Elsevier

European Urology

Volume 70, Issue 2, August 2016, Pages 256-262
European Urology

Platinum Priority – Prostate Cancer
Editorial by Srikala S. Sridhar and Christopher J. Sweeney on pp. 263–264 of this issue
Androgen Deprivation Therapy (ADT) Plus Docetaxel Versus ADT Alone in Metastatic Non castrate Prostate Cancer: Impact of Metastatic Burden and Long-term Survival Analysis of the Randomized Phase 3 GETUG-AFU15 Trial

https://doi.org/10.1016/j.eururo.2015.11.005Get rights and content

Abstract

Background

The role of chemotherapy in metastatic non castrate prostate cancer (mNCPC) is debated. Survival benefits of docetaxel (D) added to androgen-deprivation therapy (ADT) were shown in the CHAARTED trial in patients with metastatic high-volume disease (HVD).

Objective

To assess the impact of metastatic burden and to update overall survival (OS) data of the GETUG-AFU15 study.

Design, setting, and participants

Randomized phase 3 trial of ADT plus D versus ADT alone in 385 mNCPC patients; median follow-up of 7 yr.

Outcome measurements and statistical analysis

Primary end point was OS. Secondary end points were biochemical progression-free survival (bPFS) and radiographic progression-free survival (rPFS). Retrospective analysis was by tumor volume.

Results and limitations

After a median follow-up of 83.9 mo, median OS in the overall population was 62.1 mo (95% confidence interval [CI], 49.5–73.7) and 48.6 mo (95% CI, 40.9–60.6) for ADT plus D and ADT arms, respectively (hazard ratio [HR]: 0.88 [95% CI, 0.68–1.14]; p = 0.3). Median OS in ADT plus D and ADT arms, respectively, was for HVD patients: 39.8 mo (95% CI, 28.0–53.4) versus 35.1 mo (95% CI, 29.9–43.6) (HR: 0.78 [95% CI, 0.56–1.09]; p = 0.14), for low-volume disease (LVD) patients; median was not reached (NR; 95% CI, 69.5–NR) and 83.4 mo (95% CI, 61.8–NR) (HR: 1.02 [95% CI, 0.67–1.55]; p = 0.9). For upfront metastatic patients, OS was 52.6 mo (95% CI, 43.3–66.8) and 41.5 mo (95% CI, 36.3–54.5), respectively (HR: 0.93 [95% CI, 0.69–1.25]; p = 0.6). The bPFS (HR: 0.73 [95% CI, 0.56–0.94]; p = 0.014) and rPFS (HR: 0.75 [95% CI, 0.58–0.97]; p = 0.030) were significantly longer in the ADT plus D arm. Limitations included the retrospective analysis of metastatic extent and the lack of statistical power to detect a significant difference in subgroups.

Conclusions

The post hoc analyses of the GETUG-AFU15 study demonstrated a nonsignificant 20% reduction in the risk of death in the HVD subgroup. Patients with LVD had no survival improvement with early D.

Patient summary

In this study, docetaxel added to castration did not improve survival in patients with metastatic hormone-sensitive prostate cancer, partly due to methodological issues. However, early chemotherapy should be discussed with all patients, given the data of three randomized trials including GETUG-AFU15.

Introduction

Androgen-deprivation therapy (ADT) has been the standard of care for decades in metastatic prostate cancer (PCa) [1]. In the setting of metastatic castration-resistant prostate cancer (mCRPC), docetaxel (D) demonstrated an improvement in overall survival (OS) and became the mainstay of treatment [2], [3]. In recent years, several other compounds have shown survival benefits in mCRPC, such as abiraterone, enzalutamide, cabazitaxel, radium-223, and sipuleucel-T, either before or after D [4], [5], [6], [7], [8]. Therefore the treatment landscape of mCRPC has evolved dramatically. In contrast, no new strategy has been validated in metastatic noncastrate prostate cancer (mNCPC). However, it has been shown that patients with a high metastatic burden, whatever its definition, have a poor prognosis [9], [10], [11], [12].

In the phase 3 GETUG-AFU15 study, we assessed the benefits of the addition of D to ADT in patients with mNCPC and previously showed that OS was not different in both arms after a median follow-up of 49.9 mo (54.2 and 58.9 mo in the ADT and ADT plus D arms, respectively (hazard ratio [HR]: 1.01; p = 0.9) [13]. Only biochemical progression-free survival (bPFS) and radiographic progression-free survival (rPFS) were improved in the D plus ADT arm.

The results of the CHAARTED trial that had the same design as ours were presented in 2014 [14] and published in 2015 [15]. Median OS was significantly improved in the ADT plus D arm (57.6 vs 44.0 mo; HR: 0.61; p < 0.001). There was a 17.0-mo difference between arms in patients with high-volume disease (HVD; 49.2 vs 32.2 mo; HR: 0.60; p < 0.001).

We retrospectively retrieved data on metastatic volume from medical files of all patients included in the GETUG-AFU15 study, applying the CHAARTED definition of HVD and low-volume disease (LVD) and updated survival analyses. We present long-term outcomes in the overall population and in the HVD and LVD subgroups.

Section snippets

Patients and methods

The GETUG-AFU15 trial is a French multicenter open-label randomized study [13]. From October 2004 to December 2008, 385 patients were enrolled including 193 in the ADT arm and 192 in the ADT plus D arm. Eligible patients were randomized in a 1:1 ratio to ADT plus D (75 mg/m2 for 21 d, up to nine cycles) or ADT alone. ADT consisted of orchiectomy or luteinizing hormone-releasing hormone agonists, alone or combined with nonsteroidal androgen receptor inhibitors. Randomization was stratified

Results

The GETUG-AFU15 trial randomized 385 patients including 193 in the ADT arm and 192 in the ADT plus D arm. We identified 183 patients (48%) with HVD and 202 patients (52%) with LVD. Table 1 presents their characteristics. Patients were equally distributed in the two arms with regard to their metastatic burden (percentages of patients with visceral metastases and HVD/LVD distribution).

Discussion

The role of D in the management of mNCPC is still a matter of active debate [20]. The benefit–risk ratio might be negative in some patients who will have a long-lasting nonprogressive, hormone-sensitive disease, whereas in others, early chemotherapy would target less androgen receptor pathway–mediated clones right away and avoid rapid progression toward a state in which the patient would be too frail to receive chemotherapy. This latest intuitive argument is supported by two recent phase 3

Conclusions

This retrospective analysis of OS by tumor volume in mNCPC patients enrolled in the GETUG-AFU15 randomized study showed a nonsignificant survival improvement in the D arm in the HVD subgroup. This absence of statistical significance is due to a lack of power because the study was not initially designed for subgroup analysis. Thus these apparently contradictory results actually support the conclusion drawn by the CHAARTED study with longer survival in the subgroup of patients with HVD. Despite

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