Molecular characterization of enzalutamide-treated bone metastatic castration-resistant prostate cancer
E Efstathiou, M Titus, S Wen, A Hoang, M Karlou… - European urology, 2015 - Elsevier
European urology, 2015•Elsevier
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 …
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 …
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.
Elsevier