Elsevier

European Journal of Cancer

Volume 61, July 2016, Pages 111-121
European Journal of Cancer

Review
Role of the novel generation of androgen receptor pathway targeted agents in the management of castration-resistant prostate cancer: A literature based meta-analysis of randomized trials

https://doi.org/10.1016/j.ejca.2016.04.002Get rights and content

Highlights

  • The pooled analysis revealed that the new androgen receptor pathway targeted agents significantly improved the OS.

  • In chemotherapy-naïve, new androgen receptor pathway targeted agents significantly improved the OSs to a greater extent.

  • New androgen receptor pathway targeted agents improved all secondary end-points.

  • The incidence of at least a grade ≥3 adverse effect was only moderately higher.

Abstract

Background

Several novel androgen receptor pathway targeted agents have recently entered on to therapeutic landscape for metastatic castration-resistant prostate cancer (CRPC). We performed a meta-analysis to assess the effect of these novel androgen receptor pathway targeted agents in improving outcome of CRPC patients.

Methods

A literature-based meta-analysis of randomized controlled trials (RCTs) in accordance with the preferences for reported items in systematic reviews and meta-analyses guidelines was undertaken. Relevant publications from PubMed, the Cochrane Library, and abstracts from American Society of Clinical Oncology meetings were searched. The primary outcome was overall survival. The secondary end-points were time to the first symptomatic skeletal event, progression-free survival, prostatic antigen specific (PSA) response rate, time to PSA progression and safety.

Results

Pooled analysis from RCTs of novel androgen receptor pathway targeted agents revealed significantly increased overall survival compared with placebo or prednisone (hazard ratio [HR] for death: 0.79, 95% confidence interval [CI]: 0.71–0.87; P < 0.00001). All secondary end-points favoured the androgen receptor pathway targeted agents, although heterogeneity was high in some cases. The pooled analysis revealed that the androgen receptor pathway targeted agents significantly improved time to the first skeletal event (HR = 0.69, 95% CI: 0.63–0.75; P < 0.00001), progression-free survival (HR = 0.48, 95% CI: 0.37–0.62; P < 0.00001), time to PSA progression (HR = 0.37, 95% CI: 0.24–0.59; P < 0.0001) and PSA response rate (relative risk [RR] = 4.46, 95% CI: 2.63–7.55; P < 0.00001). The incidence of grade ≥3 adverse events was moderately higher with androgen receptor pathway targeted agents as compared with the control arms (RR = 1.11, 95% CI: 0.98–1.25; P = 0.09).

Conclusion

This study confirmed the efficacy and safety of the novel androgen receptor pathway targeted agents.

Introduction

Prostate cancer is the second leading cause of cancer-related deaths in men in Western countries. Advanced and metastatic prostate adenocarcinoma have been traditionally managed with androgen-deprivation therapy (ADT) [1]. Despite initial responses elicited by ADT, patients invariably relapse due to the development of treatment resistance, a condition previously considered to be ‘hormone-refractory’. The term ‘hormone resistance’ is now widely recognized as a misnomer and has been replaced with ‘castration-resistant prostate cancer’ (CRPC), as most prostate cancers maintain androgen receptor (AR) signalling and hormone sensitivity despite low levels of serum testosterone. Indeed, men with advanced CRPC who have progressed during ADT continue to benefit from novel AR–targeted agents such as abiraterone and enzalutamide. In the last few years, five new agents have been approved for the treatment of metastatic CRPC [2]. Enzalutamide, a second generation AR antagonist and abiraterone, an irreversible P450c17 (CYP17) inhibitor that blocks androgen biosynthesis, which has resulted in a significant survival advantage for men with metastatic CRPC [3], [4], [5], [6]. Orteronel (TAK-700), a nonsteroidal, reversible, selective 17,20-lyase inhibitor also demonstrated antitumour activity in patients with CRPC but did not meet its primary end-point of improved overall survival (OS) [7], [8]. The next generation of AR pathway targeted agents such as ARN-509, Galeterone and ODM-201 are in advanced stages of clinical development. The collective success of these AR pathway targeted agents reinforces the persistent dependence of AR signalling in CRPC [9], [10], [11]. In this meta-analysis, the efficacy and safety from randomized controlled trials (RCTs) of these new AR pathway targeted agents in patients with metastatic CRPC have been analysed and reported.

Section snippets

Data retrieval strategies

We conducted a meta-analysis of RCTs in accordance with the preferences for reported items in systematic reviews and meta-analyses guidelines [12]. Relevant publications from PubMed, the Cochrane Library, and the American Society of Clinical Oncology (ASCO) Meeting were identified using the following search terms: prostate cancer, castration-resistant prostate cancer, CRPC, abiraterone, enzalutamide, orteronel, ARN-509, Galeterone, and ODM-201. Publications available in these databases up to

Literature review and characteristics of the included studies

Eight studies [3], [4], [5], [6], [7], [8], [17], [18] with 4901 cases in the anti-androgenic group and 3697 cases in the control group fulfilled the inclusion and exclusion criteria and were included in the meta-analysis (Fig. 1). Among these studies, there were three post-chemotherapy studies that included 3479 cases and five pre-chemotherapy studies that included 5119 cases. For COU-AA-301 and COU-AA-302, the final reports were chosen for the analysis of the HR for OS [19], [20]. An interim

Discussion

The pivotal discovery of continued AR signalling driving prostate cancer progression, despite systemic castrate levels of testosterone, has led to the development of novel AR pathway targeted agents. To the best of our knowledge, the present study is the first literature based meta-analysis of eight RCTs with more than 8500 patients that summarizes the efficacy and safety of the new AR pathway targeted agents for the treatment of CRPC. Our results revealed a reduction in the risk of death in

Conclusions

Currently, abiraterone and enzalutamide are approved for metastatic CRPC in the chemotherapy-naïve and post-chemotherapy settings. Orteronel plus prednisone did not improve the OS; however, this treatment did result in an improved PFS. Our literature-based meta-analysis supports the existing evidence for targeting the androgenic pathway as CRPC still remains a hormone-driven disease.

Conflict of interest

S.C.N. has participated in COU-AA-301, COU-AA-302, AFFIRM, PREVAIL, ELM-PC 4 and ELM-PC 5 studies. The other authors declare that there are no conflicts of interest in this work.

Acknowledgements

The authors thank the two investigators (A.P. and S.M.) who have assessed the methodological quality of each study.

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