# PARP Inhibitors Combined with Abiraterone Overcome Resistance in Metastatic Castration-Resistant Prostate Cancer Independently of Androgen Receptor

## TL;DR

Combining Abiraterone with PARP inhibitors helps overcome resistance in advanced prostate cancer, even in cases without specific genetic mutations.

## Contribution

The study shows that combining Abiraterone with PARP inhibitors is effective in overcoming resistance in AR-negative prostate cancer models.

## Key findings

- Combining Abiraterone with PARP inhibitors significantly reduces tumor growth in resistant prostate cancer models.
- The combination therapy is more effective than using PARP inhibitors alone in Abiraterone-resistant mCRPC.
- Results support continued use of PARP inhibitors with Abiraterone to improve clinical outcomes.

## Abstract

This study investigated the therapeutic potential of combining Abiraterone with PARP inhibitors (Niraparib or Olaparib) in Abiraterone-resistant metastatic castration-resistant prostate cancer (mCRPC). Resistant PC3 and DU145 cell lines were analyzed using 2D and 3D cultures and cell-derived xenograft (CDX) mouse models. Our results show that combining Abiraterone with PARP inhibitors enhances therapeutic efficacy and overcomes the acquired resistance in mCRPC with BRCA1/2 or HRR mutations. Thus, combining Abiraterone with PARP inhibitors is more effective than using PARP inhibitors alone in Abiraterone-resistant mCRPC. The combination therapy significantly reduces tumor growth in cell and mouse models, suggesting a promising strategy to overcome treatment resistance in advanced PC. These results support continued use of PARPi with Abiraterone to improve clinical outcomes.

Background: 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. Objectives: 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. Methods: Resistant PC3 and DU145 cell lines were analyzed using 2D and 3D cultures and cell-derived xenograft (CDX) mouse models. Results: 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. Conclusions and significance: 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.