Molecular characterization of enzalutamide-treated bone metastatic castration-resistant prostate cancer

Eur Urol. 2015 Jan;67(1):53-60. doi: 10.1016/j.eururo.2014.05.005. Epub 2014 May 29.

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 160mg 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.

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

Publication types

  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / therapeutic use*
  • Bone Marrow / metabolism
  • Bone Marrow Neoplasms / drug therapy*
  • Bone Marrow Neoplasms / metabolism*
  • Bone Marrow Neoplasms / secondary
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / metabolism*
  • Bone Neoplasms / secondary
  • Cell Nucleus / metabolism
  • Cytoplasm / metabolism
  • Drug Resistance, Neoplasm
  • Gene Dosage
  • Humans
  • Ki-67 Antigen / metabolism
  • Male
  • Middle Aged
  • Phenylthiohydantoin / analogs & derivatives*
  • Phenylthiohydantoin / therapeutic use
  • Prospective Studies
  • Prostate-Specific Antigen / blood
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Prostatic Neoplasms, Castration-Resistant / metabolism*
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Protein Isoforms / metabolism
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism
  • Receptors, Glucocorticoid / metabolism
  • Retroviridae Proteins, Oncogenic / metabolism
  • Signal Transduction / drug effects
  • Steroid 17-alpha-Hydroxylase / metabolism
  • Testosterone / blood

Substances

  • Antineoplastic Agents
  • Ki-67 Antigen
  • MDV 3100
  • Protein Isoforms
  • Receptors, Androgen
  • Receptors, Glucocorticoid
  • Retroviridae Proteins, Oncogenic
  • oncogene proteins v-ets
  • Phenylthiohydantoin
  • Testosterone
  • Steroid 17-alpha-Hydroxylase
  • Prostate-Specific Antigen

Associated data

  • ClinicalTrials.gov/NCT01091103