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PARP Inhibitors

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Management of Castration Resistant Prostate Cancer

Part of the book series: Current Clinical Urology ((CCU))

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Abstract

Synthetic lethality describes the phenomenon in which non-lethal genetic mutations are innocuous when they occur individually, but which lead to cellular lethality when they occur together. Such a concept has been exploited for the development of novel molecularly targeted agents in oncology. For example, tumor cells with deleterious BRCA1/2 gene mutations have non-functioning homologous recombination (HR) and consequent defective DNA double-strand break repair. This has been shown to result in exquisitely sensitive cell killing through the inhibition of poly(ADP-ribose) polymerase (PARP). Multiple novel antitumor agents targeting PARP are currently at different stages of preclinical and clinical development. Promising results in patients harboring germline mutations in BRCA1/2 genes have been observed in clinical trials, including patients with castration-resistant prostate cancer (CRPC). Although these mutations are known to be a risk factor for the development of prostate cancer and are predictors of a more aggressive phenotype, their prevalence among patients with prostate cancer is low. However, in view of the relevance of DNA repair systems in prostate cancer biology and emerging data supporting the role of this therapeutic strategy in certain sporadic cancers bearing other HR defects, there is now great interest in identifying and validating other predictive biomarkers to widen the role of PARP inhibitors in the treatment of CRPC. This chapter reviews the biological rational and current clinical evidence for the use of PARP inhibitors for the treatment of CRPC.

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Authors and Affiliations

  1. The Royal Marsden HNS Foundation Trust, Drug Development Unit, Sycamore House, Downs Road, Sutton, Surrey, SM2 5PT, UK

    Joaquin Mateo MD, MSc, Timothy A. Yap BSc (Hons), MBBS, MRCP, PhD & Johann S. De Bono MBChB, FRCP, MSc, PhD

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  1. Joaquin Mateo MD, MSc
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  2. Timothy A. Yap BSc (Hons), MBBS, MRCP, PhD
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  3. Johann S. De Bono MBChB, FRCP, MSc, PhD
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Correspondence to Johann S. De Bono MBChB, FRCP, MSc, PhD .

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  1. Department of Surgery, University of Montreal Hospital Center, Montreal, Québec, Canada

    Fred Saad

  2. Department of Oncology, The Johns Hopkins University, Baltimore, Maryland, USA

    Mario A. Eisenberger

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Mateo, J., Yap, T.A., De Bono, J.S. (2014). PARP Inhibitors. In: Saad, F., Eisenberger, M. (eds) Management of Castration Resistant Prostate Cancer. Current Clinical Urology. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-1176-9_18

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