Emergence of BRCA Reversion Mutations in Prostate Cancer Prior to PARP Inhibitor Exposure: Clinical and Therapeutic Implications

ABSTRACT Background Inactivating BRCA1/2 mutations confer sensitivity to poly(ADP‐ribose) polymerase inhibitors (PARPi) in prostate cancer (PCA). However, secondary BRCA1/2 reversion mutations ( BRCA rev) can restore BRCA function and mediate acquired PARPi resistance. While BRCA rev typically arise under PARPi selective pressure, their occurrence in PARPi‐naïve settings remains incompletely understood. We sought to characterize the frequency, clinical context, and therapeutic correlates of BRCA rev detection in men with advanced PCA, including those without prior PARPi exposure. Methods We restrospectively analyzed clinical liquid biopsy results from men with PCA using FoundationOneLiquid CDx between January and December 2023. BRCA rev were defined as sequence alterations predicted to restore open reading frame of BRCA1 or BRCA2 harboring pathogenic inactivating variants. Clinical and treatment histories, including chemotherapy and PARPi exposure, were abstracted from medical records. Results Over a one‐year period, we identified 10 PCA patients with inactivating BRCA1/2 alterations, BRCA rev and available treatment history. BRCA rev were detected in three of 10 (30%) patients who had not received prior PARPi therapy. All three PARP‐naïve patients had previously received chemotherapy (platinum or docetaxel) and radiation, and each exhibited multiple BRCA rev events. The remaining 7 patients (70%) had prior olaparib exposure. Among these, the duration of PARPi response was longer in chemo‐naïve patients compared with previously treated with chemotherapy (median: 22 vs. 7.5 months, respectively). Conclusions BRCA rev can emerge in PCA in the absence of prior PARPi therapy, particularly following exposure to cytotoxic chemotherapy and radiation. These findings support that DNA‐damaging therapies may promote BRCA rev formation, potentially predisposing to primary PARPi resistance. Early integration of PARPi therapy before chemotherapy may enhance clinical benefit and circumvent emergence of primary resistance.