Characterizing Response to PARP Inhibitor Treatment Combinations in Advanced Prostate Cancer

Background/Objectives: Combinations of PARP inhibitors (PARPi) and androgen receptor pathway inhibitors (ARPi) have led to clinical success in treating advanced prostate cancer. However, it is unclear where in the clinical paradigm these combinations will fare best, and their mechanism of action remains unclear. We sought to address open questions and explore alternative strategies to enhance PARPi efficacy. Methods: Viability and morphology were assessed in response to (1) abiraterone, olaparib, or combination and (2) enzalutamide, talazoparib, or combination in castration-resistant C4-2B cells and abiraterone- or enzalutamide-resistant derivative cell models (ARPi-resistant). The efficacy of the ATM inhibitor lartesertib with and without a PARPi was also determined. Western blots and RNA-sequencing were used to interrogate the mechanistic effects of treatment. Results: PARPi and ARPi combinations were effective in all models but provided the most benefit in ARPi-sensitive C4-2B cells. Mechanistically, ARPi was not found to affect homologous recombination repair gene expression but may increase PARP activity. Prolonged PARP inhibition was found to increase the expression of AR target genes, and PARPi pre-treatment increased sensitivity to enzalutamide. ATM inhibition significantly increases PARPi efficacy and appears to outperform ARPi-containing combinations in ARPi-resistant models. Conclusions: PARPi and ARPi combinations are effective in ARPi-resistant models, but efficacy appears stronger in ARPi-sensitive CRPC cells. Presented findings support a novel hypothesis that PARP inhibition may increase ARPi sensitivity with increasing AR activity. Additionally, ATM inhibition may provide more benefit than an ARPi in combination with a PARPi in ARPi-resistant settings. These findings support continued PARPi development for improving patient outcomes.