Review Article | Published:

Switching and withdrawing hormonal agents for castration-resistant prostate cancer

Nature Reviews Urology volume 12, pages 3747 (2015) | Download Citation

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.

Key points

  • The antiandrogen withdrawal syndrome (AAWS) is characterized by tumour regression and declines in serum PSA levels on discontinuation of antiandrogens or other hormonal agents

  • Initially reported in relation to flutamide, withdrawal responses have been described with other antiandrogens including bicalutamide and enzalutamide, and hormonal agents including oral corticosteroids and spironolactone

  • Mutations activating the androgen receptor (AR), AR amplification and AR coactivator overexpression can all alter ligand specificity, leading to the acquisition of partial agonist properties that account for withdrawal responses

  • Therapeutic steroids, given singly or as concomitant treatment with abiraterone and taxanes, might also be associated with treatment resistance, potentially by activation of mutant AR variants or the glucocorticoid receptor

  • The discovery of the Phe876Leu mutation in the AR has raised the possibility of a withdrawal response to newer antiandrogens such as enzalutamide and ARN-509, but clinical evidence is lacking

  • Structural molecular modelling techniques have been proposed that can identify agents that retain antitumour activity in the presence of these AR mutations

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Acknowledgements

D.L., J.M., Z.Z., A.D.S., R.F. and J.S.d.B., are employees of the Section of Medicine, which is supported by a Cancer Research UK programme grant and an Experimental Cancer Medical Centre (ECMC) grant from Cancer Research UK and the Department of Health (Ref: C51/A7401). D.L. is supported by a grant from the Spanish Society for Medical Oncology 'Beca SEOM para la Investigación Traslacional en el Extranjero'. J.M. is funded by the Medical Research Council and Prostate Cancer UK-Movember Foundation and Z.Z. is supported by a grant from the Hellenic Society of Medical Oncology.

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  1. Prostate Cancer Targeted Therapy Group, The Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK.

    • David Lorente
    • , Joaquin Mateo
    • , Zafeiris Zafeiriou
    • , Alan D. Smith
    • , Shahneen Sandhu
    • , Roberta Ferraldeschi
    •  & Johann S. de Bono

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All authors contributed equally to data research, discussions of content, writing the article and editing the manuscript before submission.

Competing interests

J.S.d.B. has received consulting fees from Ortho Biotech Oncology Research and Development (a unit of Cougar Biotechnology), consulting fees and travel support from Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Dendreon, Enzon, Exelixis, Genentech, GlaxoSmithKline, Medivation, Merck, Novartis, Pfizer, Roche, Sanofi–Aventis, Supergen, and Takeda, and grant support from AstraZeneca and Genentech. D.L., J.M., Z.Z., A.D.S., S.S. and R.F. declare no competing interests.

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Correspondence to Johann S. de Bono.

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