Issues

PARP inhibitors (PARPi) have demonstrated activity in patients with mutations in homologous recombination (HR) genes such as BRCA1 and BRCA2 Three related studies identified HR gene reversion mutations that confer resistance to PARPi Kondrashova and colleagues discovered secondary reversion mutations in BRCA1, RAD51C, and RAD51D in patients with PARPi-resistant ovarian cancer Similarly, Quigley, Alumkal, and colleagues identified BRCA2 reversion mutations associated with PARPi resistance in circulating cell-free DNA (cfDNA) from two patients with prostate cancer Finally, Goodall, Mateo, and colleagues found secondary reversion mutations in BRCA2 and PALB2 in cfDNA from patients with PARPi-resistant metastatic prostate cancer Together, these studies demonstrate that HR gene reversion mutations can promote resistance to PARPi For details, please see the article by Kondrashova and colleagues on page 984, the article by Quigley, Alumkal, and colleagues on page 999, and the article by Goodall, Mateo, and colleagues on page 1006.