Abstract LB011: Combining CBP/p300 and PARP inhibitors to enhance anti-tumor efficacy in lethal prostate cancer

Abstract Metastatic castration-resistant prostate cancer (mCRPC) is a uniformly fatal disease which has displayed resistance to many single-agent therapies, underscoring the need for novel combination therapies. Histone acetyltransferases CBP/p300, which act as androgen receptor (AR) coactivators, are often upregulated in mCRPC. Elevated CBP/p300 levels correlate with reduced survival overall and progression-free survival in prostate cancer (PCa) patients. Our recent work has demonstrated that CBP/p300 have important roles in regulating DNA repair, particularly homologous recombination (HR), and that inhibition of CBP/p300 may sensitize mCRPC to existing therapeutics. A Phase 1/2a study investigating the CBP/p300 inhibitor CCS1477 alone and in combination regimens is currently underway; however, research into CCS1477 combination treatments is highly limited, necessitating further investigation into combination therapies and markers of sensitivity to improve outcomes for mCRPC patients. We hypothesized that combination treatment using CBP/p300 inhibitors with PARP inhibitors (PARPi) would enhance anticancer effects by synergistically impairing DNA damage repair in cancer cells. Using preclinical 2D and 3D models, including patient-derived explants, we evaluated the mechanistic and functional impacts of targeting CBP/p300 and PARP pathways in combination. We found that this combination therapy was significantly more effective than either monotherapy at reducing cell growth both in vitro and ex vivo. In mechanistic studies, increased expression of DNA damage markers in mCRPC cells treated with CCS1477 alongside the PARPi olaparib indicated delayed DNA damage repair. Ongoing studies are evaluating growth arrest, cytotoxicity, and apoptosis in treated cells to provide additional mechanistic insight into the observed decrease in cell viability. To assess the utility of CBP/p300 and PARP combination therapy in patients, we treated PCa tissues from a racially diverse patient cohort with CBP/p300 and PARP inhibitors. Ki67 staining revealed decreased proliferation in patient tissue treated with combination therapy, supporting the findings from 2D models. Spatial transcriptomics will identify molecular signatures distinguishing responders from non-responders, advancing precision medicine in diverse populations. In conclusion, our findings indicate that CBP/p300 inhibition in combination with PARP inhibitors may have stronger anti-tumor effects than single-agent therapies, offering a promising novel therapeutic option to improve outcomes for mCRPC patients. Citation Format: Orly Richter, Sumaira Sardar, Lakshmi Ravindranath, Christopher McNair, Xiaofeng Su, Adam Sharp, Johann de Bono, Kris Frese, Karen Knudsen, Ayesha Shafi. Combining CBP/p300 and PARP inhibitors to enhance anti-tumor efficacy in lethal prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB011.