Serial ctDNA to understand PARPi resistance

Abstract

Poly(ADP-ribose) polymerase inhibition (PARPi) is an effective therapy for castration-resistant prostate cancer (CRPC) with defects in homologous recombination repair (HRR) genes. However, resistance to PARPi can arise, for example via mutations that restore BRCA function. Reversion mutations in HRR genes can result in PARPi resistance, but these cannot arise in patients with homozygous mutations, possibly explaining why patients with homozygous BRCA2 mutations exhibit more durable responses to PARPi. The mechanisms of resistance in patients with homozygous mutations is unknown and how such mutations occur is not well understood.

A study in Cancer Cell has sought to elucidate these mechanisms, using data from the phase II TOPARP-B trial, which demonstrated antitumour activity of olaparib in patients with metastatic CRPC who had biallelic DNA-damage repair mutations. Notably, the most durable responses were seen in patients with BRCA2 homozygous deletion. These data were also supported by the PROFound trial, which showed reduced radiological progression-free survival (rPFS) in patients with BRCA2 heterozygous mutations compared with those with a homozygous mutation.