title: Switching and withdrawing hormonal agents for castration-resistant prostate cancer.
abstract: The antiandrogen withdrawal syndrome (AAWS) is characterized by tumour regression and a decline in serum PSA on discontinuation of antiandrogen therapy in patients with prostate cancer. This phenomenon has been best described with the withdrawal of the nonsteroidal antiandrogens, bicalutamide and flutamide, but has also been reported with a wide range of hormonal agents. Mutations that occur in advanced prostate cancer and induce partial activation of the androgen receptor (AR) by hormonal agents have been suggested as the main causal mechanism of the AAWS. Corticosteroids, used singly or in conjunction with abiraterone, docetaxel and cabazitaxel might also be associated with the AAWS. The discovery of the Phe876Leu mutation in the AR, which is activated by enzalutamide, raises the possibility of withdrawal responses to novel hormonal agents. This Review focusses on the molecular mechanisms responsible for withdrawal responses, the role of AR mutations in the development of treatment resistance, and the evidence for the sequential use of antiandrogens in prostate cancer therapy. The implications of AR mutations for the development of novel drugs that target the AR are discussed, as are the challenges associated with redefining the utility of older treatments in the current therapeutic landscape.
authors.affiliation: Prostate Cancer Targeted Therapy Group, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK.
authors.forename: David
authors.initials: D
authors.lastname: Lorente
authors.affiliation: Prostate Cancer Targeted Therapy Group, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Mateo
authors.affiliation: Prostate Cancer Targeted Therapy Group, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK.
authors.forename: Zafeiris
authors.initials: Z
authors.lastname: Zafeiriou
authors.affiliation: Prostate Cancer Targeted Therapy Group, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK.
authors.forename: Alan D
authors.initials: AD
authors.lastname: Smith
authors.affiliation: Prostate Cancer Targeted Therapy Group, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK.
authors.forename: Shahneen
authors.initials: S
authors.lastname: Sandhu
authors.affiliation: Prostate Cancer Targeted Therapy Group, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK.
authors.forename: Roberta
authors.initials: R
authors.lastname: Ferraldeschi
authors.affiliation: Prostate Cancer Targeted Therapy Group, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK.
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
mesh_terms: D000726:Androgen Antagonists / Q000008:administration & dosage* / Q000627:therapeutic use; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D004334:Drug Administration Schedule; D006801:Humans; D008297:Male; D009154:Mutation; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome; D028761:Withholding Treatment
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D011944:Receptors, Androgen