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Initial Biopsy Gleason Score as a Predictive Marker for Survival Benefit in Patients with Castration-resistant Prostate Cancer Treated with Docetaxel: Data from the TAX327 Study

European Urology, 2, 66, pages 330 - 336

Abstract

Background

Since 2004, docetaxel has been the standard first-line systemic therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). With abiraterone recently becoming available in the predocetaxel setting, it is warranted to identify subgroups of patients who may obtain the greatest benefit from docetaxel and particularly qualify for receiving docetaxel as first-line treatment for mCRPC.

Objective

We aimed to identify factors that could characterize subgroups of patients who obtain the greatest benefit from the use of docetaxel.

Design, setting, and participants

TAX327 was multinational, randomized, phase 3 study that was conducted from 2000 to 2002 in 1006 men with mCRPC.

Intervention

Patients were randomized to receive docetaxel every 3 wk (D3), weekly docetaxel (D1), or mitoxantrone every 3 wk (M3), each with prednisone.

Outcome measurements and statistical analysis

We investigated whether patients with poorly differentiated tumors (Gleason score ≥7) at diagnosis had greater benefit from D3 compared with M3 than patients with better differentiated tumors (Gleason score ≤6). Using a Cox model, we compared overall survival (OS) between the treatment groups within each subgroup of Gleason score.

Results and limitations

The TAX 327 data showed that the OS benefit of D3 versus M3 was greater in patients with high-grade tumors (median OS: 18.9 vs 14.5 mo;p = 0.009) than in patients with low-grade tumors (median OS: 21.6 vs 20.7 mo;p = 0.674). Limitations of a retrospective analysis apply.

Conclusions

The survival benefit obtained with docetaxel is most pronounced in patients with high-Gleason-score tumors (Gleason ≥7). In a time of shifting paradigms in mCRPC, with abiraterone becoming available prior to docetaxel chemotherapy, Gleason score may help in selecting patients who obtain the greatest benefit from docetaxel as first-line treatment for mCRPC. Prospective validation of these findings is warranted.

Take Home Message

The survival benefit obtained with docetaxel was most pronounced in patients with high-Gleason-score tumors (Gleason score ≥7).

Keywords: Castration-resistant prostate cancer, Taxanes, Gleason score.

1. Introduction

Treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) have expanded in recent years with the introduction of new agents like cabazitaxel, abiraterone, and enzalutamide. The current standard, first-line chemotherapeutic agent docetaxel has shown survival benefit as well as palliative benefit in the TAX327 and the Southwest Oncology Group 99-16 studies[1] and [2]. TAX327 was conducted in 1006 men with mCRPC who were randomized to receive docetaxel every 3 wk (D3), weekly docetaxel (D1), or mitoxantrone every 3 wk (M3), each with prednisone. Overall survival (OS) of patients who were treated with D3 was superior compared with M3, with an OS benefit of 2.9 mo in the final analysis [3] . The D3 arm also showed better palliation, with more patients having a pain and quality-of-life response compared with the M3 arm. Neutropenia was the most commonly observed grade 3 or 4 adverse event and occurred more frequently in patients receiving D3 (32%).

Recently, the phase 3 COU-AA-302 trial demonstrated superior radiologic progression-free survival and a trend toward improved OS for abiraterone in docetaxel-naïve mCRPC patients, as compared with prednisone alone [4] . Based on this trial, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved the use of abiraterone in patients with mCRPC prior to docetaxel chemotherapy. With new therapies available in the predocetaxel setting, it is warranted to identify subgroups of patients who may respond better to one of the treatment options, in order to better tailor therapy.

Gleason score is one of the strongest predictors of prostate cancer mortality in men with localized disease[5] and [6]. Men with poorly differentiated localized tumors (Gleason score 7–10) have a high probability of dying of prostate cancer within 10 yr of diagnosis when treated conservatively [5] . High Gleason scores for biopsy specimens are observed in 9% of patients diagnosed with localized prostate cancer [7] . In patients progressing to mCRPC, this proportion is higher, ranging from 25% to 30% of chemotherapy-naïve patients, to around 52% in men progressing after docetaxel chemotherapy[1], [8], and [9]. Recently, a high Gleason score (8–10) at the time of diagnosis was reported to be an independent risk factor for poor response to abiraterone[10] and [11]. For patients treated with the second-line taxane cabazitaxel, poorly differentiated tumors have been associated with pronounced benefits in terms of progression-free survival and OS[12] and [13]. In this post hoc analysis of the TAX327 study, we aimed to investigate whether Gleason score at initial diagnose could characterize a subgroup of patients who obtain the greatest benefit from D3 treatment compared with M3.

2. Patients and methods

2.1. Subjects and treatment

TAX327 was a randomized, nonblinded, phase 3 study, involving 1006 men with mCRPC, and was conducted in 24 countries. Full details of the trial are provided in the original report [1] . Briefly, patients were eligible if they had metastatic adenocarcinoma of the prostate, castration levels of serum testosterone (<50 ng/ml), and disease progression during hormonal therapy defined as clinically or radiographically measurable disease or by prostate-specific antigen (PSA) criteria. No prior treatment with chemotherapeutic agents other than estramustine was allowed. Participants were randomized to receive 75 mg/m2docetaxel every 3 wk, 30 mg/m2docetaxel weekly, or 12.5 mg/m2mitoxantrone every 3 wk, each with 5 mg prednisone twice daily. Baseline data were obtained for D3 and M3 in subgroups of Gleason score ≥7 and Gleason score ≤6 at diagnosis. Baseline information collected on each individual included PSA level, age, performance status, pain score, hemoglobin (Hb) level, alkaline phosphatase level, prior treatments, time from first hormonal treatment to start of study drug, time from diagnosis to start of study drug, the presence of visceral disease, and the proportion of patients with bone metastases. Treatment was planned for 30 wk in the absence of progression. The primary end point of the study was OS. The study was conducted from March 2000 through June 2002 and was approved by an institutional review board at every participating institution. Written informed consent was obtained from all participants.

2.2. Prostate-specific antigen response

Serum PSA was measured at baseline and every 3 wk during treatment. PSA decline was defined as a reduction of at least 30% or 50% from baseline that was maintained for at least 3 wk.

2.3. Statistical analyses

The TAX327 database was used to investigate if patients with poorly differentiated tumors (Gleason score ≥7) at diagnosis had greater benefit from D3 compared with M3 than patients with better differentiated tumors (Gleason score ≤6). To test whether there were differences in baseline variables known to predict OS between D3 and M3 in the Gleason score subgroups, we used the Pearson chi-square test for all categorical variables, and a two-samplettest with Cochran and Cox approximation for all continued variables. OS for D3 and M3 in the Gleason subgroups was assessed using the Kaplan-Meier method and tested by a log-rank test. To correct for baseline variables, OS between the treatment groups was further tested by a Cox regression analysis stratified by each single prognostic factor. A Cox regression without stratification was also performed.

PSA response was evaluated for D3 and M3 in the subgroups of Gleason score ≥7 and Gleason score ≤6. The Fisher's exact test was used to compare PSA response for D3 and M3 within the Gleason score subgroups.

3. Results

3.1. Baseline characteristics

Biopsy Gleason scores were available from 482 of 672 patients who received either D3 or M3. We identified 349 patients with a biopsy Gleason score of ≥7, of whom 185 were in the D3 arm and 164 in the M3 arm. There were 133 patients with a biopsy Gleason score of ≤6, of whom 62 were in the D3 arm and 71 in the M3 arm. Baseline characteristics of the Gleason score subgroups are listed in Table 1 and were well balanced between patient groups, except for an imbalance in the group of patients with an impaired Karnofsky performance score (PS) (7.6% for D3 vs 14.6% for M3;p = 0.034), and the proportion of patients with bone metastases (89.7% for D3 vs 96.3% for M3;p = 0.017).

Table 1 Baseline characteristics for patients receiving docetaxel or mitoxantone every 3 wk in the Gleason score subgroups

  Gleason 7–10 Gleason 2–6
  D3 M3 D3 M3
Patients, no. 185 164 62 71
Age, yr, median (range) 67 (42–92) 68 (43–83) 67 (49–86) 69 (45–86)
p value 0.825 0.667
Visceral disease, no. (%) 41 (22.2) 39 (23.8) 12 (19.4) 13 (18.3)
p value 0.720 0.878
Karnofsky performance score ≤70, no. (%) 14 (7.6) 24 (14.6) 10 (16.1) 10 (14.1)
p value 0.034 0.742
PSA, ng/ml, median (range) 92 (0–40 740) 144 (3–8022) 87 (4–2259) 113 (0–5720)
p value 0.444 0.163
Time from first hormonal treatment to start study drug, yr, no. (%)
 <2.5 77 (41.6) 71 (43.3) 22 (35.5) 20 (28.2)
 ≥2.5 68 (36.7) 60 (36.6) 29 (46.7) 39 (54.9)
 Missing 40 (21.6) 33 (20.1) 11 (17.7) 12 (16.9)
p value 0.920 0.806
Pain at baseline, no. (%) 85 (45.9) 81 (49.4) 28 (45.2) 35 (49.3)
p value 0.451 0.697
Hb at baseline, g/dl, median (range) 12.7 (8.9–16.2) 12.7 (8.6–16) 13 (6.4–16.2) 12.6 (9–15.7)
p value 0.905 0.292
ALP at baseline, IU/l, median (range) 191 (26–4438) 207 (51–6075) 176 (59–9900) 172 (18–5005)
p value 0.826 0.721
Prior prostatectomy, no. (%) 32 (17.3) 27 (16.5) 19 (30.6) 21 (29.6)
p value 0.836 0.893
Prior radiotherapy, no. (%) 100 (54.1) 87 (53.0) 39 (62.9) 42 (59.2)
p value 0.851 0.659
Bone metastases, no. (%) 166 (89.7) 158 (96.3) 56 (90.3) 63 (88.7)
p value 0.017 0.766
Time from diagnosis to start study drug, mo, median (range) 39.0 (2.8–197.5) 36.6 (2.3–163.6) 60.3 (8.6–234.6) 62.8 (6.6–146.3)
p value 0.716 0.394

ALP = alkaline phosphatase; D3 = docetaxel every 3 wk; Hb = hemoglobin; M3 = mitoxantone every 3 wk; PSA = prostate-specific antigen.

3.2. Overall survival in the Gleason score subgroups

The analysis showed that the OS benefit of D3 versus M3 was greater in patients diagnosed with a biopsy Gleason score ≥7 (log-rank testp = 0.009; median OS: 18.9 vs 14.5 mo), compared to patients diagnosed with a biopsy Gleason score ≤6 (log-rank testp = 0.674; median OS: 21.6 vs 20.7 mo). Survival curves are shown in Figure 1 and details are listed in Table 2 . Hazard ratios for the comparison between treatment groups were 0.69 (95% CI, 0.52–0.91) for D3 versus M3 in the Gleason ≥7 subgroup and 0.90 (95% CI, 0.56–1.46) for D3 versus M3 in the Gleason ≤6 subgroup.

gr1

Fig. 1 Kaplan-Meier estimates of overall survival for the docetaxel (75 mg/m2every 3 wk) arm and the mitoxantrone (every 3 wk) arm in (A) the Gleason score 7–10 subgroup and (B) the Gleason score 2–6 subgroup.

Table 2 Median overall survival for patients receiving docetaxel or mitoxantone every 3 wk in the Gleason score subgroups

  Gleason 7–10 Gleason 2–6
  D3 M3 D3 M3
Patients, no. 185 164 62 71
OS time, mo, median(95% CI) 18.9 (16.7–21.2) 14.5 (12.6–16.5) 21.6 (16.8–23.7) 20.7 (17.1–23.5)
Log-rank test p value 0.009 0.674

CI = confidence interval; D3 = docetaxel every 3 wk; M3 = mitoxantone every 3 wk; OS = overall survival.

To correct for baseline variables, we performed a stratified Cox regression analysis on treatment effect as assessed by OS for the Gleason subgroups, with each single stratified prognostic factor. When stratified for every baseline variable known to predict OS,pvalues for treatment effect on OS in the Gleason score ≥7 subgroup remained significant ( Table 3 ).

Table 3 Stratified Cox regression analysis on treatment effect assessed by overall survival with each single, stratified prognostic factor

  OS D3 vs M3

Gleason 7–10
OS D3 vs M3

Gleason 2–6
Stratified baseline prognostic factors p value HR (95% CI) p value HR (95% CI)
Without stratification 0.009 0.69

(0.52–0.91)
0.675 0.9

(0.56–1.46)
Age 0.008 0.68

(0.51–0.91)
0.654 0.9

(0.55–1.45)
Visceral disease 0.008 0.68

(0.52–0.91)
0.508 0.85

(0.52–1.38)
Bone metastases 0.020 0.72

(0.54–0.95)
0.693 0.91

(0.56–1.47)
Karnofsky performance score 0.014 0.7

(0.52–0.93)
0.625 0.89

(0.55–1.44)
PSA level 0.002 0.64

(0.48–0.85)
0.776 0.93

(0.57–1.51)
Time from first hormonal treatment to start study drug 0.006 0.64

(0.47–0.88)
0.983 0.99

(0.57–1.74)
Pain 0.015 0.7

(0.53–0.93)
0.966 1.01

(0.62–1.64)
Hb 0.009 0.69

(0.52–0.91)
0.625 0.89

(0.55–1.44)
Alkaline phosphatase level 0.002 0.63

(0.48–0.85)
0.667 0.9

(0.56–1.45)

CI = confidence interval; D3 = docetaxel every 3 wk; Hb = hemoglobin; HR = hazard ratio; M3 = mitoxantrone every 3 wk; PSA = prostate-specific antigen.

3.3. Prostate-specific antigen declines in the Gleason score subgroups

Clinical benefit of D3 versus M3 as assessed by the proportion of patients with a ≥30% decline in PSA level was higher in patients with Gleason score ≥7 (71.3% for D3 vs 51.3% for M3;p < 0.001) than in patients with Gleason score ≤6 (67.7% for D3 vs 56.3% for M3;p = 0.212) ( Table 4 ). Likewise, the effects of D3 versus M3 as assessed by the proportion of patients with a ≥50% decline in PSA level was also higher in the subgroup with Gleason score ≥7 (61.9% for D3 vs 41.9% for M3;p < 0.001) than in the subgroup with Gleason score ≤6 (58.1% for D3 vs 47.9% for M3;p = 0.297).

Table 4 Prostate-specific antigen response for patients receiving docetaxel or mitoxantone every 3 wk in the Gleason score subgroups

  Gleason 7–10 Gleason 2–6
  D3 M3 D3 M3
Patients, no. 185 164 62 71
Patients with missing data, no. 4 4 0 0
≥30% PSA decline, no. (%) 129 (71.3) 82 (51.3) 42 (67.7) 40 (56.3)
p value <0.001 0.212
≥50% PSA decline, no. (%) 112 (61.9) 67 (41.9) 36 (58.1) 34 (47.9)
p value <0.001 0.297

D3 = docetaxel every 3 wk; M3 = mitoxantone every 3 wk; PSA = prostate-specific antigen.

4. Discussion

In this post hoc analysis of the TAX327 study, we found that the survival benefit obtained with D3 compared with M3 was greatest in patients with high-Gleason-score tumors (Gleason score 7–10) at diagnosis. In addition, the PSA response rates for patients treated with D3 compared with M3 were higher in patients with high-Gleason-score tumors.

To our knowledge, we are the first to demonstrate the pronounced benefit of docetaxel in high-Gleason-score tumors. Our results are mirrored by findings from the TROPIC trial, which was conducted in patients with mCRPC who progressed after docetaxel chemotherapy and were randomized to cabazitaxel plus prednisone (CP) or mitoxantrone plus prednisone (MP) [14] . In that study, the OS benefit was 2.4 mo superior for CP compared with MP. In a recent post hoc analysis, a significant OS benefit for cabazitaxel versus mitoxantrone was also linked to patients with poorly differentiated tumors evaluated by World Health Organization grade (median OS: 15.2 mo vs 12.7 mo;p < 0.0001), whereas for patients with well or moderately differentiated tumors this benefit was less robust, with a median OS of 15.5 mo for cabazitaxel and 13.3 mo for mitoxantrone (p = 0.56) [12] .

In the present study, more pronounced effects of D3 in patients diagnosed with high-Gleason-score tumors were demonstrated by both OS benefit and PSA response rate. Interestingly, this reflects findings of an earlier report on the TAX327 trial by Armstrong et al., which demonstrated a decline in PSA level of ≥30% within 3 mo of chemotherapy initiation to have the highest degree of surrogacy for OS [15] .

In our opinion, the most interesting finding of the current analysis is that docetaxel is active in high-Gleason-score tumors, with an OS survival benefit of 4.4 mo in this subgroup of patients compared to 2.9 mo for the whole patient cohort in the original TAX327 study [3] . These findings are of particular interest in the light of potential contrasting findings with the new-generation hormonal agent abiraterone. In contrast with the findings for docetaxel and cabazitaxel, high Gleason score (8–10) at the time of diagnosis seems to be an independent risk factor for poor response to abiraterone (odds ratio: 0.60; 95% CI, 0.39–0.85)[10] and [11]. This finding points toward a modest efficacy of abiraterone in poorly differentiated tumors.

With new compounds for the treatment of mCRPC becoming available for clinical use and the recent FDA and EMA approval of abiraterone in the predocetaxel setting, treatment selection for individual patients becomes increasingly challenging. The observation in our study that docetaxel has the most pronounced antitumor activity in patients with high-Gleason-score tumors may provide additional guidance in treatment decisions regarding the use of docetaxel chemotherapy as first-line treatment for patients with mCRPC, especially for those patients with high-Gleason-score tumors. Conclusions from this post hoc analysis with regard to patients with low Gleason grade tumors are somewhat limited, considering the smaller subset of patients with Gleason score 2–6.

Another limitation of the current study is that the revision of the Gleason grading at the 2005 International Society of Urological Pathology consensus conference led to a grade migration or upgrading in both needle biopsy and radical prostatectomy specimens[16] and [17]. Billis et al., reported a change from Gleason 5–6 to group 7 and Gleason 5–6 to 8–10 in 15.7% and 0.6% of biopsies, respectively, using the revised Gleason grading compared to the Gleason grading before 2005 [18] . These data indicate that our results might not be applicable to a small proportion of patients (16.3%) with tumors now receiving a Gleason score 7–10 but that might have had a Gleason score 2–6 in the TAX327 era. However, although based on the Gleason grading before 2005, we have demonstrated a very strong relation between clinical benefit obtained by docetaxel and tumor differentiation in a pivotal phase 3 trial that led to the approval of this drug, which is the largest database available to address the current clinical question. Taking into account the retrospective nature of the analysis, our findings should be prospectively validated in the current setting to evaluate the implications for individual treatment decisions. With prospective studies to personalize treatment choices for the current treatment options in mCRPC still lacking, our findings are important to take into account when qualifying patients for treatment with docetaxel.

Greater benefit from docetaxel in patients with high-grade tumors might be caused by a higher proliferation rate of these tumors. Multiple reports have found a positive correlation between Gleason score and the proliferation marker Ki-67[19], [20], and [21]. In breast cancer, clinical benefit from docetaxel-based chemotherapy has been consistently higher in tumors with high Ki-67 expression[22], [23], and [24]. Moreover, poor histologic grade in locally advanced breast cancer proved to be predictive of pathologic complete response to chemotherapy containing docetaxel in a neoadjuvant setting [25] . The relationship between markers such as Ki-i67 and clinical benefit from docetaxel in prostate cancer still needs to be elucidated.

5. Conclusions

In the setting of mCRPC, the survival benefit obtained with D3 compared with M3 was most pronounced in patients with poorly differentiated tumors (Gleason score 7–10). In an era of shifting paradigms in mCRPC and with abiraterone becoming available prior to docetaxel chemotherapy, Gleason score may serve to discriminate between patients who benefit most from docetaxel chemotherapy as first-line treatment, which seems to exert pronounced efficacy in high-Gleason-score tumors, or patients with better differentiated tumors in whom treatment with abiraterone might be more beneficial. Prospective validation of the implications for the choice of first-line treatment in mCRPC is warranted.


Author contributions:Robert J. van Soest 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:De Wit, van Soest, de Morrée.

Acquisition of data:De Wit, Tannock, Eisenberger.

Analysis and interpretation of data:Van Soest, Shen, de Wit.

Drafting of the manuscript:Van Soest.

Critical revision of the manuscript for important intellectual content:De Wit, Tannock, Eisenberger, de Morrée.

Statistical analysis:Shen.

Obtaining funding:None.

Administrative, technical, or material support:Van Soest, de Morrée.

Supervision:De Wit.

Other(specify): None.

Financial disclosures:Robert J. van Soest 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: R. de Wit has received consultancy and speaker honoraria from Sanofi, Janssen, and Millenium; and research funding from Sanofi. L. Shen is employed by and owns stock in Sanofi. I. Tannock has received research funding from Sanofi. M. Eisenberger has received research funding from Sanofi. R.J. van Soest and E.S. de Morrée have no conflicts of interest to disclose.

Funding/Support and role of the sponsor:None.

Acknowledgment statement:We thank the many patients who participated in the TAX327 study and the investigators who recruited them.

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Footnotes

a Department of Urology, Erasmus University Medical Center, Rotterdam, The Netherlands

b Sanofi, Malvern, PA, USA

c Department of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, ON, Canada

d Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD, USA

e Department of Medical Oncology, Erasmus University Medical Center and Erasmus MC Cancer Institute, Rotterdam, The Netherlands

lowast Corresponding author. Department of Urology, Erasmus University Medical Center, Dr. Molewaterplein 50, Be-331, 3015 GE Rotterdam, The Netherlands. Tel. +31 107043381; Fax: +31 107044661.