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

Patients with metastatic castration-resistant prostate cancer and a BRCA mutation can benefit from treatment with rucaparib. In a cohort of 100 patients, we identify subclonal secondary BRCA reversion mutations as a major mechanism of acquired resistance to rucaparib. Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are approved in the USA for the treatment of patients with BRCA1 or BRCA2 (BRCA) mutated (BRCA+) metastatic castration-resistant prostate cancer (mCRPC). BRCA reversion mutations are a known mechanism of acquired resistance to PARP inhibitors in multiple cancer types, although their impact and prevalence in mCRPC remain unknown. To examine the prevalence of BRCA reversion mutations in the plasma of patients with BRCA+ mCRPC after progression on rucaparib. Men with BRCA+ mCRPC enrolled in Trial of Rucaparib in Prostate Indications 2 (TRITON2) were treated with rucaparib after progressing on one to two lines of androgen receptor–directed and one taxane-based therapy. Cell-free DNA from the plasma of 100 patients, collected at the end of treatment after confirmed progression before May 5, 2020, was queried for BRCA reversion mutations using next-generation sequencing (NGS). The association of clinical efficacy and postprogression genomics was measured in 100 patients with BRCA+ mCRPC treated with rucaparib. No baseline BRCA reversion mutations were observed in 100 BRCA+ patients. NGS identified somatic BRCA reversion mutations in 39% (39/100) of patients after progression. Reversion rates were similar for BRCA2 and BRCA1, irrespective of germline or somatic status, but higher in samples with a high tumor DNA fraction. Most patients with reversions (74%, 29/39) had two or more reversion mutations occurring subclonally at lower allele frequencies than the original BRCA mutations. The incidence of BRCA reversion mutations increased with the duration of rucaparib treatment. The frequency of reversion mutations was higher in patients with an objective (58%) or a prostate-specific antigen (69%) response compared with those without either (39% and 29%, respectively). These findings suggest that BRCA reversion mutations are a significant mechanism of acquired resistance to rucaparib in patients with BRCA+ mCRPC, with evidence of subclonal convergence promoting systemic resistance. Men with BRCA mutated metastatic castration-resistant prostate cancer enrolled in TRITON2 were treated with rucaparib after progressing on one to two lines of and