Phase 1 trial of oral ASTX727 plus talazoparib in previously treated triple-negative metastatic breast cancer patients.

This Phase 1 study evaluated the safety and preliminary efficacy of oral DNMTi ASTX727 combined with PARPi talazoparib in patients with previously treated triple-negative metastatic breast cancer (TNBC), hormone-resistant metastatic breast cancer (HRBC), or HER2-negative metastatic breast cancer. The cohort included 34 evaluable patients, and the treatment duration was 4.0 months. No comparator group was reported in this early-phase investigation.

The primary analysis focused on objective responses and stable disease. Among the 29 patients assessed for response, there were 0 objective responses. However, six patients demonstrated stable disease, with three of these patients maintaining disease stability for more than 4 months. Additionally, methylation changes were observed in peripheral blood mononuclear cells (PBMCs), with LINE1 demethylation ranging from approximately 2% to 10% and immune-specific CpG methylation changes occurring 1% to 5% at day 15.

Safety and tolerability were significant concerns in this trial. Myelosuppression was common, characterized by grade >3 neutropenia in 42% of patients. Grade 3 anemia and thrombocytopenia were observed in 13% of patients. Dose-limiting toxicity was limited to neutropenia, and no other adverse events were reported. Serious adverse events and discontinuations were not reported. The combination produced significant myelosuppression without other adverse events.

Key limitations include the small sample size inherent to Phase 1 studies and the lack of a control group or long-term follow-up data beyond 4.0 months. Causality cannot be definitively established from this observational design. The practice relevance remains uncertain given the early phase of development and the significant hematologic toxicity profile. Clinicians should interpret these findings with caution until further data are available.