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Emerging data demonstrate homologous recombination (HR) defects in castration-resistant prostate cancers, rendering these tumours sensitive to PARP inhibition. Here we demonstrate a direct requirement for the androgen receptor (AR) to maintain HR gene expression and HR activity in prostate cancer. We show that PARP-mediated repair pathways are upregulated in prostate cancer following androgen-deprivation therapy (ADT). Furthermore, upregulation of PARP activity is essential for the survival of prostate cancer cells and we demonstrate a synthetic lethality between ADT and PARP inhibition in vivo. Our data suggest that ADT can functionally impair HR prior to the development of castration resistance and that, this potentially could be exploited therapeutically using PARP inhibitors in combination with androgen-deprivation therapy upfront in advanced or high-risk prostate cancer., Tumours with homologous recombination (HR) defects become sensitive to PARPi. Here, the authors show that androgen receptor (AR) regulates HR and AR inhibition activates the PARP pathway in vivo, thus inhibition of both AR and PARP is required for effective treatment of high risk prostate cancer.

Since androgen receptors (AR) stimulate growth and block regression of the prostate through direct binding to nuclear sites, androgen withdrawal therapies must effectively eliminate AR from nuclei to bring about regression of prostatic carcinoma. Using this criterion, we compared the effects of surgical castration with those of 12 different androgen-withdrawal regimens on the rat prostate. The most potent treatment in this regard, a combination of cyproterone acetate and low-dose diethylstilbestrol, caused an initial objective response rate of 98% in 51 patients with stage D prostate cancer. Thus, although assays for AR are useful for evaluating new drugs, the high initial response rates to treatment make them irrelevant for routine patient selection. Accordingly, the principal reason for studying AR is to determine the cellular and molecular processes leading to the eventual emergence of androgen-resistant stem cells. At the cellular level, tumor recurrence in the androgen-dependent Shionogi tumor system is characterized by a 30-fold enrichment of stem cells that possess cytoplasmic AR but that lack the ability to retain AR in the nucleus. While at the molecular level definitive results await the purification of AR and their genes, the occurrence of biologically active truncated and chimeric forms of AR, analogous to those that have been synthesized in vitro for other steroid receptors, would predictably yield an androgen-resistant phenotype.

Hormonal responsiveness should be considered in terms of at least three homeostatic constraint mechanisms. Observations on the induction of specific responses in rat prostate reveal that certain of these are controlled differentially, and also that immature cells can be modified by low levels of androgen. The conditioning effect of low levels of steroid is further demonstrated by the benefits of fractional hormone-replacement therapy in controlling and delaying tumor progression. A revised approach to endocrine therapy of cancer should be seriously considered. This would entail the fractional replacement of hormone after ablative surgery.