PARP Inhibitors Combined with Abiraterone Overcome Resistance in Metastatic Castration-Resistant Prostate Cancer...

PC is the second most common malignancy in men, and progression to metastatic castration-resistant prostate cancer (mCRPC) after androgen deprivation therapy (ADT) remains incurable. Current treatments for mCRPC include chemotherapy, immunotherapy, radiopharmaceuticals, and second-line androgen receptor signaling inhibitors (ARSIs) such as Abiraterone. PARP inhibitors (PARPis) have recently shown clinical benefits in tumors with homologous recombination repair (HRR) deficiencies, particularly BRCA1/2 mutations. Combining PARPi with ARSIs has improved progression-free (PFS) and overall survival (OS), especially in ARSI-naïve patients, but limited data exist for resistant disease.

This work focuses on intrinsically hormone-insensitive, AR-negative, BRCA-wildtype models, representing a clinically distinct population with limited therapeutic options. We thus investigated the therapeutic potential of combining Abiraterone with PARPis (Niraparib or Olaparib) in Abiraterone-resistant prostate cancer.

Resistant PC3 and DU145 cell lines were analyzed using 2D and 3D cultures and cell-derived xenograft (CDX) mouse models.

Cytotoxicity assays revealed significantly reduced cell viability with combination therapy compared to single agents. These findings were supported by RT-qPCR, Western blot, and immunofluorescence analyses of xenograft tumors, demonstrating enhanced antitumor activity with the combination.

Overall, the results indicate that maintaining Abiraterone treatment in combination with PARPis after resistance develops provides superior therapeutic efficacy compared to PARP inhibition alone, offering a promising strategy for managing Abiraterone-resistant prostate cancer. Combining Abiraterone with PARPis enhances therapeutic efficacy and overcomes the acquired insensitivity in mCRPC with BRCA1/2 or HRR mutations. These results support continued use of PARPis with Abiraterone to improve clinical outcomes.