Emergence of BRCA Reversion Mutations in Patients with Metastatic Castration-resistant Prostate Cancer After...

Area of Science:

• Oncology
• Genetics
• Pharmacology

Background:

• Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are approved for BRCA-mutated metastatic castration-resistant prostate cancer (mCRPC).
• BRCA reversion mutations are a known resistance mechanism to PARP inhibitors, but their prevalence in mCRPC is unknown.

Purpose of the Study:

• To determine the prevalence of BRCA reversion mutations in plasma from patients with BRCA-mutated mCRPC who progressed on rucaparib.
• To investigate the association between clinical efficacy and postprogression genomic alterations.

Main Methods:

• Analysis of cell-free DNA from 100 patients with BRCA-mutated mCRPC in the TRITON2 trial.
• Next-generation sequencing (NGS) was used to identify somatic BRCA reversion mutations after progression on rucaparib.

Main Results:

• No baseline BRCA reversion mutations were detected.
• NGS identified BRCA reversion mutations in 39% of patients post-progression.
• Reversion mutations were more common with longer rucaparib treatment and in patients with objective responses.

Conclusions:

• BRCA reversion mutations are a significant mechanism of acquired resistance to rucaparib in BRCA-mutated mCRPC.
• Subclonal convergence of reversion mutations may promote systemic resistance.