PROJECT SUMMARY/ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA-22-039. Recent studies have demonstrated synergism of combined poly (ADP-ribose) polymerase (PARP) and selective cyclin-dependent kinase (CDK)4/6 inhibition in high-grade serous ovarian cancer (HGSOC) and triple-negative breast cancer (TNBC) cell lines, prompting the development of an NCI-CTEP- sponsored combination clinical trial of the PARP inhibitor olaparib and the CDK4/6 inhibitor abemaciclib. However, synergism is context-dependent and appears to occur in a background of MYC amplification or overexpression. In the absence of high levels of MYC, the G1 arrest afforded by a CDK4/6 inhibitor may antagonize PARP inhibitor-mediated cytotoxicity, which occurs during S phase. In contrast, high MYC expression may overcome CDK4/6 inhibitor-induced G1 arrest; CDK4/6 inhibition during the S and G2 phases may reduce expression of DNA repair genes, including those involved in homologous recombination (HR) repair, facilitating sensitization to PARP inhibition. Similar biology may also operate in cells expressing high levels of cyclin E. In cells with high MYC or cyclin E, concomitant exposure may produce cytotoxic synergism; however, in cells without a high degree of MYC or cyclin E expression, a sequential schedule may be required, in which olaparib precedes abemaciclib. To develop in vivo data supporting the ongoing clinical trial, we have established a Patient Derived Xenograft (PDX) Development and Treatment Center–Experimental Therapeutics Clinical Trials Network (ETCTN) collaboration to study the combination of olaparib and abemaciclib in HGSOC and TNBC PDX models. In the first Specific Aim, we will evaluate 6 models with high MYC and/or CCNE1 amplification to assess efficacy of concomitant olaparib/abemaciclib exposure compared to monotherapies. We will evaluate biomarkers of G1 arrest, reduced HR gene expression, DNA damage and apoptosis. Efficacy and pharmacodynamic endpoints will be correlated with plasma and intratumoral pharmacokinetic assessments, to evaluate potential drug-drug interactions and to establish drug concentrations required for antitumor activity and biological effectiveness. In the second Specific Aim, similar experiments will be conducted with HGSOC and TNBC PDX models that do not express high levels of MYC or cyclin E, where concomitant and sequential administration schedules will be compared, along with similar pharmacodynamic and pharmacokinetic assessments. The data derived through this collaborative effort will establish the mechanism of synergism for the combination and provide a biomarker-driven approach to the scheduling of drug administration.