Abstract PS5-08-04: A phase 1b, multi-centre, open-label, randomized study to evaluate the safety, tolerability, and clinical activity of combining paxalisib with olaparib or pembrolizumab/chemotherapy in patients with advanced breast cancer

Abstract Background: PaxPlus-ABC (ACTRN12624001340527) is a Phase 1b open-label, parallel-group study evaluating the dual PI3K-mTOR inhibitor paxalisib in women with advanced breast cancer. Previously presented preclinical data (SABC 2024 abstract SESS-2122) support the rationale for combining paxalisib with agents such as olaparib or pembrolizumab plus chemotherapy in this setting (Melino, Tu et al 2025). In this presentation, we will share additional preclinical findings from our liquid biopsy biomarker analyses and provide an updated overview of the ongoing clinical trial. Methods: Preclinical: Liquid biopsy biomarker analysis was used to evaluate the efficacy of paxalisib in combination with either immunotherapy or olaparib in the 4T1 triple-negative breast cancer (TNBC) mouse model. Circulating tumor cells (CTCs) were characterized through detailed immunofluorescence profiling, while immune cell interactions and spatial dynamics within the tumor microenvironment were assessed using PhenoCycler-Fusion (CODEX®) spatial proteomics technology. Clinical: This Phase 1b open-label, parallel group study has two arms. Arm A (paxalisib + olaparib) will enrol patients with germline BRCA-mutated HER2-negative metastatic breast cancer previously treated with chemotherapy. Patients will receive olaparib (300 mg BID) plus daily paxalisib (15 mg or 30 mg) in 28-day cycles. Arm B (paxalisib + pembrolizumab/chemotherapy) will enrol patients with recurrent, unresectable, or metastatic triple-negative breast cancer with PD-L1 CPS ≥10. Patients will receive daily paxalisib (15 mg or 30 mg) in 21-day cycles, pembrolizumab (200 mg IV every 3 weeks), and standard-of-care chemotherapy (investigator’s choice: nab-paclitaxel or gemcitabine-carboplatin). Primary objectives are to assess the safety, tolerability, and establish a recommended Phase 2 dose of paxalisib in both combinations. Secondary objectives include evaluating liquid biopsy markers (circulating tumour cells, immune cell signatures, reinvigoration/exhaustion scoring) using digital pathology and flow cytometry. Clinical efficacy measures include progression-free survival, overall response rate, clinical benefit rate, time to response, time to progression, and overall survival. Results: Preclinical: Dual inhibition of PI3K and mTOR using paxalisib in combination with either anti-PD-1 immunotherapy or the PARP inhibitor olaparib significantly reduced circulating tumor cell (CTC) counts in the 4T1 triple-negative breast cancer (TNBC) mouse model. Further characterization revealed a marked decrease in the aggressive, mesenchymal CTC phenotype (CD45-/VIM+/SNAIL+). Spatial profiling with PhenoCycler-Fusion (CODEX®) uncovered distinct differences in immune cell localization between the paxalisib + anti-PD-1 and paxalisib + olaparib treatment groups, highlighting divergent patterns of immune cell-tumor microenvironment interactions. Clinical: Upcoming data will include updated liquid biopsy biomarker analyses, encompassing CTC enumeration and phenotyping, as well as profiling of immune cell exhaustion and reinvigoration signatures. Conclusions: Our preclinical studies demonstrated that combining paxalisib with either immunotherapy or PARP inhibition significantly reduced CTC burden and reshaped the immune landscape, leading to a decrease in metastasis. These promising findings have advanced into a Phase 1b clinical trial in patients with advanced breast cancer, with updated analysis to be presented at this meeting. References: Melino, M., Tu, WJ et al. (2025). Molecular Cancer Therapeutics PMID: 40497697 Citation Format: M. Nottage, M. Melino, A. Bain, W. Tu, S. Goh, K. Houston, J. Sanmugarajah, J. Friend, S. Rao. A phase 1b, multi-centre, open-label, randomized study to evaluate the safety, tolerability, and clinical activity of combining paxalisib with olaparib or pembrolizumab/chemotherapy in patients with advanced breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-08-04.