BRCA2 reversion mutations as a resistance mechanism to olaparib in patients with BRCA2-mutated mCRPC: A Case Series

Background: Prostate cancer with BRCA2 mutations has shown sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors such as olaparib. However, acquired resistance remains a clinical concern. One potential mechanism of resistance is the emergence of reversion mutations that restore the function of BRCA2. Although this mechanism has been observed in other tumor types, only a limited number of clinical reports have described this phenomenon in prostate cancer. This case series highlights three patients in whom BRCA2 reversion mutations were detected following disease progression on olaparib. Case presentation: We present three male patients diagnosed with metastatic castration-resistant prostate cancer, each carrying a germline BRCA2 mutation. All patients initially responded to olaparib, with a reduction in prostate-specific antigen levels and radiographic disease control. However, after approximately one year of treatment, each patient developed disease progression. Circulating tumor DNA analysis using a commercial liquid biopsy platform was performed after progression. In all cases, additional BRCA2 mutations were detected, including multiple variants predicted to restore the disrupted open reading frame of the BRCA2 gene. These findings were consistent with reversion mutations potentially restoring BRCA2 protein function and thereby conferring resistance to the PARP inhibitor. One patient additionally developed neuroendocrine differentiation during disease progression, highlighting the complexity of resistance evolution. Conclusions: This case series provides clinical evidence that BRCA2 reversion mutations may underlie acquired resistance to olaparib in prostate cancer. These observations support the utility of liquid biopsy for detecting molecular mechanisms of resistance and suggest that reversion mutations may serve as a biomarker of treatment failure. Understanding such resistance mechanisms is essential for optimizing treatment sequencing and developing novel therapeutic strategies in BRCA2 -mutated prostate cancer.