Abstract 4047: CBP/p300 and PARP inhibitor combination treatment synergistically enhances anti-tumor efficacy in models of advanced 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 are associated with reduced progression-free and overall survival in prostate cancer patients. Our recent work has demonstrated that CBP/p300 play 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 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. To assess the utility of CBP/p300 and PARP combination therapy in patients, we treated PCa patient-derived explants (PDEs) 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. To investigate genomic alterations that may underlie differential treatment responses, we performed whole-exome sequencing (WES) on tissues from our PDE cohort. This analysis identified distinct germline and somatic variants that segregated with treatment responders versus non-responders. 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. Analysis of patient-derived models provides insight into the patient subsets most likely to benefit from this combination therapy, supporting its potential as a novel therapeutic approach 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 E. Knudsen, Ayesha A. Shafi. CBP/p300 and PARP inhibitor combination treatment synergistically enhances anti-tumor efficacy in models of advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4047.