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Efficacy Outcomes by Baseline Prostate-specific Antigen Quartile in the AFFIRM Trial

European Urology, 2, 67, pages 223 - 230

Abstract

Background

Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer (PCa) after docetaxel in the randomised, phase 3, double-blind, placebo-controlled, multinational Patients with Progressive Castration-Resistant Prostate Cancer Previously Treated with Docetaxel-Based Chemotherapy (AFFIRM) trial ( NCT00974311 ). Prostate-specific antigen (PSA) is commonly used as a marker of PCa disease burden, and the relationship of baseline PSA level to consequent treatment effect is of clinical interest.

Objective

Exploratory analysis to evaluate any differences in patient characteristics and efficacy outcomes by baseline PSA level in the AFFIRM trial.

Design, setting, and participants

Post hoc subanalysis of all randomised patients (n = 1199) from the AFFIRM trial.

Intervention

Participants were randomly assigned in a two-to-one ratio to receive oral enzalutamide 160 mg/d or placebo.

Outcome measurements and statistical analysis

The major clinical efficacy end points were overall survival (OS), radiographic progression-free survival (rPFS), and time to PSA progression (TTPP) versus placebo; baseline characteristics, treatment duration, and subsequent antineoplastic therapy were compared by baseline PSA quartile.

Results and limitations

Baseline PSA quartiles corresponded to the following PSA groups: <40 ng/ml (n = 299), 40 to <111 ng/ml (n = 300), 111 to <406 ng/ml (n = 300), and ≥406 ng/ml (n = 300). Enzalutamide consistently improved OS, rPFS, and TTPP compared with placebo across all subgroups, regardless of baseline PSA level. Hazard ratios for improvements in OS were 0.55 (95% confidence interval [CI], 0.36−0.85), 0.69 (95% CI, 0.47−1.02), 0.73 (95% CI, 0.53−1.01), and 0.53 (95% CI, 0.39−0.73) for PSA groups 1–4, respectively. The post hoc design of this analysis was not statistically powered to assess the relationship between baseline PSA and clinical efficacy outcomes.

Conclusions

This post hoc analysis of the AFFIRM trial demonstrates consistent benefits in OS, rPFS, and TTPP with enzalutamide regardless of baseline disease severity, as assessed by PSA.

Patient summary

Exploratory post hoc analysis of the AFFIRM trial showed that enzalutamide improves overall survival, radiographic progression-free survival, and time to prostate-specific antigen progression compared with placebo regardless of baseline disease severity, as assessed by prostate-specific antigen.

Trial registration

ClinicalTrials.gov identifier NCT00974311 .

Take Home Message

Post hoc analysis of the AFFIRM trial showed that enzalutamide consistently improved outcomes regardless of disease severity, as assessed by baseline prostate-specific antigen levels.

Keywords: Androgen receptor inhibitor, Enzalutamide, Metastatic castration-resistant prostate cancer, Prostate-specific antigen, AFFIRM trial.

1. Introduction

Prostate cancer (PCa) growth is driven by androgen receptor signalling across the clinical spectrum of the disease, including the metastatic castration-resistant PCa (mCRPC) state[1], [2], and [3]. Enzalutamide inhibits multiple steps in the androgen receptor signalling pathway, including androgen binding to the receptor, nuclear translocation of the ligand-bound androgen receptor complex, and binding of the complex to DNA [4] . Enzalutamide is approved for the treatment of patients with mCRPC previously treated with docetaxel, based on results from the randomised, double-blind, placebo-controlled, multinational, phase 3 Patients with Progressive Castration-Resistant Prostate Cancer Previously Treated with Docetaxel-Based Chemotherapy (AFFIRM) trial [5] .

AFFIRM evaluated the efficacy, safety, and tolerability of enzalutamide in men with mCRPC who had previously received docetaxel, with a primary end point of overall survival (OS) [5] . Enzalutamide demonstrated a significant benefit in OS; median OS was 18.4 mo compared with 13.6 mo in the placebo group (hazard ratio [HR]: 0.63;p < 0.001), with significant benefits in all secondary end points, including radiographic progression-free survival (rPFS), time to prostate-specific antigen progression (TTPP), time to first skeletal-related event, and soft tissue response rate [5] (allp < 0.001 vs placebo). Enzalutamide was well tolerated; the most common adverse events reported more frequently in the enzalutamide group compared with the placebo group included fatigue, diarrhoea, and hot flushes.

Prostate-specific antigen (PSA) was established as a biological marker of PCa in the 1980s [6] and is widely used to monitor disease status. PSA levels have been shown to consistently correlate with disease burden [7] and are included in several prognostic tools for survival. This relationship becomes more complex in castrate disease states [8] , in which tumours acquire more aggressive phenotypes and become more heterogeneous, both in individual disease sites and across sites [9] .

Given the evolving role of PSA in PCa disease management, we conducted a post hoc analysis of AFFIRM to investigate the efficacy profile of enzalutamide versus placebo across a spectrum of baseline PSA levels, used as an indicator of disease burden. To do so, we studied OS, rPFS, and TTPP in relation to patient groups stratified by baseline PSA levels in quartiles. Findings from the present analysis may help treating physicians to make informed decisions based on their patients’ PSA levels before initiating a treatment regimen.

2. Methods

2.1. Study design

Details of the AFFIRM trial design, patient eligibility, trial end points, and statistical analysis have been published [5] . In brief, the study was conducted at 156 centres in 15 countries in Europe, North America, Australia, South America, and South Africa. Patients with progressive mCRPC following docetaxel treatment were randomised in a 2:1 ratio to enzalutamide 160 mg/d or placebo administered orally once daily. Patients were allowed, but not required, to continue or start corticosteroids. Randomisation was stratified according to baseline Eastern Cooperative Oncology Group performance status (ECOG PS) score (0 or 1, vs 2) [10] and average daily pain scores 7 d prior to randomisation using the Brief Pain Inventory–Short Form question 3 (<4 versus ≥4) [11] . Patients were required to have a PSA level ≥2 μg/1 (2 ng/ml) at screening. Patients remained on treatment until radiographic disease progression requiring initiation of new systemic antineoplastic therapy (treatment discontinuation because of PSA level progression alone was discouraged [12] ).

2.2. Study end points

The clinical end points of AFFIRM chosen for this post hoc analysis were OS, rPFS, and TTPP. OS was defined as time from randomisation to death from any cause. rPFS, defined as time from randomisation to earliest objective evidence of radiographic progression or death due to any cause, was assessed by bone scan and computed tomography/magnetic resonance imaging scan at screening, weeks 13 and 25, and every subsequent 12 wk. Progression of soft tissue disease was assessed using Response Evaluation Criteria in Solid Tumors v.1.1, and progression of osseous disease was assessed according to bone scans showing two or more new lesions, as per the Prostate Cancer Working Group guidelines. PSA progression was defined according to the Prostate Cancer Working Group guidelines. For patients with PSA declines at week 13, PSA progression was the date that a ≥25% increase and an absolute increase of ≥2 ng/ml above the nadir were documented, confirmed by a second consecutive value obtained ≥3 wk later. For patients with no PSA decline at week 13, PSA progression was the date that a ≥25% increase and an absolute increase of ≥2 ng/ml above the baseline were documented, confirmed by a second consecutive value obtained ≥3 wk later. TTPP was defined as time from randomisation to PSA progression. Patients who were not determined to have PSA progression were censored at the date of the last assessment showing no evidence of PSA progression.

Patient demographics and characteristics at baseline, along with the use of subsequent antineoplastic therapy following discontinuation from the study, were recorded. Data obtained by 25 September 2011 (cut-off date for the planned interim analysis, which demonstrated efficacy [5] ) were included in this analysis.

2.3. Analysis by baseline prostate-specific antigen level

Based on the intent-to-treat population of AFFIRM, all randomised patients (n = 1199) were divided into quartiles by PSA level measured at baseline, which corresponded to the following PSA subgroups: <40 ng/ml (n = 299); 40 to <111 ng/ml (n = 300); 111 to <406 ng/ml (n = 300); and ≥406 ng/ml (n = 300).

2.4. Statistical analysis

All analyses were performed on the intent-to-treat population (n = 1199). Study end points comparing enzalutamide versus placebo included OS, rPFS, TTPP, duration of treatment, and subsequent antineoplastic therapy analysed by baseline PSA level quartile subgroups. Consistent with the patient sample analysis from AFFIRM [5] , the HR and 95% confidence interval (CI) were determined from a stratified Cox regression comparing enzalutamide with placebo, and estimates of median survival times and their 95% CIs for both enzalutamide and placebo arms were determined based on the Kaplan-Meier method. No formal statistical analysis was performed to compare baseline patient demographic and disease characteristics, including pain scores assessed on the Brief Pain Inventory–Short Form and ECOG PS.

3. Results

The median age and Gleason score at diagnosis were comparable among quartile subgroups. Time from diagnosis at study entry was also consistent among subgroups ( Table 1 ). Differences included median alkaline phosphatase and lactate dehydrogenase levels at baseline, which increased by quartile in relation to PSA, consistent with more advanced disease ( Table 1 ). Similarly, the proportion of patients with >20 bone metastases at screening increased with increasing baseline PSA level across the quartiles. The group with the lowest PSA levels at baseline generally had the lowest disease impairment, as indicated by the lowest frequency of percentages of patients with an ECOG PS of 2, along with mean pain score ≥4, visceral hepatic disease, and >20 bone metastases at screening. Time on the study ( Table 2 ) was also longest in patients in the lowest baseline PSA quartile (median duration of 9.6 mo for quartile 1 vs 8.0 mo for quartile 4 for enzalutamide; 3.9 mo for quartile 1 vs 2.8 for quartile 4 for placebo).

Table 1 Baseline disease characteristics

  Baseline PSA, ng/ml
  <40

(n = 299)
40 to <111

(n = 300)
111 to <406

(n = 300)
≥406

(n = 300)
  Enz PBO Enz PBO Enz PBO Enz PBO
No. 194 105 217 83 192 108 197 103
Age, yr, median (range) 68 (63–74) 69 (62–75) 69 (63–74) 68 (61–74) 70 (64–76) 70 (65–75) 70 (64–74) 70 (62–75)
Time from initial diagnosis, mo, median (range) 72.9 (40.7–133.3) 68.9 (40.2–102.1) 69.2 (43.4–119.2) 69.0 (39.7–110.0) 70.5 (42.0–112.5) 71.8 (34.0–112.6) 70.9 (40.3–120.9) 77.7 (41.3–115.2)
Gleason score at initial diagnosis, median (range) 8.0 (7.0–9.0) 8.0 (7.0–9.0) 7.5 (7.0–9.0) 8.0 (7.0–9.0) 7.0 (7.0–8.0) 7.0 (7.0–9.0) 8.0 (7.0–9.0) 8.0 (7.0–9.0)
ECOG PS 2, % 7.2 6.7 6.9 8.4 6.8 10 14 6.8
Mean pain score ≥4, % 20 26 28 24 33 39 33 25
Haemoglobin, g/l, median (range) 127 (119–135) 125 (114–134) 122 (110–130) 123 (110–133) 118 (110–130) 120 (110–129) 112 (98–122) 112 (101–126)
Alkaline phosphatase, U/l, median (range) 82 (65–114) 86 (62–117) 101 (75–186) 111 (71–233) 136 (83–278) 121 (83–277) 213 (118–452) 176 (100–409)
LDH, U/l, median (range) 187 (167–221) 201 (168–244) 198 (170–255) 204 (173–283) 219 (179–289) 214 (179–301) 257 (192–359) 239 (197–343)
Visceral liver disease at screening, % 9.8 6.7 12 9.6 12 8.3 13 9.7
Visceral lung disease at screening, % 14 17 16 16 15 17 16 9.7
>20 bone metastases at screening, % 13 16 27 37 47 39 65 59

ECOG PS = Eastern Cooperative Oncology Group performance status; Enz = enzalutamide group; LDH = lactate dehydrogenase; PBO = placebo group; PSA = prostate–specific antigen.

Table 2 Duration of study drug treatment

  Baseline PSA, ng/ml
  <40

(n = 299)
40 to <111

(n = 300)
111 to <406

(n = 300)
≥406

(n = 300)
  Enz PBO Enz PBO Enz PBO Enz PBO
No. 194 105 217 83 192 108 197 103
Median, mo 9.6 3.9 8.5 3.2 8.2 3.0 8.0 2.8
Range, mo 0.223.2 0.219.6 0.419.2 0.218.1 0.119.5 0.217.9 0.021.3 0.220.7
<3 mo, % 17 39 20 48 23 52 20 61
3–6 mo, % 16 32 21 34 18 35 19 27
6–9 mo, % 14 12 12 6.0 14 7.4 18 2.9
9–12 mo, % 23 8.6 21 6.0 23 3.7 22 5.8
12–18 mo, % 22 6.7 25 4.8 19 1.9 18 1.9
>18 mo, % 8.2 1.0 1.4 1.2 2.1 0 3.0 1.0

Enz = enzalutamide group; PBO = placebo group; PSA = prostate-specific antigen.

A summary of efficacy outcomes in all four subgroups defined by baseline PSA level is provided in Table 3 , including median (95% CI) OS, rPFS, and TTPP for enzalutamide and placebo, with corresponding HRs. Enzalutamide consistently improved OS compared with placebo in all subgroups ( Fig. 1 a−1d); HRs were 0.55 (95% CI, 0.36−0.85), 0.69 (95% CI, 0.47−1.02), 0.73 (95% CI, 0.53−1.01), and 0.53 (95% CI, 0.39−0.73) for quartiles 1–4, respectively. For quartiles 2 and 3, the 95% CIs around the HR for OS crossed unity. For quartile 1, the median OS was not reached at the data cut-off date for enzalutamide and was 19.2 mo for placebo; in comparison, for quartile 4, the median OS was 14.7 mo for enzalutamide and 9.5 mo for placebo.

Table 3 Efficacy outcomes

  Baseline PSA, ng/ml
  <40

(n = 299)
40 to <111

(n = 300)
111 to <406

(n = 300)
≥406

(n = 300)
OS
 Enzalutamide, mo, median (95% CI) n = 194

NYR

(NYR–NYR)
n = 217

18.8

(17.0–NYR)
n = 192

15.4

(13.0–NYR)
n = 197

14.7

(12.3–17.4)
 Placebo, mo, median (95% CI) n = 105

19.2

(15.8–NYR)
n = 83

16.2

(10.4–NYR)
n = 108

10.9

(9.5–14.4)
n = 103

9.5

(6.8–11.3)
 HR (95% CI) 0.55

(0.36–0.85)
0.69

(0.47–1.02)
0.73

(0.53–1.01)
0.53

(0.39–0.73)
rPFS
 Enzalutamide, mo, median (95% CI) n = 194

10.9

(8.3–13.5)
n = 217

8.3

(8.0–10.1)
n = 192

8.2

(5.6–9.0)
n = 197

8.1

(5.9–10.6)
 Placebo, mo, median (95% CI) n = 105

3.8

(2.8–5.5)
n = 83

3.2

(2.8–5.5)
n = 108

2.8

(2.8–3.0)
n = 103

2.8

(2.8–4.0)
 HR (95% CI) 0.38

(0.28–0.52)
0.39

(0.28–0.52)
0.40

(0.30–0.53)
0.41

(0.31–0.55)
TTPP
 Enzalutamide, mo, median (95% CI) n = 194

11.1

(8.3–14.0)
n = 217

8.3

(5.6–8.4)
n = 192

8.2

(5.6–8.3)
n = 197

5.8

(5.6–8.2)
 Placebo, mo, median (95% CI) n = 105

2.9

(2.8–3.0)
n = 83

3.1

(2.8–3.7)
n = 108

2.9

(2.8–3.7)
n = 103

3.7

(3.0–4.6)
 HR (95% CI) 0.20

(0.14–0.30)
0.25

(0.17–0.38)
0.23

(0.15–0.34)
0.31

(0.20–0.48)

CI = confidence interval; HR = hazard ratio; NYR = not yet reached; OS = overall survival; PSA = prostate-specific antigen; rPFS = radiographic progression-free survival; TTPP = time to PSA progression.

HR was assessed by Cox regression with treatment as covariate. HR <1 favours enzalutamide over placebo.

gr1

Fig. 1 Kaplan-Meier curves for duration of overall survival by baseline prostate-specific antigen quartile (intent-to-treat population): (a) quartile 1 (<40 ng/ml); (b) quartile 2 (40 to <111 ng/ml); (c) quartile 3 (111 to <406 ng/ml); (d) quartile 4 (≥406 ng/ml). CI = confidence interval; HR = hazard ratio; NYR = not yet reached.

Enzalutamide consistently improved rPFS and TTPP compared with placebo in all subgroups ( Fig. 2 a−2d); HRs for quartiles 1 to 4 were 0.38, 0.39, 0.40, and 0.41, respectively, for rPFS, and 0.20, 0.25, 0.23, and 0.31, respectively, for TTPP ( Fig. 3 a−3d), with 95% CIs <1 for both end points in all quartiles ( Table 3 ).

gr2

Fig. 2 Kaplan-Meier curves for duration of radiographic progression-free survival by baseline prostate-specific antigen quartile (intent-to-treat population): (a) quartile 1 (<40 ng/ml); (b) quartile 2 (40 to <111 ng/ml); (c) quartile 3 (111 to <406 ng/ml); (d) quartile 4 (≥406 ng/ml). CI = confidence interval; HR = hazard ratio.

gr3

Fig. 3 Kaplan-Meier curves for time to prostate-specific antigen progression by baseline prostate-specific antigen quartile (intent-to-treat population): (a) quartile 1 (<40 ng/ml); (b) quartile 2 (40 to <111 ng/ml); (c) quartile 3 (111 to <406 ng/ml); (d) quartile 4 (≥406 ng/ml). CI = confidence interval; HR = hazard ratio; PSA = prostate-specific antigen.

Evaluation of subsequent antineoplastic therapy in patients who progressed during the study after enzalutamide or placebo treatment showed high use of abiraterone across all PSA groups, and the numbers of patients receiving cabazitaxel and docetaxel were relatively similar ( Table 4 ). Cumulative use of antineoplastic drugs decreased with increased disease severity and disease burden as defined by baseline PSA level.

Table 4 Subsequent antineoplastic therapy

  Baseline PSA, ng/ml
Therapy <40

(n = 299)
40 to <111

(n = 300)
111 to <406

(n = 300)
≥406

(n = 300)
  Enz PBO Enz PBO Enz PBO Enz PBO
No. 194 105 217 83 192 108 197 103
Abiraterone, no. (%) 50 (26) 31 (30) 47 (22) 30 (36) 35 (18) 22 (20) 35 (18) 14 (14)
Cabazitaxel, no. (%) 23 (12) 17 (16) 25 (12) 11 (13) 15 (7.8) 16 (15) 15 (7.6) 11 (11)
Docetaxel, no. (%) 26 (13) 20 (19) 17 (7.8) 14 (17) 13 (6.8) 15 (14) 12 (6.1) 8 (7.8)
Mitoxantrone, no. (%) 3 (1.5) 11 (10) 7 (3.2) 9 (11) 9 (4.7) 14 (13) 2 (1.0) 10 (9.7)
Cumulative use, no. (%) a 80 (41) 61 (58) 82 (38) 48 (58) 61 (32) 51 (47) 53 (27) 36 (35)

a Use of multiple products by some patients (not necessarily concurrent use).

Enz = enzalutamide group; PBO = placebo group; PSA = prostate-specific antigen.

4. Discussion

This post hoc analysis was performed on four subgroups of AFFIRM patients divided by baseline PSA level as a marker of disease burden, which was supported by a higher frequency of factors associated with a shorter time to radiographic progression and inferior survival in patients in the highest quartile, and a lower frequency of visceral disease and pain and patients with a lesser performance status in the lowest quartile.

The results showed that the clinical benefit of enzalutamide relative to placebo was consistent across all subgroups, independent of disease burden. The effects were seen on all time-to-event end points, including OS, rPFS, and TTPP. Even patients in the highest quartile level of PSA experienced benefit with enzalutamide versus placebo: the HRs for OS in quartiles 1 and 4 were 0.55 and 0.53, respectively (95% CIs for HRs in quartiles 2 and 3 crossed unity); corresponding HRs for rPFS were 0.38 and 0.41. However, as expected, the median times to the different time-to-event measures were shorter as disease burden increased. In addition, enzalutamide has recently been shown to significantly improve OS and rPFS versus placebo in chemotherapy-naive patients with mCRPC in the phase 3 PREVAIL study, showing that this drug is associated with efficacy benefits across different mCRPC treatment settings [13] . Results presented in this paper also show that patients with lower baseline PSA levels were less likely to discontinue therapy because of death or disease progression, as reflected in the duration of study drug treatment across the four subgroups.

An additional finding in this post hoc analysis was that patients with higher baseline PSA levels had not only greater burden of disease at baseline but also lower rates of individual, as well as cumulative, subsequent antineoplastic drug use. In particular, the higher use of abiraterone after enzalutamide observed in this analysis is consistent with treatment patterns at the time of the AFFIRM trial for postchemotherapy patients [14] .

This analysis has limitations. There is a lack of clear correlation in the literature between PSA levels and clinical parameters such as pathologic stage, measurable soft tissue metastases, or pain, among others[15], [16], [17], [18], and [19]. In the advanced, mCRPC disease state, PSA may no longer correlate with clinical status or degree of disease burden. Therefore, rather than selecting arbitrary PSA cut-off points based on specific clinical variables, we chose to systematically evaluate response rates according to PSA quartiles, noting that PSA elevation correlates with general, baseline disease severity. In castration-resistant PCa (CRPC), the use of PSA monitoring can be misleading: for example, approximately 20% of patients who eventually respond to docetaxel first experience a PSA surge during the first weeks of treatment [20] . Assessment of TTPP may have been affected by the lack of early on-treatment measurement of PSA level; PSA was first measured at the week 13 visit in AFFIRM. The ability of this post hoc analysis to assess disease burden versus disease biology may be limited because of the specific point in the disease pathway during which these patients were enrolled in the AFFIRM trial. The assessment of PSA as an independent predictor of mortality risk above and beyond disease severity is thus outside the scope of this post hoc analysis.

Another limitation is that AFFIRM was neither designed nor powered to assess differences among subgroups defined by PSA level at baseline. Nevertheless, such differences were shown to exist in baseline characteristics and disease burden and were associated with differences in median OS. Our results were obtained in a post hoc analysis, and as such they should be interpreted with caution. Other factors, such as prognosis based on the characterisation of PSA responses at various time points following treatment, were not part of this analysis and will be addressed in future analyses. Finally, statistical significance was difficult to properly assess because of the post hoc nature of this analysis. Thus, CIs have been provided to illustrate the precision associated with point estimates.

There are few other studies assessing the effects of baseline PSA levels on outcomes with different drugs in patients with advanced mCRPC after chemotherapy. In the phase 3 trial in patients with mCRPC after docetaxel, an OS benefit with abiraterone acetate plus prednisone versus placebo plus prednisone was seen in subgroups with baseline PSA level greater than median (HR: 0.65; 95% CI, 0.53−0.79) and less than or equal to median (HR: 0.79; 95% CI, 0.63−0.99) [21] . Similarly, in the analysis of the AFFIRM trial, the OS benefit of enzalutamide versus placebo was seen in both subgroups with baseline PSA level greater than median (HR: 0.62; 95% CI, 0.50−0.78) and less than or equal to median (HR: 0.67; 95% CI, 0.50−0.89) [5] . In both the abiraterone acetate and enzalutamide trials[5] and [21], the OS benefits were greatest (but not statistically different) in the subgroups with baseline PSA level less than or equal to median, that is, PSA levels indicative of a less severe disease and lower disease burden.

In the phase 3 trial assessing ipilimumab in patients with CRPC progressing after docetaxel, a post hoc analysis suggested higher activity (including on OS) for patients with a lower disease burden [22] . In contrast, in the TROPIC study of cabazitaxel/prednisone compared with mitoxantrone/prednisone, a greater treatment benefit was observed with cabazitaxel in patients with rising baseline PSA levels, which may indicate a different underlying biology [23] . In an exploratory analysis of the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial of sipuleucel-T versus control in patients with mCRPC, lower baseline PSA was associated with a greater OS benefit from sipuleucel-T [24] . Cabozantinib does not typically induce PSA drops, although it is active clinically and according to bone scans[25] and [26].

Our results further extend and refine the report from the primary analysis of the AFFIRM trial [5] by analysing the associations between baseline PSA levels and the secondary end points of rPFS and TTPP. For both secondary end points, a numerically greater difference in time to event for enzalutamide versus placebo was seen in the lowest compared with the highest baseline PSA level group.

5. Conclusions

The current analysis provides further support for the use of enzalutamide after docetaxel in patients with mCRPC by demonstrating that consistent clinical benefits are seen with enzalutamide versus placebo irrespective of baseline disease severity as defined by baseline PSA levels. As clinically meaningful responses were observed even in patients with high baseline PSA levels, the results suggest that in patients with advanced mCRPC disease after docetaxel, life-extending therapy such as enzalutamide should be considered across the full spectrum of disease severity defined by baseline PSA level.


Author contributions:Fred Saad 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:Saad, de Bono, Shore, Fizazi, Loriot, Hirmand, Franks, Haas, Scher.

Acquisition of data:Saad, de Bono, Shore, Fizazi, Loriot, Scher.

Analysis and interpretation of data:Saad, de Bono, Shore, Fizazi, Loriot, Hirmand, Franks, Haas, Scher.

Drafting of the manuscript:Saad, de Bono, Shore, Fizazi, Loriot, Hirmand, Franks, Haas, Scher.

Critical revision of the manuscript for important intellectual content:Saad, de Bono, Shore, Fizazi, Loriot, Hirmand, Franks, Haas, Scher.

Statistical analysis:Franks.

Obtaining funding:None.

Administrative, technical, or material support:None.

Supervision:None.

Other(specify): None.

Financial disclosures:Fred Saad 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: Fred Saad has received consulting fees and travel support from Astellas and Medivation. Johann de Bono has received consulting fees and travel support from Astellas and Medivation. Karim Fizazi has participated as an advisory board member and speaker for Astellas. Yohann Loriot reports grants and personal fees from Astellas during the conduct of the study and grants and personal fees from Sanofi, Janssen, Bayer, and Cellgene outside the submitted work. Mohammad Hirmand is an employee of Medivation and owns stock in Medivation. Billy Franks and Gabriel P. Haas are employees of Astellas. Howard I. Scher has received funding from Medivation and Veridex; consulting fees from Millennium, Orion/Endo, and Sanofi-Aventis; travel support from Medivation, Millennium, Orion/Endo, Sanofi-Aventis, and AstraZeneca; and fees for participation in review activities from AstraZeneca, and he owns stock in Johnson & Johnson.

Funding/Support and role of the sponsor:Astellas and Medivation had a role in the design and conduct of the study; the collection, management, and analysis of the data; and review of the study. The authors had full access to the data and participated in reviewing and interpreting the data and paper. Writing assistance was funded by Astellas and Medivation.

Acknowledgement statement:The authors would like to thank Karen Brayshaw, PhD, at Complete HealthVizion for assistance with writing and revising the draft manuscript, based on detailed discussion and feedback from all authors.

References

  • [1] R.B. Montgomery, E.A. Mostaghel, R. Vessella, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68:4447-4454 Crossref
  • [2] C. Massard, K. Fizazi. Targeting continued androgen receptor signaling in prostate cancer. Clin Cancer Res. 2011;17:3876-3883 Crossref
  • [3] H.I. Scher, C.L. Sawyers. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol. 2005;23:8253-8261 Crossref
  • [4] C. Tran, S. Ouk, N.J. Clegg, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787-790 Crossref
  • [5] H.I. Scher, K. Fizazi, F. Saad, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197
  • [6] T.A. Stamey, N. Yang, A.R. Hay, J.E. McNeal, F.S. Freiha, E. Redwine. Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med. 1987;317:909-916 Crossref
  • [7] G.F. Carvalhal, S.N. Daudi, D. Kan, et al. Correlation between serum prostate-specific antigen and cancer volume in prostate glands of different sizes. Urology. 2010;76:1072-1076 Crossref
  • [8] S. Halabi, C.Y. Lin, W.K. Kelly, et al. Updated prognostic model for predicting overall survival in first-line chemotherapy for patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2014;32:671-677 Crossref
  • [9] R.B. Shah, R. Mehra, A.M. Chinnaiyan, et al. Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program. Cancer Res. 2004;64:9209-9216 Crossref
  • [10] M.M. Oken, R.H. Creech, D.C. Tormey, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655
  • [11] C.S. Cleeland, K.M. Ryan. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore. 1994;23:129-138
  • [12] H.I. Scher, S. Halabi, I. Tannock, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26:1148-1159 Crossref
  • [13] T.M. Beer, A.J. Armstrong, D.E. Rathkopf, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424-433
  • [14] A. Zivi, C. Massard, J. De-Bono. Changing therapeutic paradigms in castrate-resistant prostate cancer. Clin Genitourin Cancer. 2010;8:17-22 Crossref
  • [15] K. Miller, P.-A. Abrahamsson, K. Akakura, F.M.J. Debruyne, C.P. Evans, L. Klotz. The continuing role of PSA in the detection and management of prostate cancer. Eur Urol Suppl. 2007;6:327-333 Crossref
  • [16] T.A. Stamey, M. Caldwell, J.E. McNeal, R. Nolley, M. Hemenez, J. Downs. The prostate specific antigen era in the United States is over for prostate cancer: what happened in the last 20 years?. J Urol. 2004;172:1297-1301 Crossref
  • [17] W.D. Figg, K. Ammerman, N. Patronas, et al. Lack of correlation between prostate-specific antigen and the presence of measurable soft tissue metastases in hormone-refractory prostate cancer. Cancer Invest. 1996;14:513-517 Crossref
  • [18] S.L. Turner, S. Gruenewald, N. Spry, V. Gebski. Less pain does equal better quality of life following strontium-89 therapy for metastatic prostate cancer. Br J Cancer. 2001;84:297-302 Crossref
  • [19] A.J. Armstrong, E. Garrett-Mayer, Y.C. Ou Yang, et al. Prostate-specific antigen and pain surrogacy analysis in metastatic hormone-refractory prostate cancer. J Clin Oncol. 2007;25:3965-3970 Crossref
  • [20] A. Italiano, C. Ortholan, S. Oudard, et al. Docetaxel-based chemotherapy in elderly patients (age 75 and older) with castration-resistant prostate cancer. Eur Urol. 2009;55:1368-1376 Crossref
  • [21] K. Fizazi, H.I. Scher, A. Molina, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012;13:983-992 Crossref
  • [22] E.D. Kwon, C.G. Drake, H.I. Scher, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184–043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15:700-712 Crossref
  • [23] J.S. de Bono, S. Oudard, M. Ozguroglu, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147-1154 Crossref
  • [24] P.F. Schellhammer, G. Chodak, J.B. Whitmore, R. Sims, M.W. Frohlich, P.W. Kantoff. Lower baseline prostate-specific antigen is associated with a greater overall survival benefit from sipuleucel-T in the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial. Urology. 2013;81:1297-1302 Crossref
  • [25] R.J. Lee, P.J. Saylor, M.D. Michaelson, et al. A dose-ranging study of cabozantinib in men with castration-resistant prostate cancer and bone metastases. Clin Cancer Res. 2013;19:3088-3094 Crossref
  • [26] D.C. Smith, M.R. Smith, C. Sweeney, et al. Cabozantinib in patients with advanced prostate cancer: results of a phase II randomized discontinuation trial. J Clin Oncol. 2013;31:412-419 Crossref

Footnotes

a University of Montreal Hospital Centre, Montreal, QC, Canada

b Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, UK

c Carolina Urologic Research Center, Myrtle Beach, SC, USA

d Gustave Roussy, Cancer Campus Grand Paris, University of Paris Sud, Villejuif, France

e Medivation, Inc., San Francisco, CA, USA

f Astellas Global Medical Affairs, Inc., Northbrook, IL, USA

g Memorial Sloan-Kettering Cancer Center, New York, NY, USA

lowast Corresponding author. University of Montreal Health Centre, Montreal, Quebec, H2W 1T7, Canada. Tel. +1 514 890 8000 ext. 27466; Fax: +1 514 412 7620.