Abstract 516: Integrated genomic and transcriptional profiling of patient-derived ovarian cancers reveals HRD-associated features and <i>in vivo</i> response to PARP inhibition.

Abstract Introduction: Homologous recombination deficiency (HRD) and BRCA1/2 alterations are key biomarkers for PARP inhibitor sensitivity in ovarian cancer. Transcriptional features such as RB1 expression may further refine biologic subgroups and therapeutic hypotheses. We performed integrated DNA/RNA profiling of FFPE ovarian tumors to characterize histologic distribution, genomic alterations, genomic instability score (GIS), RB1 expression, and in vivo olaparib response in selected HRD-positive models. Methods: Thirty-two patient-derived FFPE ovarian tumor blocks were prepared, and H&amp;E sections were reviewed by an anatomic pathologist (SR) to confirm sufficient tumor content prior to next-generation sequencing. Comprehensive genomic, immune profiling, and HRD assessment were performed. RNA-seq quantified RB1 expression, with “RB1-low” defined as TPM ≤ 6.26 (study 25th percentile). Two HRD-positive models were subjected to in vivo testing of olaparib response in female NSG mice following subcutaneous implantation. Results: The cohort consisted predominantly of serous adenocarcinomas (71.9%), followed by ovarian adenocarcinoma NOS (21.9%), mucinous adenocarcinoma (3.1%), and carcinosarcoma (3.1%). TP53 mutations were present in 93.8% of cases. BRCA1 alterations were identified in 37.5% of tumors and BRCA2 alterations in 25.0%. HRD status was positive in 34.4% of cases, negative in 43.8%, and indeterminate in 21.9%. GIS scores varied across HRD categories, with HRD-positive tumors showing a range of 12-61 (median 29, mean 32.9), HRD-negative tumors ranging from 3-41 (median 11.5, mean 17.2), and indeterminate tumors ranging from 7-32 (median 19, mean 18.1). RB1-low expression was observed in 21.9% of tumors overall, with enrichment in HRD-positive cases (45.5%) compared to HRD-negative (7.1%) and indeterminate (14.3%) groups. To assess translatability of HRD findings, two HRD-positive serous adenocarcinomas were tested for olaparib response in vivo. One BRCA2-mutated tumor (LCOV-2089, GIS=32) demonstrated a robust therapeutic effect, with a median tumor volume reduction of 68.1% and durable complete responses in 33.3% of treated mice. In contrast, a second BRCA2-mutated tumor (LCOV-2118, GIS=17) did not exhibit tumor regression but showed an increased time to progression of &amp;gt;85% compared to untreated controls. Conclusions: Overall, these findings suggest a meaningful correlation between genomic HRD status and in vivo therapeutic response, supporting the translational relevance of integrated profiling and the use of patient-derived models for preclinical investigations. Citation Format: Kyle C. Strickland, Sheri Barnes, Zachary D. Wallen, Michelle F. Green, Laine V. Morris, Paul DePietro, Kobina A. Amoah, Jennifer B. Jackson, Pratheesh Sathyan, Taylor J. Jensen, Brian Caveney, Eric A. Severson, Rebecca A. Previs, Shakti Ramkissoon, Scott C. Wise. Integrated genomic and transcriptional profiling of patient-derived ovarian cancers reveals HRD-associated features and in vivo response to PARP inhibition [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 516.