;14:6302–9.
[19] Arora VK, Schenkein E, Murali R, et al. Glucocorticoid receptor
[29] Olmos D, Arkenau HT, Ang JE, et al. Circulating tumour cell (CTC)
confers resistance to antiandrogens by bypassing androgen recep-
counts as intermediate end points in castration-resistant prostate
tor blockade. Cell 2013;155:1309–22.
cancer (CRPC): a single-centre experience. Ann Oncol 2009;20:27–33.
[20] Antonarakis ES, Armstrong AJ. Evolving standards in the treatment
[30] Scher HI, Jia X, de Bono JS, et al. Circulating tumour cells as prognostic
of docetaxel-refractory castration-resistant prostate cancer. Pros-
markers in progressive, castration-resistant prostate cancer: a reanal-
tate Cancer Prostatic Dis 2011;14:192–205.
ysis of IMMC38 trial data. Lancet Oncol 2009;10:233–9.
Please cite this article in press as: Azad AA, et al. Efficacy of Enzalutamide Following Abiraterone Acetate in Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer Patients. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.06.045
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Prostate Cancer Editorial by XXX on pp. x–y of this issue
Efficacy of Enzalutamide Following Abiraterone Acetate in Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer Patients Arun A. Azad, Bernhard J. Eigl, R. Nevin Murray, Christian Kollmannsberger, Kim N. Chi * Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
Article info
Abstract
Article history: Accepted June 23, 2014
Background: The activity of enzalutamide after prior treatment with both abiraterone acetate (abiraterone) and docetaxel has been examined in several retrospective studies. However, limited data are available on the efficacy of enzalutamide following abiraterone in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (mCRPC). Objective: To compare the activity of enzalutamide after abiraterone in docetaxelexperienced and docetaxel-naive mCRPC patients. Design, setting, and participants: The British Columbia Cancer Agency Cancer Registry was searched for mCRPC patients who received enzalutamide after prior abiraterone. Clinicopathologic characteristics, confirmed prostate-specific antigen (PSA) response rates (PSA decline 50% confirmed 3 wk later), and survival data were collected. Outcome measurements and statistical analysis: Outcomes on enzalutamide were compared between docetaxel-experienced and docetaxel-naive patients using chisquare for PSA response and log-rank test for time to PSA progression and overall survival (OS). Univariate analysis was performed to identify variables associated with confirmed PSA response on enzalutamide, using either chi-square for categorical variables or logistic regression for continuous variables. Results and limitations: A total of 115 patients received enzalutamide after abiraterone: 68 had received prior docetaxel and 47 were docetaxel naive. Median time on enzalutamide was 4.1 mo. Confirmed PSA response rates (22% vs 26%; p = 0.8), median time to radiologic/clinical progression (4.6 mo vs 6.6 mo; p = 0.6), and median OS (10.6 mo vs 8.6 mo; p = 0.2) did not differ significantly between docetaxel-experienced and docetaxel-naive patients. No clinical variables (including prior response to abiraterone) were found to associate significantly with confirmed PSA response to enzalutamide. Conclusions: Antitumour activity of enzalutamide following abiraterone was limited in mCRPC patients irrespective of prior docetaxel use. Identifying clinical and molecular factors predictive of response to enzalutamide remains a high priority for future research. Patient summary: We looked at the effectiveness of enzalutamide after abiraterone acetate for treatment of advanced prostate cancer. We found that patients who had received docetaxel chemotherapy before abiraterone gained similar benefit from enzalutamide compared with patients who had not received docetaxel. These results suggest that earlier treatment with docetaxel does not have a large impact on the activity of enzalutamide after abiraterone. # 2014 Published by Elsevier B.V. on behalf of European Association of Urology.
Keywords: Enzalutamide Abiraterone acetate Abiraterone Docetaxel Castration-resistant prostate cancer
* Corresponding author. Department of Medical Oncology, British Columbia Cancer Agency, 600 West 10th Avenue, Vancouver, BC, V5Z 4E6, Canada. Tel.: +1 604 877 6000; Fax: +1 604 877 0585. E-mail address: [email protected] (K.N. Chi). http://dx.doi.org/10.1016/j.eururo.2014.06.045 0302-2838/# 2014 Published by Elsevier B.V. on behalf of European Association of Urology.
Please cite this article in press as: Azad AA, et al. Efficacy of Enzalutamide Following Abiraterone Acetate in Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer Patients. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.06.045
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1.
Introduction
and log-rank test for time to PSA progression and OS. Univariate analysis was performed to identify variables associated with
The therapeutic armamentarium for metastatic castrationresistant prostate cancer (mCRPC) has rapidly expanded in recent years with several novel agents demonstrating a benefit on overall survival (OS) [1]. Among these agents are the novel androgen receptor (AR)-targeted therapies abiraterone acetate (abiraterone) and enzalutamide that inhibit CYP17 and AR, respectively. Both abiraterone and enzalutamide are increasingly being used in chemotherapynaive mCRPC patients on the basis of positive data from the COU-AA-302 (abiraterone) and PREVAIL (enzalutamide) phase 3 studies [2,3]. Despite their efficacy, however, many questions regarding the use of abiraterone and enzalutamide remain unanswered including the optimal sequencing of treatment. Several prior studies have reported on outcomes in mCRPC patients treated with enzalutamide after abiraterone [4–9]. All but one of these studies [9] were restricted to patients previously treated with docetaxel, and currently little is known about the activity of enzalutamide following abiraterone in docetaxel-naive mCRPC patients. The aim of this study was to examine the activity of enzalutamide after abiraterone in mCRPC patients not previously treated with docetaxel chemotherapy and to compare outcomes with docetaxel-experienced patients. 2.
Methods
2.1.
Patient population
The British Columbia Cancer Agency (BCCA) consists of six distinct centres located throughout British Columbia, Canada. The Cancer Registry at BCCA was reviewed for mCRPC patients treated with enzalutamide following abiraterone. Patient demographics, prior treatments including docetaxel and abiraterone, clinicopathologic characteristics, and outcomes on postabiraterone enzalutamide (prostate-specific antigen [PSA] response and survival parameters) were documented from medical records of each patient. Patients who had previously received a minimum of one cycle of docetaxel were classified as docetaxel experienced; all other patients were classified as docetaxel naive. Research ethics board approval was obtained prior to commencing this study.
2.2.
Outcome measures
The primary objective of this study was to compare the efficacy of enzalutamide following abiraterone in docetaxel-experienced and docetaxel-naive patients. Data were collected for the following end points: confirmed PSA response rate (PSA decline 50% from baseline maintained 3 wk), time to progression, and OS (time from initiation of enzalutamide to death of any cause or censoring on March 31, 2014). Progression was defined as radiologic (Prostate Cancer Working Group 2 [PCWG2] criteria) or clinical (worsening disease-related symptoms requiring a change in antineoplastic therapy or a decrease in Eastern Cooperative Oncology Group performance status of two or more levels). Reasons for discontinuation of enzalutamide were recorded as follows: PSA progression (PCWG2
confirmed PSA response to enzalutamide, using either chi-square for categorical variables or logistic regression for continuous variables. Progression-free survival (PFS) and OS were calculated using KaplanMeier estimates.
3.
Results
3.1.
Patient population
A total of 115 patients were treated with enzalutamide following abiraterone: 68 had received at least one cycle of docetaxel previously (‘‘docetaxel experienced’’); the remaining 47 patients were docetaxel naive. Table 1 lists the patient characteristics at the initiation of enzalutamide. Docetaxelexperienced and docetaxel-naive patients were matched for all clinicopathologic characteristics with the exception of age and serum lactate dehydrogenase (LDH). 3.2.
Enzalutamide treatment
Median duration of enzalutamide treatment was 4.1 mo and did not significantly differ between docetaxel-experienced and docetaxel-naive patients (Table 2). Overall, 21% of patients (24 of 115) received enzalutamide 6 mo. Median time between cessation of abiraterone and initiation of enzalutamide was 21 d (interquartile range: 2–68). A total of 13% of patients (15 of 115) received another systemic agent between stopping abiraterone and starting enzalutamide. Seven of these 15 patients were docetaxel experienced and were rechallenged with docetaxel between abiraterone and enzalutamide. The remaining patients received BEZ235 (n = 2), PX-866 (n = 2), mitoxantrone (n = 1), and AZD2171 (n = 1); two patients were enrolled in the Study of Cabozantinib (XL184) versus Mitoxantrone Plus Prednisone in Men with Previously Treated Symptomatic Castrationresistant Prostate Cancer (COMET-2) trial (cabozantinib vs mitoxantrone). A total of 61% of patients (70 of 115) were on corticosteroids at the start of enzalutamide and 28% (32 of 115) remained on corticosteroids at the cessation of enzalutamide. Reasons for enzalutamide discontinuation (more than one could apply) were clinical progression (43%), PSA progression (25%), radiologic progression (10%), and toxicity (9%); 28% of patients (32 of 115) remained on treatment as of March 31, 2014. Among patients stopping enzalutamide due to toxicity (n = 10), four were docetaxel experienced and six were docetaxel naive. Postenzalutamide systemic treatment was administered to 25% (17 of 68) and 16% (7 of 45) of docetaxel-experienced and docetaxel-naive patients, respectively ( p = 0.3; chi-square).
criteria), radiologic progression (PCWG2 criteria), clinical progression, and toxicity. Patients who stopped enzalutamide due to toxicity were censored
3.3.
Prostate-specific antigen response
for time to progression analysis.
2.3.
Statistics
Outcomes on enzalutamide were compared between docetaxel-naive and docetaxel-experienced patients using chi-square for PSA response
Confirmed PSA declines 90%, 50%, and 30% were seen in 4% (5 of 115), 23% (27 of 115), and 35% (40 of 115) of patients, respectively. Waterfall plots of maximal PSA decrease on enzalutamide are presented in Figure 1A and
Please cite this article in press as: Azad AA, et al. Efficacy of Enzalutamide Following Abiraterone Acetate in Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer Patients. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.06.045
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Table 1 – Baseline characteristics at initiation of enzalutamide in metastatic castration-resistant prostate cancer patients previously treated with abiraterone acetate Characteristic
Age Median (IQR) Gleason score, n (%) 6–7 8–10 Unknown Disease sites, n (%) Bone Lymph node Visceral Prior therapy Docetaxel, n (%) No. of cycles, median (range) No PSA decline, n (%) PSA decline <50%, n (%) PSA decline 50%, n (%) Abiraterone, Treatment duration, mo, median (95% CI) No PSA decline, n (%) PSA decline <50%, n (%) PSA decline 50%, n (%) Other therapy*, n (%) Laboratory LDH, U/l, median (IQR) Elevated, 250, n (%) Normal, n (%) Unknown, n (%) ALP, U/l, median (IQR) Elevated (160), n (%) Normal, n (%) Unknown, n (%) Albumin, g/l, median (IQR) Low, <40, n (%) Normal, n (%) Unknown, n (%) Haemoglobin, g/l, median (IQR) Low (<100), n (%) Normal, n (%) Unknown, n (%)
Docetaxel naive (n = 47)
p
Test
<0.001
Mann-Whitney
All (n = 115)
Docetaxel experienced (n = 68)
72 (67–81)
70 (64–74)
81 (72–86)
39 (34) 65 (57) 11 (10)
21 (31) 39 (57) 8 (12)
18 (38) 26 (55) 3 (6)
0.5
Chi-square
107 (93) 40 (35) 17 (15)
64 (94) 24 (35) 13 (19)
43 (91) 16 (34) 4 (9)
0.6 0.9 0.1
Chi-square Chi-square Chi-square
7.36 (6.00–8.72) 20 (29) 15 (22) 33 (49) 18 (26)
7.89 (5.41–10.36) 9 (19) 15 (32) 23 (49) 8 (17)
0.5 0.3
Log-rank Chi-square
0.2
Chi-square
0.046
Mann-Whitney
0.3
Mann-Whitney
0.7
Mann-Whitney
0.2
Mann-Whitney
68 8 10 21 37
(59) (1–12) (15) (31) (54)
7.56 (6.45–8.67) 29 (25) 30 (26) 56 (49) 26 (23) 257 62 49 4 166 58 55 2 37 83 24 8 121 18 97 0
(204–351) (54) (43) (3) (107–316) (50) (48) (2) (34–40) (72) (21) (7) (108–129) (16) (84) (0)
246 30 35 3 178 37 29 2 37 49 16 3 121 10 58 0
(186–308) (44) (51) (4) (110–329) (54) (43) (3) (34–40) (72) (24) (4) (114–129) (15) (85) (0)
266 32 14 1 145 21 26 0 36 34 8 5 116 8 39 0
(233–354) (68) (30) (2) (92–263) (45) (55) (0) (33–40) (72) (17) (11) (106–129) (17) (83) (0)
ALP = alkaline phosphatase; CI = confidence interval; IQR = interquartile range; LDH = lactate dehydrogenase; PSA = prostate-specific antigen. Systemic agents excluding androgen deprivation therapy (luteinising hormone-releasing hormone antagonist/agonist, antiandrogens).
*
Table 2 – Outcomes with enzalutamide treatment in metastatic castration-resistant prostate cancer patients previously treated with abiraterone acetate Characteristic
PSA decline 50%, n (%) <50%, n (%) None, n (%) Time on treatment, mo, median Time to progression, mo*, median Overall survival, moy, median
All n = 115
Docetaxel experienced n = 68
Docetaxel naive n = 47
27 (23.5) 46 (40) 42 (36.5) 4.1 5.3 10.6
15 (22) 29 (42.6) 24 (35.3) 4.1 4.6 10.6
12 (25.5) 17 (36.2) 18 (38.3) 4.6 6.6 8.6
Difference (95% CI)
3.5 (12 to 19) 6.4 (12 to 23) 3 (14 to 21) NA NA NA
HR (95% CI)
p
Test
NA NA NA 1.09 (0.69–1.74) 0.87 (0.50–1.51) 1.58 (0.82–3.02)
0.8
Chi-square
0.7 0.6 0.2
Log-rank Log-rank Log-rank
CI = confidence interval, HR = hazard ratio; NA = not available; PSA = prostate-specific antigen. Radiologic and/or clinical progression. y From start of enzalutamide. *
stratified by prior treatment with docetaxel in Figure 1B. Notably, confirmed PSA response rates (PSA decline 50%) did not differ between docetaxel-experienced and docetaxel-naive patients (Table 2). Univariate analysis was also performed to identify any clinicopathologic factors
predictive of response to enzalutamide. As shown in Table 3, no factors significantly correlated with a confirmed PSA response to enzalutamide including response to prior abiraterone, duration of prior abiraterone, and corticosteroid treatment at commencement or cessation of enzalutamide.
Please cite this article in press as: Azad AA, et al. Efficacy of Enzalutamide Following Abiraterone Acetate in Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer Patients. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.06.045
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Fig. 1 – (A) Waterfall plot showing maximum prostate-specific antigen (PSA) decline in patients treated with enzalutamide following abiraterone; (B) maximal PSA decline after enzalutamide administration stratified by prior treatment with docetaxel.
Fig. 2 – Overall survival and progression-free survival from the start of enzalutamide stratified by prior treatment with docetaxel.
Treatment with another systemic agent between abiraterone and enzalutamide was also not significantly associated with PSA response on enzalutamide. Interestingly, however, no PSA responses to enzalutamide were observed in the seven docetaxel-experienced patients who were rechallenged with docetaxel after abiraterone. 3.4.
Survival
Accurate data on time to progression and OS were available in 108 and 115 patients (94% and 100%, respectively). Median time to progression and OS were 5.3 mo and 10.6 mo, respectively. Kaplan-Meier survival curves are shown in Figure 2. Median time to progression and median OS on enzalutamide were not significantly different between docetaxel-experienced and docetaxel-naive patients (Table 2). 4.
Discussion
In this retrospective study, we examined the antitumour activity of enzalutamide after abiraterone in mCRPC
patients. We found that the efficacy of enzalutamide was comparable in docetaxel-experienced and docetaxel-naive patients in terms of confirmed PSA response rates (22% vs 26%; p = 0.8), median time to radiologic/clinical progression (4.6 mo vs 6.6 mo; p = 0.6), and median OS (10.6 mo vs 8.6 mo; p = 0.2). These findings are somewhat surprising because we had anticipated that enzalutamide would be less efficacious in more heavily pretreated patients, that is, those who had also received prior docetaxel. The differences in baseline age and LDH between the cohorts, which were biased against the docetaxel-naive group, may have had an impact on our results, although age and LDH have not been shown differentially to affect the benefit of enzalutamide [10,11]. Population-based studies have shown that only a third of mCRPC patients receive docetaxel [12]. However, results from the recently presented Androgen Ablation Therapy with or Without Chemotherapy in Treating Patients with Metastatic Prostate Cancer (CHAARTED) trial [13] are likely to lead to an increase in docetaxel use in patients with highrisk metastatic castration-sensitive disease. Our results, which indicate that earlier treatment with docetaxel does not have a large impact on the activity of enzalutamide after
Please cite this article in press as: Azad AA, et al. Efficacy of Enzalutamide Following Abiraterone Acetate in Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer Patients. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.06.045
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Table 3 – Univariate analysis examining association between baseline clinicopathologic factors and confirmed prostate-specific antigen response rate (decline I50% maintained I3 wk) in patients treated with enzalutamide after abiraterone acetate Variable Docetaxel preabiraterone Yes No PSA decline 50% on docetaxel Yes No PSA decline 50% on abiraterone Yes No Gleason score 7 8–10 ECOG performance status 0–1 2 Lymph node metastases Absent Present Visceral metastases Absent Present On steroids at start of enzalutamide Yes No On steroids at end of enzalutamide Yes No Systemic treatment postabiraterone and pre-enzalutamide Yes No Duration of abiraterone (continuous) Age at start of enzalutamide (continuous) Time from start of ADT to start of enzalutamide (continuous) Serum LDH (continuous) Serum ALP (continuous) Serum albumin (continuous) Haemoglobin (continuous)
n
PSA RR, %
Difference (95% CI)
p
68 47
22.0 25.5
3.5 (12 to 19)
0.7
37 31
27.0 16.1
10.9 (9 to 29)
0.3
56 59
28.6 18.6
10.0 (6 to 25)
0.2
39 65
23 23
0 (16 to 18)
1.0
67 47
25.4 21.3
4.1 (12 to 19)
0.6
75 40
26.7 17.5
9.2 (8 to 23)
0.3
98 17
24.5 17.6
6.9 (18 to 22)
0.5
70 45
20 28.9
8.9 (7 to 25)
0.3
32 83
18.8 25.3
6.5 (12 to 21)
0.5
15 100 115 115 114 112 114 111 115
13.3 25 NA NA NA NA NA NA NA
11.7 (14 to 25)
0.3
NA NA NA NA NA NA NA
0.3 0.9 0.5 0.7 0.9 0.1 0.4
ADT = androgen deprivation therapy; ALP = alkaline phosphatase; CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; LDH = lactate dehydrogenase; NA = not available; PSA = prostate-specific antigen; RR = response rate.
abiraterone, may therefore be of increasing relevance to the management of patients with metastatic prostate cancer. The findings of this study point to a common mechanism of resistance to enzalutamide in docetaxel-experienced and -naive patients. Resistance mechanisms to enzalutamide include induction of AR splice variants [14], an activating point mutation in the AR (F876L) [15,16], upregulation of the stress-activated chaperone protein clusterin [17], enhanced protein kinase C/Twist1 signalling [18], and activation of the glucocorticoid receptor [19]. These factors do not overlap with known mechanisms of docetaxel resistance [20], although it has been postulated that crossresistance may develop between docetaxel, enzalutamide, and abiraterone because all of these agents are known to modulate AR nuclear translocation [21]. The similar efficacy of enzalutamide regardless of prior docetaxel use in our study suggests that cross-resistance between abiraterone and enzalutamide emerges independently of docetaxel. The PSA response rate to enzalutamide in our cohort was 23%, median time to progression was 5.3 mo, and median OS was 10.6 mo. These results are broadly in keeping with earlier studies that reported PSA response rates of
13–29%, median PFS of 2.9–4.0 mo, and median OS of 7.3– 7.5 mo in mCRPC patients treated with enzalutamide after abiraterone [4–9]. In our chemotherapy-naive cohort, PSA declines 50% and 30% were seen in 23% and 35% of patients, respectively. These findings are also comparable with the only prior study to include chemotherapy-naive patients [9], which reported PSA declines 30% in 40% of patients. Collectively, these data indicate that enzalutamide has relatively modest activity when used after abiraterone. Abiraterone is also reported to have limited efficacy after prior treatment with enzalutamide [22,23]. This lends weight to the possibility of a common mechanism of resistance between enzalutamide and abiraterone. In support of this, a recent report linked detection of the AR-V7 splice variant with primary and acquired resistance to both enzalutamide and abiraterone [24]. Despite its limited overall activity, enzalutamide did confer longer-term benefit for a subset of patients in our study with 21% of patients remaining on treatment for at least 6 mo. However, predicting which patients will benefit from treatment with enzalutamide remains a major challenge. We could not find any clinicopathologic factors
Please cite this article in press as: Azad AA, et al. Efficacy of Enzalutamide Following Abiraterone Acetate in Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer Patients. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.06.045
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that predicted a PSA decline 50% on enzalutamide. Although prior PSA decline 50% on abiraterone has been linked to subsequent response to enzalutamide [8,9], we and other investigators [4,5] have not corroborated these findings. Gleason score has also been implicated as a predictor for enzalutamide response following abiraterone [4]; however, we did not find this to be the case. Similarly, although coadministration of corticosteroids was found to be associated with inferior survival parameters in a post hoc analysis of the Safety and Efficacy Study of MDV3100 in the Patients with Castration-resistant Prostate Cancer Who Have Been Previously Treated with Docetaxel-based Chemotherapy (AFFIRM) trial [25], we did not observe lower PSA response rates in patients receiving corticosteroids at the initiation of enzalutamide. Participation in clinical trials has also been linked to improved outcomes with systemic therapy in mCRPC patients [26]. However, this was not relevant to our study because no patients received enzalutamide in the context of a clinical trial. The absence of predictive clinicopathologic factors for enzalutamide efficacy illustrates the need for further translational studies to identify novel predictive biomarkers. Pretreatment measurement of serum androgens [27] and enumeration of circulating tumour cells (CTCs) [28–30] are avenues of interest, having been identified as prognostic factors in mCRPC patients receiving systemic therapy. Correlating outcomes on enzalutamide with genomic aberrations (eg, AR amplification, AR mutations, and TMPRSS2-ERG rearrangement) detectable in tumour biopsies, CTCs, and/or circulating tumour DNA would also be of significant interest. We acknowledge that this study has several limitations. The limited cohort size means our data must be interpreted with due caution and require validation in larger, prospective series. Other limitations of this study include its retrospective design, its restriction to a single province in Canada, and the relatively short follow-up period. We also could not assess radiologic response to treatment because imaging was not consistently performed, and postenzalutamide treatment may have confounded assessment of OS.
Author contributions: Kim N. Chi 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: Chi, Eigl, Azad. Acquisition of data: Chi, Eigl, Azad, Kollmannsberger, Murray. Analysis and interpretation of data: Kollmannsberger, Chi, Eigl, Azad. Drafting of the manuscript: Chi, Eigl, Azad, Kollmannsberger, Murray. Critical revision of the manuscript for important intellectual content: Chi, Eigl, Azad, Kollmannsberger, Murray. Statistical analysis: Azad. Obtaining funding: None. Administrative, technical, or material support: Chi, Eigl, Azad. Supervision: Chi, Eigl. Other (specify): None. Financial disclosures: Kim N. Chi 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: Kim N. Chi receives research funding from OncoGenex Technologies Inc., Astellas, Janssen, and Novartis, and is a consultant for Janssen, Astellas, Amgen, Bayer, Millennium, Novartis, and Sanofi. Bernhard J. Eigl has received an unrestricted educational grant from Janssen. Arun A. Azad receives research funding from Astellas. Funding/Support and role of the sponsor: None.
References [1] Heidenreich A, Pfister D, Merseburger A, Bartsch G. Castrationresistant prostate cancer: where we stand in 2013 and what urologists should know. Eur Urol 2013;64:260–5. [2] Beer TM, Armstrong AJ, Sternberg CN, et al. Enzalutamide in men with chemotherapy-naive metastatic prostate cancer (mCRPC): results of phase III PREVAIL study [abstract LBA1^]. J Clin Oncol 2014;32 (Suppl 4). [3] Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013;368:138–48. [4] Schrader AJ, Boegemann M, Ohlmann CH, et al. Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and abiraterone. Eur Urol 2014;65:30–6. [5] Bianchini D, Lorente D, Rodriguez-Vida A, et al. Antitumour activity
5.
Conclusions
We found that the antitumour efficacy of enzalutamide following abiraterone is similar in docetaxel-experienced and docetaxel-naive mCRPC patients. Our data suggest that therapeutic resistance to enzalutamide is not linked to prior treatment with docetaxel. Notably, enzalutamide had limited overall activity after abiraterone with or without prior docetaxel. This illustrates the importance of conducting clinical trials examining novel therapeutic approaches in patients progressing on abiraterone. Nevertheless, a subset of patients did attain relatively durable benefit from treatment with enzalutamide following abiraterone, and developing robust predictive biomarkers to identify these patients is paramount. In turn, this would optimise the use of enzalutamide and potentially lead to improved clinical outcomes for patients with mCRPC.
of enzalutamide (MDV3100) in patients with metastatic castrationresistant prostate cancer (CRPC) pre-treated with docetaxel and abiraterone. Eur J Cancer 2014;50:78–84. [6] Thomsen FB, Roder MA, Rathenborg P, Brasso K, Borre M, Iversen P. Enzalutamide treatment in patients with metastatic castrationresistant prostate cancer progressing after chemotherapy and abiraterone acetate. Scand J Urol 2014;48:268–75. [7] Schmid SC, Geith A, Boker A, et al. Enzalutamide after docetaxel and abiraterone therapy in metastatic castration-resistant prostate cancer. Adv Ther 2014;31:234–41. [8] Badrising S, van der Noort V, van Oort IM, et al. Clinical activity and tolerability of enzalutamide (MDV3100) in patients with metastatic, castration-resistant prostate cancer who progress after docetaxel and abiraterone treatment. Cancer 2014;120:968–75. [9] Cheng HH, Nadal R, Gulati R, et al. The effect of prior abiraterone (Abi) use on the activity of enzalutamide (Enza) in men with mCRPC [abstract 18]. J Clin Oncol 2014;32 (Suppl 4). [10] Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012;367:1187–97.
Please cite this article in press as: Azad AA, et al. Efficacy of Enzalutamide Following Abiraterone Acetate in Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer Patients. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.06.045
EURURO-5717; No. of Pages 7 EUROPEAN UROLOGY XXX (2014) XXX–XXX
7
[11] Sternberg CN, de Bono JS, Chi KN, et al. Improved outcomes
[21] van Soest RJ, van Royen ME, de Morree ES, et al. Cross-resistance
in elderly patients with metastatic castration-resistant prostate
between taxanes and new hormonal agents abiraterone and enza-
cancer treated with the androgen receptor inhibitor enzaluta-
lutamide may affect drug sequence choices in metastatic castra-
mide: results from the phase III AFFIRM trial. Ann Oncol 2014;
tion-resistant prostate cancer. Eur J Cancer 2013;49:3821–30.
25:429–34.
[22] Noonan KL, North S, Bitting RL, Armstrong AJ, Ellard SL, Chi KN.
[12] Zielinski RR, Tyldesley S, Chi KN. Population-based impact on
Clinical activity of abiraterone acetate in patients with metastatic
overall survival (OS) after the introduction of docetaxel as standard
castration-resistant prostate cancer progressing after enzaluta-
therapy for metastatic castration resistant prostate cancer (CRPC) [abstract 77]. J Clin Oncol 2013;31 (Suppl 6). [13] NIH-funded study shows increased survival in men with metastatic
mide. Ann Oncol 2013;24:1802–7. [23] Loriot Y, Bianchini D, Ileana E, et al. Antitumour activity of abiraterone acetate against metastatic castration-resistant prostate cancer pro-
prostate cancer who receive chemotherapy when starting hormone
gressing after docetaxel and enzalutamide (MDV3100). Ann Oncol
therapy [news release]. National Cancer Institute Web site. http://
2013;24:1807–12.
www.nih.gov/news/health/dec2013/nci-05.htm.
[24] Antonarakis ES, Lu C, Wang H, et al. Androgen receptor splice
[14] Cao B, Qi Y, Zhang G, et al. Androgen receptor splice variants
variant, AR-V7, and resistance to enzalutamide and abiraterone
activating the full-length receptor in mediating resistance to an-
in men with metastatic castration-resistant prostate cancer
drogen-directed therapy. Oncotarget 2014;30:1646–56.
(mCRPC) [abstract 5001]. J Clin Oncol 2014; 32:5s(Suppl).
[15] Joseph JD, Lu N, Qian J, et al. A clinically relevant androgen receptor
[25] Scher HI, Fizazi K, Saad F, et al. Impact of on-study corticosteroid
mutation confers resistance to second-generation antiandrogens
use on efficacy and safety in the phase III AFFIRM study of enza-
enzalutamide and ARN-509. Cancer Discov 2013;3:1020–9. [16] Korpal M, Korn JM, Gao X, et al. An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide). Cancer Discov 2013;3:1030–43. [17] Matsumoto H, Yamamoto Y, Shiota M, et al. Cotargeting androgen
lutamide (ENZA), an androgen receptor inhibitor [abstract 6]. J Clin Oncol 2013;31 (Suppl 6). [26] Goyal J, Nuhn P, Huang P, et al. The effect of clinical trial participation versus non-participation on overall survival in men receiving first-line docetaxel-containing chemotherapy for metastatic cas-
receptor and clusterin delays castrate-resistant prostate cancer
tration-resistant prostate cancer. BJU Int 2012;110:E575–82.
progression by inhibiting adaptive stress response and AR stability.
[27] Ryan CJ, Molina A, Li J, et al. Serum androgens as prognostic biomarkers
Cancer Res 2013;73:5206–17. [18] Shiota M, Yokomizo A, Takeuchi A, et al. Inhibition of protein kinase C/ Twist1 signaling augments anticancer effects of androgen deprivation
in castration-resistant prostate cancer: results from an analysis of a randomized phase III trial. J Clin Oncol 2013;31:2791–8. [28] de Bono JS, Scher HI, Montgomery RB, et al. Circulating tumor cells
and enzalutamide in prostate cancer. Clin Cancer Res 2014;20:
predict survival benefit from treatment in metastatic castration-
951–61.
resistant prostate cancer. Clin Cancer Res 2008;14:6302–9.
[19] Arora VK, Schenkein E, Murali R, et al. Glucocorticoid receptor
[29] Olmos D, Arkenau HT, Ang JE, et al. Circulating tumour cell (CTC)
confers resistance to antiandrogens by bypassing androgen recep-
counts as intermediate end points in castration-resistant prostate
tor blockade. Cell 2013;155:1309–22.
cancer (CRPC): a single-centre experience. Ann Oncol 2009;20:27–33.
[20] Antonarakis ES, Armstrong AJ. Evolving standards in the treatment
[30] Scher HI, Jia X, de Bono JS, et al. Circulating tumour cells as prognostic
of docetaxel-refractory castration-resistant prostate cancer. Pros-
markers in progressive, castration-resistant prostate cancer: a reanal-
tate Cancer Prostatic Dis 2011;14:192–205.
ysis of IMMC38 trial data. Lancet Oncol 2009;10:233–9.
Please cite this article in press as: Azad AA, et al. Efficacy of Enzalutamide Following Abiraterone Acetate in Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer Patients. Eur Urol (2014), http://dx.doi.org/10.1016/j.eururo.2014.06.045