Sacituzumab Govitecan, combination with PARP inhibitor, Talazoparib, in metastatic triplenegative breast cancer (TNBC): Translational investigation

Abstract Background: Sacituzumab Govitecan (SG), the first antibody-drug conjugate approved for metastatic TNBC (mTNBC), is comprised of SN-38 (active metabolite of irinotecan), a topoisomerase I (TOP1) inhibitor, coupled via a hydrolyzable linker to monoclonal antibody targeting trophoblast cell surface antigen 2 (Trop-2), an antigen overexpressed in mTNBC. Poly (ADP-ribose) polymerase inhibitors (PARPi) block resolution of TOP1 cleavage complexes (TOP1CCs) induced by TOP1 inhibitors, thus unmasking the inability of remaining pathways to repair DNA damage. However, previous clinical trials combining PARPi with standard TOP1 inhibitors (irinotecan, topotecan) were terminated early due to dose-limiting myelosuppression. We evaluated the combination of SG with PARP inhibitor in both pre-clinical models and phase 1b clinical trial. Methods and Results: In pre-clinical models we demonstrated that the targeted antibody-based delivery of SN-38 increased the ratio of tumor-to-normal cell SN-38, resulting in stabilized TOP1CCs, enhanced DNA damage and increased cytotoxicity with the combination, selectively in tumor cells but not normal cells, despite temporal separation of SG and PARPi exposure. To validate the hypothesis, we conducted a phase 1b investigator-initiated clinical trial combining SG with PARPi (talazoparib) in patients with mTNBC (NCT04039230). Inclusion criteria included female patients ≥ 18 years of age with mTNBC (per ASCO/CAP guidelines) and previous treatment with at least one prior therapeutic regimen for mTNBC. Clinical outcomes were assessed by Objective Response Rate per RECIST v1.1. In the phase 1b clinical trial (SG day 18, every 21 days with talazoparib), the staggered schedule with supportive therapy was relatively well-tolerated without DLTs, as predicted by the pre-clinical models. Furthermore, the staggered schedule demonstrated promising clinical activity. Molecular analysis of paired pre-treatment and on-treatment specimens demonstrated γ-H2AX accumulation, confirming pharmacodynamic inhibition with combination therapy. The dose-escalation portion of clinical trial successfully completed enrollment with a recommended phase-2 dose (R2PD) of sequential SG (10 mg/kg on days 1,8) with talazoparib (1 mg on days 15-21), every 21 days. Conclusion: Staggered dosing of SG and PARPi, leveraging the selective drug delivery mechanism of SG to minimize toxicity while maintaining efficacy, was feasible and demonstrated encouraging evidence of clinical activity with objective responses among patients with mTNBC. The translational study highlights how mechanistic insights and innovative scheduling could be utilized to develop promising drug combinations, including previously rejected combinations, for patients with mTNBC. Citation Format: Aditya Bardia, James T. Coates, Laura Spring, Sheng Sun, Dejan Juric, Nayana Thimmiah, Andrzej Niemierko, Phoebe Ryan, Ann Partridge, Jeffrey Peppercorn, Heather Parsons, Seth Wander, Kelsey Pierce, Victoria Attaya, Donna Fitzgerald, Brenda Lormil, Maria Shellock, Aiko Nagayama, Veerle Bossuyt, Bev Moy, Sara Tolaney, Leif Ellisen. Sacituzumab Govitecan, combination with PARP inhibitor, Talazoparib, in metastatic triple-negative breast cancer (TNBC): Translational investigation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2638.