Early Data Suggest DNA Damage Boost in R/R AML with Talazoparib Plus GO

An evaluation of the safety, tolerability, and preliminary efficacy the oral polymerase (PARP) inhibitor talazoparib combined with CD33 antibody drug conjugate gemtuzumab ozogamicin (GO) warrants study, according to poster presentation by Ross McCauley, MD, hematology/oncology fellow, Roswell Park Comprehensive Cancer Center during the EHA 2025 Congress in Milan, Italy.

The conclusion was drawn from a phase I/Ib study in patients with relapsed/refractory acute myeloid leukemia (AML).

The open-label, multicenter trial enrolled 24 patients with relapsed/refractory CD33+ AML. Their median age was 70.8 years (range, 48.1-84.8 years). Patients had undergone a median of 3 prior therapies (range, 1-7). Most (79%) had failed venetoclax and hypomethylating agents and 17% had prior allogeneic transplant. Common mutations included TET2 (32%), IDH1 (27%), RUNX1 (27%), and FLT3-ITD (23%). During the dose-escalation phase, patients received oral talazoparib 0.5, 0.75, or 1mg daily plus fixed-dose GO 3mg/m² on days 1, 4, and 7 using a 3_3 design. The dose-limiting toxicity (DLT) window was 28 days. The recommended phase II dose of talazoparib 1mg daily was further evaluated in an expansion cohort. Patients received bone marrow assessments on day 28 of cycles 1 and 2.

No DLTs were observed. The most frequent adverse events (AEs) included sepsis (54%), lung infection (50%), nausea (50%), diarrhea (42%), febrile neutropenia (38%), thrush (38%), and peripheral edema (38%). The most common grade ≥3 AE was sepsis, occurring in 18 patients. AEs specific to GO included neutropenia (25%), thrombocytopenia (50%), and elevated liver enzymes (ALT 21%, AST 21%, hyperbilirubinemia 12.5%, alkaline phosphatase 8%). No cases of sinusoidal obstructive syndrome were reported. Median duration of therapy was 28.5 days (range, 5-170).

In 20 response-evaluable patients, the regimen achieved a complete remission (CR) rate of 33% (n=6). Four of these patients had IDH mutations, with one surviving post-subsequent allogeneic transplant, suggesting a potential biomarker-driven response. Three patients (17%) had stable disease for at least two cycles. Among those who achieved CR, median leukemia-free survival (LFS) was 75.5 days (rang, 21-622). Median overall survival (OS) was 2.9 months (range, 1.8-4.8) with a median follow-up of 15.2 months.

Based on these findings, which suggest that combining PARP inhibitors with cytotoxic agents like GO could enhance DNA damage in AML, the researchers concluded that “further evaluation of talazoparib plus chemotherapy for prior venetoclax-treated patients may be warranted.”