TY - JOUR
T1 - Molecular characterization of enzalutamide-treated bone metastatic castration-resistant prostate cancer
AU - Efstathiou, Eleni
AU - Titus, Mark
AU - Wen, Sijin
AU - Hoang, Anh
AU - Karlou, Maria
AU - Ashe, Robynne
AU - Tu, Shi Ming
AU - Aparicio, Ana
AU - Troncoso, Patricia
AU - Mohler, James
AU - Logothetis, Christopher J.
N1 - Funding Information:
Funding/Support and role of the sponsor: This study was supported in part by Medivation, Inc. (San Francisco, CA, USA) and Astellas (Northbrook, IL, USA) and by a Prostate Cancer Foundation Young Investigator Award and Career Development Award (E. Efstathiou), a National Cancer Institute Cancer Center Support Grant 5P30 CA16672-35 (E. Efstathiou), a US Department of Defense grant award (W81XWH-10-1-0273 MT), the Prostate Cancer Foundation Therapy Consortium, the Stanford Alexander Tissue Derivatives Laboratory, and the David H. Koch Center for Applied Research of Genitourinary Cancers. The sponsors reviewed and approved the manuscript.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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.
AB - 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.
KW - Adaptive feedback mechanism
KW - Androgen receptor
KW - Androgen signaling inhibition
KW - Bone metastasis
KW - Bone tumor microenvironment
KW - Castration-resistant prostate cancer
KW - Enzalutamide
KW - Predictors of outcome
KW - Primary resistance to enzalutamide
KW - Tissue-based research
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U2 - 10.1016/j.eururo.2014.05.005
DO - 10.1016/j.eururo.2014.05.005
M3 - Article
C2 - 24882673
AN - SCOPUS:84926160408
SN - 0302-2838
VL - 67
SP - 53
EP - 60
JO - European urology
JF - European urology
IS - 1
ER -