PARP Inhibitors: Extending Benefit Beyond BRCA-Mutant Cancers

Abstract

A mounting body of evidence now indicates that PARP inhibitors have the potential to be used as a foundation for both monotherapy and combination strategies across a wide spectrum of molecular backgrounds and tumor types. Although PARP inhibitors as a class display many similarities, critical differences in structure can translate into differences in tolerability and antitumor activity that have important implications for the clinic. Furthermore, while PARP inhibitors have demonstrated a clear role in treating tumors with underlying homologous recombination deficiencies, there is now biological and early clinical evidence to support their use in other molecular subsets of cancer, including tumors associated with high levels of replication stress such as small-cell lung cancer. In this article, we highlight the key similarities and differences between individual PARP inhibitors and their implications for the clinic. We discuss data that currently support clinical strategies for extending the benefit of PARP inhibitors beyond BRCA-mutant cancers, toward broader populations of patients through the use of novel biomarkers of homologous recombination repair deficiency (HRD), as well as predictive biomarkers rooted in mechanisms of sensitivity outside of HRD. We also explore the potential application of PARP inhibitors in earlier treatment settings, including neoadjuvant, adjuvant, and even chemoprevention approaches. Finally, we focus on promising combination therapeutic strategies, such as those with other DNA damage response (DDR) inhibitors such as ATR inhibitors, immune checkpoint inhibitors, and non-DDR-targeted agents that induce "chemical BRCAness."

PARP and PARG inhibitors in cancer treatment

“…Talazoparib administered at the recommended dose of 1 mg/d demonstrated high antitumor activity in BRCA mutated breast and ovarian cancer patients with fatigue, anemia, and thrombocytopenia as the most pronounced adverse effects (de Bono et al 2017). Clinically recommended doses and the severity of side effects correlate with the PARP inhibitor trapping potency; talazoparib as the strongest PARP trapper has the lowest recommended dose and shows the highest occurrence of anemia (de Bono et al 2017;Litton et al 2018;Pilié et al 2019a).…”

Antibody–Drug Conjugates: Future Directions in Clinical and Translational Strategies to Improve the Therapeutic Index

“…Although these types of sensitivity markers have been identified for some chemotherapies (45-48), they have not been used for patient selection; however, the more targeted approaches of ADCs may enable patient selection strategies based on warhead sensitivity profiles. Biomarkers of DNA damage response have been used for patient selection for DNA damage repair inhibitors such as PARP inhibitors (49)(50)(51)(52)(53)(54)(55)(56). Similarly, with warheads that induce DNA damage, such as topoisomerase inhibitors (TOPi) and PBD dimers, patients with aberrations in DNA damage repair pathways may have improved responses and, potentially, a broader therapeutic window.…”

ADP-ribosylation: from molecular mechanisms to human disease

“…The clinical success of PARP inhibitors in BRCA1/2-mutated breast and ovarian cancers has ignited a push for more widespread use of these compounds in cancers with a molecular signature of defective HR, irrespec-ADP-ribose mechanisms and disease 7 tive of which HR gene is mutated and in which tissue the tumour originated (Pilie et al, 2019). Similarly, novel inhibitors that selectively target different PARPs, including PARP3, PARP5a/5b, PARP7, PARP10, PARP11 and PARP14 are under investigation for the targeted treatment of cancers with alterations in particular pathways (Ishida et al, 2006;Lindgren et al, 2013;Iwata et al, 2016;Wang, Y. Q. et al, 2016b;Ferri et al, 2017;Yoneyama-Hirozane et al, 2017;Kirby et al, 2018;Moustakim et al, 2018;Murthy et al, 2018).…”