The sequential use of sacituzumab govitecan as a promising strategy in breast cancer

A phase 1b clinical trial recently published in Clinical Cancer Research shows that a sequential use of the antibody-drug conjugate sacituzumab govitecan followed by talazoparib can prevent the toxicity of a concomitant therapy with both agents in patients with metastatic triple-negative breast cancer, enabling a treatment combining a topoisomerase 1 (TOP1) inhibitor and a PARP inhibitor.

This trial was designed to test a sequential use of sacituzumab govitecan, an antibody-drug conjugate with the TOP1 inhibitor SN-38 coupled to a monoclonal antibody targeting trophoblast cell surface antigen 2 (TROP-2), and talazoparib, a PARP inhibitor. PARP and TOP1 inhibition could synergize but previous combination studies failed due to a dose-limiting mielosuppression. In this study, authors hypothesized that tumor-selective delivery of TOP1 inhibition via sacituzumab govitecan would reduce non-tumor toxicity and create a temporal window for the subseqiuent use of a PARP inhibitor. To test the hypothesis, 30 patients with metastatic triple-negative breast cancer received sacituzumab govitecan and talazoparib in a concurrent or sequential schedule. The sequential strategy demonstrated median progression-free survival of 7.6 months without dose-limiting toxicities, while concurrent dosing yielded 2.3 months progression-free survival and multiple dose-limiting toxicities including severe myelosuppression. «Antibody–drug conjugates are emerging as promising cancer therapeutics, but their unique drug delivery mechanism has not been extensively leveraged for combination therapy», authors say. «We proposed that the antibody-drug conjugate-based delivery mechanism could enhance the therapeutic window for the combination, while also creating a temporal window to enable a novel sequential dosing strategy. In the clinical trial, sequential dosing overcame dose-limiting toxicities observed with concurrent dosing, allowing successful determination of the recommended phase 2 dose. These results support further clinical development of this combination, and more broadly suggest that unique features of antibody-drug conjugates may facilitate novel, mechanism-based dosing strategies that render viable previously abandoned therapeutic combinations in oncology».