Abstract PR019: 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 overall and progression-free survival in prostate cancer patients. Our recent work has demonstrated that CBP/p300 have important roles in regulating DNA repair, particularly homologous recombination, and that inhibition of CBP/p300 may sensitize mCRPC to existing therapeutics. A Phase 1/2a study investigating a 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 (CBP/p300i) 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. Importantly, a comprehensive screen with clinically relevant PARPi revealed that combination of CBP/300 and PARP inhibition demonstrate synergy across several PCa cell lines. In mechanistic studies, increased expression of DNA damage markers in mCRPC cells treated with CCS1477 alongside a PARPi (olaparib) indicated delayed DNA damage repair. Cell cycle analysis revealed G1 arrest induced by combination treatment and an increase in cell size consistent with this finding. To assess the utility of CBP/p300 and PARP combination therapy in patients, we treated PCa tissues from a racially diverse cohort with CBP/p300i and PARPi. Ki67 staining revealed decreased proliferation in combination therapy-treated tissue, supporting the findings from 2D models. Spatial transcriptomics will identify molecular signatures distinguishing responders from non-responders, advancing precision medicine in diverse populations. Our findings indicate that CBP/p300 inhibition in combination with PARPi 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 I. Richter, Sumaira Sardar, Xiaohu Zhang, Jessica D. Kindrick, Lakshmi Ravindranath, Cindy H. Chau, Craig J. Thomas, Christopher McNair, Xiaofeng A. Su, Adam Sharp, Johann de Bono, Kris Frese, William D. Figg, Karen Knudsen, Ayesha A. Shafi. Combining CBP/p300 and PARP inhibitors to enhance anti-tumor efficacy in lethal prostate cancer abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86 (2Suppl): Abstract nr PR019.