Original Article
Serum testosterone level as possible predictive marker in androgen receptor axis-targeting agents and taxane chemotherapies for castration-resistant prostate cancer

https://doi.org/10.1016/j.urolonc.2018.10.020Get rights and content

Abstract

Purpose

Currently, several therapeutic options for castration-resistant prostate cancer (CRPC) are available, for which predictive biomarkers have not been established. Therefore, we aimed to reveal the association between pretreatment serum testosterone level and antitumor outcomes when treated with androgen receptor axis-targeting agents and taxane chemotherapies for CRPC.

Patients and methods

The present study included Japanese patients with metastatic prostate cancer whose serum testosterone levels during androgen-deprivation therapy were available. The antitumor outcomes when treated with enzalutamide, abiraterone, docetaxel, and cabazitaxel with clinicopathological parameters including serum testosterone levels during androgen-deprivation therapy, as well as prognoses including progression-free survival and overall survival, were examined.

Results

Progression-free survival among men with higher serum testosterone level was superior to that among men with lower serum testosterone level when treated with enzalutamide. On the contrary, progression-free survival and overall survival among men with higher serum testosterone level were significantly inferior to those among men with lower serum testosterone level when treated with docetaxel and cabazitaxel, respectively.

Conclusions

The present study indicated distinct prognostic values of serum testosterone level when treated with androgen receptor axis-targeting agent and taxane chemotherapy for CRPC, suggesting that serum testosterone level may be useful predictive biomarker to navigate the appropriate therapy in patients with CRPC.

Introduction

Androgen-deprivation therapy (ADT) with or without up-front docetaxel or abiraterone is currently the standard treatment for metastatic prostate cancer [1], [2], [3]. However, most castration-sensitive prostate cancers (CRPCs) progress in a castration-resistant manner despite consecutive ADT, and become CRPC. For the treatment of CRPC, taxane chemotherapies including docetaxel and cabazitaxel, and radio-isotope radium-223 as well as novel androgen receptor (AR) axis-targeting (ARAT) agents including antiandrogen enzalutamide and CYP17 inhibitor abiraterone have shown various benefits including survival in patients with CRPC in clinical trials [4]. Several therapeutic options for CRPC therapy are available. Therefore, biomarkers for selecting the most appropriate therapy for the patient are urgently required.

Several possible biomarkers have been suggested for prediction of the antitumor response of ARAT agents and taxane chemotherapies. Prostate specific antigen (PSA) response and progression-free survival (PFS) when treated with ARAT agents were favorable if patients responded to primary ADT over 12 months [5]. In contrast, no significant difference in PSA response and PFS by responding duration to primary ADT was observed when treated with docetaxel [6]. As well, the presence of visceral metastasis and aggressive phenotype may be possible predictors for navigating the selection of ARAT agent or chemotherapy as suggested in APCCC 2017 [7]. Furthermore, various laboratory tests such as AR V7, and aberrations of the AR gene such as amplification and mutation, as well as aberrations in DNA repair genes and tumor-suppressor genes have been suggested as possible predictive biomarkers of therapeutic agents for CRPC [8], [9], [10]. However, it remains unclear which agent should be utilized according to the patient's characteristics since there is no established predictive biomarker for selection of a suitable therapy for the patient.

Serum testosterone levels before ADT [11], [12] and during ADT [13], [14] are well known prognostic factors for primary ADT. In addition, de novo androgen synthesis in prostate cancer tissues promotes the progression to CRPC, resulting in increased androgen level in CRPC [15], [16]. In the COU-AA-301 trial, it was reported that pretreatment serum testosterone level was a prognostic marker when treated with abiraterone and placebo in a postchemotherapy setting [17]. However, the significance of pretreatment serum testosterone level on antitumor outcomes when treated with ARAT agents and taxane chemotherapies for CRPC remains limited. Thus, in the present study, we aimed to reveal the association between pretreatment serum testosterone level and antitumor outcomes when treated with ARAT agents and taxane chemotherapies for CRPC.

Section snippets

Patients

Japanese patients who had been treated with ARAT agents including enzalutamide and abiraterone or taxane chemotherapies including docetaxel and cabazitaxel for metastatic CRPC at Kyushu University Hospital (Fukuoka, Japan) between 2008 and 2017 were included. This study was performed in accordance with the principles described in the Declaration of Helsinki and the Ethical Guidelines for Epidemiological Research enacted by the Japanese Government, and approved by the institutional review board.

Results

Patients’ background was shown in Table 1. Serum testosterone levels in all cases were confirmed to be below castration level (50 ng/ml). Most cases carried multiple distant metastatic sites to lymph node, bone, and visceral sites. Over half patients were treated as first-line therapy for CRPC while remaining cases were treated as second-, third-, and fourth-line therapies.

First, the therapeutic outcome of enzalutamide was examined according to pretreatment serum testosterone level, where

Discussion

PSA response, PSA-PFS, and cause-specific survival were better in men with higher serum testosterone level when treated with traditional antiandrogen such as bicalutamide and flutamide [21]. Consistently, higher serum testosterone level has been reported to be correlated with better PSA response when treated with various AR-targeting therapies such as diethylstilbestrol, ketoconazole, abiraterone, bicalutamide, cyproterone acetate, and enzalutamide [22]. In line with these retrospective

Conflict of interest

Masaki Shiota and Masatoshi Eto have received honoraria from Astellas, Janssen, AstraZeneca and Sanofi.

Acknowledgments

We would like to thank Edanz Group Japan for editorial assistance. This work was supported by JSPS KAKENHI (grant no. 17K11145), Medical Research Promotion Grant from Takeda Science Foundation, and Research Promotion Grant from Shin-Nihon Foundation of Advanced Medical Research.

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