BRCA1/2 reversion mutations (BRCArev) in advanced prostate cancer in the absence of prior PARP inhibitor (PARPi) therapy.

5056 Background: In prostate cancer (PCA), BRCA1/2 alterations confer sensitivity to PARPi; however, in cases other than PCA with homozygous BRCA deletions, somatic BRCArev may restore BRCAfunction and mediate treatment resistance. In this study, we analyzed liquid biopsies of men with advanced PCA to (1) identify BRCArev, (2) to determine the clinical context in which BRCArev developed, and (3) to ascertain potential effect of prior chemotherapy on duration of PARPi response. Methods: BRCA1/2mutations were examined via liquid biopsies (FoundationOne Liquid CDx) during the course of clinical care for PCA patients during a 12-month period (from 01/2023 to 12/2023). Clinicopathological features and treatment history were extracted from medical records and/or treating oncologists’ notes. Results: Among 416 PCA patients with detected BRCA1/2 alterations, 25 (6.0%) patients harbored BRCArev that were predicted to restore BRCA function. Ten of 25 (40%) patients had detailed clinical and treatment history available. In three of 10 (30%) patients, somatic BRCArev were detected in the absence of prior PARPi therapy. All three PARP-naïve patients had been previously treated with chemotherapy (platinum or docetaxel) and radiation. Two patients had castration-resistant prostatic adenocarcinoma, while the third patient had de novo high-stage prostatic small cell neuroendocrine carcinoma without prior androgen deprivation. In all three PARP-naïve patients, multiple reversion mutations were detected per patient post-chemotherapy/radiation. Two of the three patients were predicted to have an original germline BRCA2alteration. The remaining 7 BRCArev-positive patients (70%) had prior PARPi treatment (all Olaparib). In PARPi-treated patients, duration of PARPi treatment prior to identification of BRCArev ranged from 5 to 24 months. 4 out of 7 PARPi-treated patients had received prior docetaxel, and duration of PARPi response was longer in chemo-naïve patients compared with those who had received prior docetaxel before PARPi (Mean: 18.6 vs 8.3 months, respectively). Conclusions: In men with BRCA-mutated PCA, chemotherapy and/or radiation may induce BRCArev in the absence of PARPi therapy. Testing of post-chemotherapy or radiation patients for BRCArev may be warranted prior to the start of PARPi therapy in patients with PCA. Our results support early PARPi therapy prior to radiation or chemotherapy as post-chemotherapy/radiation BRCArev may potentially dampen the future success of subsequent PARPi strategies.[Table: see text]