Dr. Dorff on Biomarkers of Response to PARP Inhibitors in Prostate Cancer

Tanya B. Dorff, MD, a medical oncologist, associate clinical professor, Department of Medical Oncology & Therapeutics Research, City of Hope, discusses biomarkers of response to PARP inhibitors under investigation in prostate cancer.

In 2020, olaparib (Lynparza) and rucaparib (Rubraca) were FDA approved for the treatment of patients with prostate cancer who harbor BRCA1/2 mutation, which can be established through tissue genomics, liquid genomics, or genetic testing, according to Dorff. Additionally, rarer mutations could also have sensitivity to PARP inhibition, but because so few patients have been studied in these areas, it is difficult to establish whether these subsets would derive a survival benefit with these agents, Dorff says.

A cohort of patients examined on the phase 3 PROfound trial (NCT02987543) of olaparib included those with a variety of mutations, such as CDK12, PALP2, FANCA, and CHEK2, Dorff continues. Because some of these alterations may be stronger predictors of response to PARP inhibitors than others, it is necessary to study the efficacy of these agents further in these subsets, Dorff says.

It is also important to look beyond DNA sequencing to understand other factors that might impact DNA repair, where there could be a synthetic lethality effect achieved with a clear DNA repair alteration, and how other actions of PARP inhibitors can be leveraged in the cross-talk with an androgen receptor (AR), Dorff adds. Currently, investigators from City of Hope are evaluating triplicate repeats in the AR to see whether they are potential novel biomarkers indicative of those who might derive benefit from PARP inhibitors, Dorff concludes.