Androgen receptor inhibition extends PARP inhibitor activity in prostate cancer models beyond BRCA mutations and defects in homologous recombination repair.

Abstract

Clinical trials show benefit of the combination of poly(ADP-ribose) polymerase inhibitors (PARPi) with androgen receptor (AR) pathway inhibitors (ARPi) in metastatic, castration-resistant prostate cancer. While benefit was evident in patients with tumours harbouring mutations in homologous recombination repair (HRR) genes, improved outcomes were also observed in the absence of such alterations. Although there is literature linking AR with DNA repair, the basis of the interaction between the AR and PARP is unclear. We show that benefit of the combination of ARPi and PARPi in prostate cancer models with no HRR mutations requires ARPi-responsive cells and a PARPi with PARP1-trapping activity, and does not involve an effect of PARPi treatment in modulating AR transcription. Combination benefit is driven by an increase in DNA double-strand breaks and micronuclei formation, which is not due to a control of HRR gene transcription by the AR. Also, we uncover a novel role of PARP1 modulating AR recruitment to chromatin in the presence of DNA damage. These data shed light on the interplay between PARP1 and the AR in dealing with genotoxic insults and provide a mechanism-of-action consistent with the clinical benefit of the combination of PARPi and ARPi in patients with prostate cancer.