For about a decade, poly [ADP ribose] polymerases (PARP) inhibitors have been used almost exclusively to treat tumours that are deficient in one of the BRCA genes. In advanced prostate cancer, which is largely driven by the activity of the androgen receptor (AR), accumulating preclinical evidence has suggested an interplay between the AR and PARP, which could be therapeutically exploited independently of defects in the tumour's DNA homologous recombination repair (HRR) machinery. This includes the regulation of HRR genes by the AR, a mutual influence between the activities of PARP and the AR, and the co-localisation of BRCA2 to the retinoblastoma gene in the human genome. Based on these findings, randomised clinical trials have been initiated to study the addition of a PARP inhibitor to AR pathway inhibitor therapy. Three of four randomised studies demonstrated a significantly increased anti-tumour activity in men with metastatic prostate cancer, irrespective of HRR gene alterations. In this review, we summarise the available preclinical evidence that provides the rationale for the combination of inhibitors for PARP and the AR and discuss how it might contribute to the efficacy observed in the clinic.
European journal of cancer (Oxford, England : 1990). 2023 Jul 23 [Epub ahead of print]
Neeraj Agarwal, Tian Zhang, Eleni Efstathiou, Nicolas Sayegh, Arne Engelsberg, Fred Saad, Karim Fizazi
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. Electronic address: ., Division of Hematology and Oncology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA., Houston Methodist Cancer Center, Houston, TX, USA., Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA., Pfizer Oncology Global Medical Affairs, Berlin, Germany., Centre Hospitalier de l'Université de Montréal, Université de Montréal, Montreal, Québec, Canada., Institut Gustave Roussy, University of Paris Sud, Villejuif, France.