Functional and omics-based rationale for the induction of BRCAness by androgen receptor pathway inhibitors to sensitize prostate cancer to PARP inhibition, regardless of HRR status

BACKGROUND: Two PARP inhibitors (PARPis), olaparib and talazoparib, have been approved in combination with androgen receptor pathway inhibitors (ARPIs) for metastatic castration-resistant prostate cancer (mCRPC) in Europe, regardless of homologous-recombination repair (HRR) status. However, the mechanism in HRR-negative patients remains unclear. METHODS: We assessed PARP inhibitors (PARPis; olaparib, talazoparib) alone and with ARPIs (abiraterone, enzalutamide, apalutamide) in prostate cancer cell lines, metastatic patient-derived organoids (mPDOs), and LN-metastatic tissue slice cultures. HRDetect and multi-omics analyses were used to investigate response mechanisms. RESULTS: PARPi-ARPI combinations significantly reduced survival in LNCaP, DU145, and 22RV1 cells and produced greater cytotoxicity than either agent alone in all models. In three metastatic mPDOs, olaparib alone had no effect, whereas talazoparib reduced survival in one mPDO and ARPIs reduced survival in two. In all tested models, PARPi-ARPI combinations produced greater cytotoxicity than either agent alone. None of the mPDOs showed BRCAness by HRDetect. ARPIs downregulated RAD51 and induced a BRCAness-like state, with reduced RAD51 foci formation at DNA double-strand break sites and impaired repair capacity, thereby sensitizing cells to PARPis. In LN-metastatic tissue slice cultures, combination therapy reduced double-strand break repair capacity in 67% of samples. Proteomic analysis showed that olaparib suppressed prometastatic pathways, including epithelial-mesenchymal transition and angiogenesis. CONCLUSION: ARPIs induce a BRCAness-like phenotype through RAD51 downregulation and enhance PARPi sensitivity in metastatic prostate cancer models, supporting combined ARPI-PARPi therapy.