Poster Presentation 38th Lorne Cancer Conference 2026

Expanding the utility of PARP inhibitors using combination therapy with androgen receptor signalling inhibitors in prostate cancer (#245)

Mahsa Rostamiandelavar 1 , Weranja Ranasinghe 1 , Nicholas Choo 1 , Kaylene J. Simpson 2 3 , Renea Taylor 3 4 5 6 , Mitchell G. Lawrence 1 3 4 5 , Gail P. Risbridger 1 3 4 5
  1. Prostate Cancer Research Group, Monash Biomedicine Discovery Institute, Cancer Program, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia
  2. Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  3. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia 
  4. Melbourne Urological Research Alliance, Monash University, Clayton, VIC, Australia
  5. Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  6. Prostate Cancer Research Group, Monash Biomedicine Discovery Institute, Cancer Program, Department of Physiology, Monash University, Clayton, VIC, Australia

Introduction: PARP inhibitors (PARPi) are clinically approved as monotherapy for patients with defects in DNA damage response (DDR) genes, representing 20–30% of advanced prostate cancer cases. Therefore, new treatments are required for the remaining majority of prostate cancer patients without DDR deficiency. Co-targeting PARP and the androgen receptor (AR) has emerged as a promising approach to treat prostate cancer lacking DDR alterations. This study aimed to assess whether combinations of PARPi and AR signalling inhibitor (ARSi) synergistically decrease the growth of DDR-proficient prostate tumours. Methods: Organoids derived from patient-derived xenografts (PDXs) were grown in Matrigel and treated with PARPi, ARSi or their combination for 11 days. The PrestoBlue and CellTiter-Glo assays were performed to assess changes in organoids’ metabolic activity. Using an automated system, several imaging endpoints were also measured to explore the full complexity of the response to the combination treatment. SynergyFinder+ was used to score the degree of synergy at each endpoint. DDR-proficient PDXs were treated with PARPi+ARSi for 4 weeks to evaluate efficacy and tolerability, followed by IHC and RNA sequencing analyses. Results: DDR-proficient AR-positive organoids were treated with six different combinations of PARPi and ARSi demonstrating synergy in both hormone-resistant and sensitive organoids. Additionally, high-throughput assays revealed consistent synergistic effects of PARPi+ARSi on viability, morphology, and composition of DDR-proficient organoids across several metabolic and imaging readouts. The levels of synergy were comparable regardless of the type of PARPi or ARSi agent used. PARPi+ARSi significantly suppressed the growth of DDR-proficient PDXs compared to vehicle and monotherapy with acceptable tolerability. Mechanistically, the combination induced higher levels of DNA damage and reduced tumour cell proliferation. Conclusions: Overall, this study shows that PARPi+ARSi combination can synergistically suppress the growth of both DDR-proficient prostate cancer organoids and PDXs. These findings may help to broaden the spectrum of prostate cancer patients benefiting from PARPi. Furthermore, PARPi+ARSi combinations are synergistic in prostate cancer organoids regardless of the agents used. This shows that there is scope for new PARPi+ARSi combination trials with the flexibility to select and alternate between different ARSi or PARPi based on their safety profiles.