Differential Response to Olaparib Treatment Among Men with Metastatic Castration-resistant Prostate Cancer Harboring BRCA1 or BRCA2 Versus ATM Mutations

Background: Poly ADP-ribose polymerase (PARP) inhibitors, such as olaparib, are being explored as a treatment option for metastatic castration-resistant prostate cancer (mCRPC) in men harboring mutations in homologous recombination DNA-repair genes. Whether responses to PARP inhibitors differ according to the affected gene is currently unknown.

Objective: To determine whether responses to PARP inhibitors differ between men with BRCA1/2 and those with ATM mutations.

Design, setting, and participants: This was a multicenter retrospective review of 23 consecutive men with mCRPC and pathogenic germline and/or somatic BRCA1/2 or ATM mutations treated with olaparib at three academic sites in the USA.

Outcome measurements and statistical analysis: The proportion of patients achieving a ≥50% decline in prostate-specific antigen (PSA₅₀ response) was compared using Fisher's exact test. Clinical and radiographic progression-free survival (PFS) and overall survival were estimated using Kaplan-Meier analyses and compared using the log-rank test.

Results and limitations: The study included two men with BRCA1 mutations, 15 with BRCA2 mutations, and six with ATM mutations. PSA₅₀ responses to olaparib were achieved in 76% (13/17) of men with BRCA1/2 versus 0% (0/6) of men with ATM mutations (Fisher's exact test; p=0.002). Patients with BRCA1/2 mutations had median PFS of 12.3mo versus 2.4mo for those with ATM mutations (hazard ratio 0.17, 95% confidence interval 0.05-0.57; p=0.004). Limitations include the retrospective design and relatively small sample size.

Conclusions: Men with mCRPC harboring ATM mutations experienced inferior outcomes to PARP inhibitor therapy compared to those harboring BRCA1/2 mutations. Alternative therapies should be explored for patients with ATM mutations.

Patient summary: Mutations in BRCA1/2 and ATM genes are common in metastatic prostate cancer. In this study we compared outcomes for men with BRCA1/2 mutations to those for men with ATM mutations being treated with olaparib. We found that men with ATM mutations do not respond as well as men with BRCA1/2 mutations.