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Platinum Priority – Prostate Cancer
Editorial by Martin Gleave and Kim Chi on pp. 61–63 of this issue

Molecular Characterization of Enzalutamide-treated Bone Metastatic Castration-resistant Prostate Cancer

By: Eleni Efstathiou a b , Mark Titus a , Sijin Wen a , Anh Hoang a , Maria Karlou a , Robynne Ashe a , Shi Ming Tu a , Ana Aparicio a , Patricia Troncoso c , James Mohler d and Christopher J. Logothetis a lowast

European Urology, Volume 67 Issue 1, January 2015, Pages 53-60

Published online: 01 January 2015

Keywords: Enzalutamide, Castration-resistant prostate cancer, Predictors of outcome, Bone metastasis, Bone tumor microenvironment, Adaptive feedback mechanism, Androgen receptor, Primary resistance to enzalutamide, Androgen signaling inhibition, Tissue-based research

Abstract Full Text Full Text PDF (1,7 MB) Patient Summary

Abstract

Background

Enzalutamide is a novel antiandrogen with proven efficacy in metastatic castration-resistant prostate cancer (mCRPC).

Objective

To evaluate enzalutamide's effects on cancer and on androgens in blood and bone marrow, and associate these with clinical observations.

Design, setting, and participants

In this prospective phase 2 study, 60 patients with bone mCRPC received enzalutamide 160 mg orally daily and had transilial bone marrow biopsies before treatment and at 8 wk of treatment.

Outcome measurements and statistical analysis

Androgen signaling components (androgen receptor [AR], AR splice variant 7 (ARV7), v-ets avian erythroblastosis virus E26 oncogene homolog [ERG], cytochrome P450, family 17, subfamily A, polypeptide 1 [CYP17]) and molecules implicated in mCRPC progression (phospho-Met, phospho-Src, glucocorticoid receptor, Ki67) were assessed by immunohistochemistry; testosterone, cortisol, and androstenedione concentrations were assessed by liquid chromatography–tandem mass spectrometry; AR copy number was assessed by real-time polymerase chain reaction. Descriptive statistics were applied.

Results and limitations

Median time to treatment discontinuation was 22 wk (95% confidence interval, 19.9–29.6). Twenty-two (37%) patients exhibited primary resistance to enzalutamide, discontinuing treatment within 4 mo. Maximal prostate-specific antigen (PSA) decline ≥50% and ≥90% occurred in 27 (45%) and 13 (22%) patients, respectively. Following 8 wk of treatment, bone marrow and circulating testosterone levels increased. Pretreatment tumor nuclear AR overexpression (>75%) and CYP17 (>10%) expression were associated with benefit (p = 0.018). AR subcellular localization shift from the nucleus was confirmed in eight paired samples (with PSA decline) of 23 evaluable paired samples. Presence of an ARV7 variant was associated with primary resistance to enzalutamide (p = 0.018). Limited patient numbers warrant further validation.

Conclusions

The observed subcellular shift of AR from the nucleus and increased testosterone concentration provide the first evidence in humans that enzalutamide suppresses AR signaling while inducing an adaptive feedback. Persistent androgen signaling in mCRPC was predictive of benefit and ARV7 was associated with primary resistance.

Patient summary

We report a first bone biopsy study in metastatic prostate cancer in humans that searched for predictors of outcome of enzalutamide therapy. Benefit is linked to a pretreatment androgen-signaling signature.

Trial registration

ClinicalTrials.gov identifier NCT01091103 .

Take Home Message

This bone biopsy study confirms the experimentally defined enzalutamide mechanism in human metastatic castrate-resistant prostate cancer. We provide the first evidence in humans associating wild-type androgen receptor (AR) signaling with benefit and ARV7 with primary resistance, and we identify adaptive feedback between AR and androgen biosynthesis.

Keywords: Enzalutamide, Castration-resistant prostate cancer, Predictors of outcome, Bone metastasis, Bone tumor microenvironment, Adaptive feedback mechanism, Androgen receptor, Primary resistance to enzalutamide, Androgen signaling inhibition, Tissue-based research.

Footnotes

a Department of Genitourinary Medical Oncology, Stanford Alexander Tissue Derivatives Laboratory, David H. Koch Center for Applied Research of Genitourinary Cancers, Houston, TX, USA

b Department of Clinical Therapeutics, University of Athens, Athens, Greece

c Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

d Department of Urology, Roswell Park Cancer Institute, Buffalo, NY, USA

lowast Corresponding author. University of Texas M.D. Anderson Cancer Center, Department of Genitourinary Medical Oncology, Unit 1374, 1515 Holcombe Blvd., Houston, TX 77030, USA. Tel. +1 713 563 7210.

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