Data from Antibody–Drug Conjugate Sacituzumab Govitecan Enables a Sequential TOP1/PARP Inhibitor Therapy Strategy in Patients with Breast Cancer

• DOI: 10.1158/1078-0432.c.7348821.v1
• Publication Date: 2024-07-15T07:30:14Z
• Authors: Aditya Bardia; Sheng Sun; Nayana Thimmiah; James T. Coates; Bogang Wu; Rachel O. Abelman; Laura Spring; Beverly Moy; Phoebe Ryan; Mark N. Melkonyan; Ann Partridge; Dejan Juric; Jeffrey Peppercorn; Heather Parsons; Seth A. Wander; Victoria Attaya; Brenda Lormil; Maria Shellock; Aiko Nagayama; Veerle Bossuyt; Steven J. Isakoff; Sara M. Tolaney; Leif W. Ellisen
• Keywords: Conjugate; Antibody-drug conjugate; PARP inhibitor; Cancer Therapy

<div>AbstractPurpose:<p>The antibody–drug conjugate (ADC) sacituzumab govitecan (SG) comprises the topoisomerase 1 (TOP1) inhibitor (TOP1i) SN-38, coupled to a monoclonal antibody targeting trophoblast cell surface antigen 2 (TROP-2). Poly(ADP-ribose) polymerase (PARP) inhibition may synergize with TOP1i and SG, but previous studies combining systemic PARP TOP1 inhibitors failed due dose-limiting myelosuppression. Here, we assess proof-of-mechanism clinical feasibility for SG talazoparib (TZP) employing an innovative sequential dosing schedule.</p>Patients Methods:<p>In vitro models tested pharmacodynamic endpoints, in phase 1b trial (NCT04039230), 30 patients metastatic triple-negative breast cancer (mTNBC) received TZP concurrent (<i>N</i> = 7) or 23) schedule. Outcome measures included safety, tolerability, preliminary efficacy, establishment of recommended dose.</p>Results:<p>We hypothesized that tumor-selective delivery via would reduce nontumor toxicity create temporal window, enabling inhibition. In vitro, followed by delayed cleavage complex clearance, increased DNA damage, promoted apoptosis. trial, SG/TZP successfully met primary objectives demonstrated median progression-free survival (PFS) 7.6 months without toxicities (DLT), while yielded 2.3 PFS multiple DLTs including severe myelosuppression.</p>Conclusions:<p>While dosed concurrently is not tolerated clinically insufficient therapeutic proved viable strategy. These findings support further development combination suggest ADC-based therapy facilitate novel, mechanism-based strategies.</p></div>