Resistance mechanisms to PARP inhibitors (PARPi) in castration-resistant prostate cancer (CRPC) with homologous recombination repair (HRR) gene defects have been further elucidated through circulating tumor DNA (ctDNA) analysis. A recent study in Cancer Cell leveraged data from the phase II TOPARP-B trial to investigate these mechanisms, particularly in patients with biallelic DNA-damage repair mutations who demonstrated anti-tumor activity with olaparib.
The TOPARP-B trial highlighted that patients with BRCA2 homozygous deletions exhibited the most durable responses to olaparib. This observation was corroborated by findings from the PROFound trial, which indicated reduced radiological progression-free survival (rPFS) in patients with BRCA2 heterozygous mutations compared to those with homozygous mutations. These findings underscore the significance of HRR gene status in predicting treatment response.
Reversion mutations in HRR genes are a known mechanism of PARPi resistance; however, these mutations cannot arise in patients with homozygous mutations. This may explain why patients with homozygous BRCA2 mutations exhibit more durable responses to PARPi. The mechanisms of resistance in patients with homozygous mutations remain less understood, highlighting an area of ongoing research.
The study provides valuable insights into the mechanisms driving PARPi resistance, which is crucial for developing strategies to overcome resistance and improve patient outcomes in mCRPC.
