Urologic Oncology: Seminars and Original Investigations
Original ArticleSerum testosterone level as possible predictive marker in androgen receptor axis-targeting agents and taxane chemotherapies for castration-resistant prostate cancer
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.
References (31)
- et al.
Prior long response to androgen deprivation predicts response to next-generation androgen receptor axis targeted drugs in castration resistant prostate cancer
Eur J Cancer
(2015) - et al.
Management of patients with advanced prostate cancer: the report of the advanced prostate cancer consensus conference APCCC 2017
Eur Urol
(2018) - et al.
Biomarkers in prostate cancer–current clinical utility and future perspectives
Crit Rev Oncol Hematol
(2017) - et al.
The association of polymorphisms in the gene encoding gonadotropin releasing hormone with serum testosterone level during androgen deprivation therapy and prognosis in metastatic prostate cancer
J Urol
(2018) - et al.
Molecular characterization of enzalutamide-treated bone metastatic castration-resistant prostate cancer
Eur Urol
(2015) - et al.
Testosterone diminishes cabazitaxel efficacy and intratumoral accumulation in a prostate cancer xenograft model
EBioMedicine
(2018) - et al.
Current status of primary pharmacotherapy and future perspectives toward upfront therapy for metastatic hormone-sensitive prostate cancer
Int J Urol
(2016) - et al.
Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer
N Engl J Med
(2017) - et al.
Abiraterone for prostate cancer not previously treated with hormone therapy
N Engl J Med
(2017) Novel agents for castration-resistant prostate cancer: early experience and beyond
Int J Urol
(2016)
Efficacy of docetaxel chemotherapy in metastatic prostate cancer (mPC) patients (pts) experiencing early castration resistance (CR)
Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer
Nat Med
Independent prognostic factors in patients with metastatic (stage D2) prostate cancer. The Zoladex Study Group
JAMA
Prognostic impact of serum testosterone and body mass index before androgen-deprivation therapy in metastatic prostate cancer
Anticancer Res
Cited by (23)
Steroidogenesis in castration-resistant prostate cancer
2023, Urologic Oncology: Seminars and Original InvestigationsAndrogen and Estrogen Receptor Signaling
2022, Encyclopedia of Cell Biology: Volume 1-6, Second EditionSerum testosterone levels and testosterone ‘bounce’ phenomenon predict response to novel anti-androgen therapies in castration-resistant prostate cancer
2021, Urologic Oncology: Seminars and Original InvestigationsCitation Excerpt :Hashimoto et al. [22] had demonstrated that a higher TT level >5 ng/dl before NAAT was predictive of treatment efficacy (PSA response, PSA PFS, and overall survival) with AA and ENZ. Shiota et al. [23] echoed similar findings in his small studies of 35 CRPC patients treated with ENZ, albeit there were issues of varying timing of serum TT measurement and study population heterogeneity. Furthermore, in the post chemotherapy setting of the COU-AA-301 study, higher baseline TT levels before starting AA again demonstrated better OS [24].
Retrospective analysis of serum testosterone levels by LC-MS/MS in chemically castrated prostate cancer patients: Biological variation and analytical performance specifications
2021, Clinica Chimica ActaCitation Excerpt :For example, Ryan et al. [36] found that in a large prostate cancer population on abiraterone treatment, higher baseline serum testosterone levels (≥0.30 nmol/L) obtained by chemical castration were associated with significantly longer overall survival than lower baseline serum testosterone levels (≤0.080 nmol/L). Other reports also suggest a potential role for testosterone as a prognostic biomarker, although they lack sufficient power or appropriate study endpoints [37–39]. Although our findings indicate a potential application of the sensitive LC-MS/MS-based testosterone assay method for castrated prostate cancer patients, certain limitations of our study are apparent.
A Prospective Study of the Relationship Between Clinical Outcomes After Enzalutamide and Serum Androgen Levels Measured via Liquid Chromatography-tandem Mass Spectrometry in Patients with Castration-resistant Prostate Cancer
2021, European Urology Open ScienceCitation Excerpt :De novo androgen synthesis in prostate cancer tissues promotes progression to CRPC, resulting in an increase in androgen levels [13,14]. Several retrospective studies in CRPC found that patients with higher serum T levels before ARTA treatment experienced better therapeutic effects than patients with lower T levels did [15–17]. We thus decided to elucidate the kinetics of androgen levels after ENZ administration.
Emerging promising biomarkers for treatment decision in metastatic castration-resistant prostate cancer
2020, Urologic Oncology: Seminars and Original InvestigationsCitation Excerpt :Via this mechanism, enzalutamide has proven itself to be a potent drug in the treatment of mCRPC [51]. Serum testosterone (T) level: Shiota et al. investigated the prognostic value of serum testosterone level (T) in patients with mCRPC prior to and during therapy with either new generation AR targets (abiraterone acetate, enzalutamide) or chemotherapy (docetaxel, cabazitaxel) [52]. Data revealed that PFS in men treated with enzalutamide was significantly higher with high T levels than with low T levels.