Dr Garcia-Manero on the GLORA-4 Trial of Lisaftoclax Plus Azacitidine in High-Risk MDS

“[Lisaftoclax] has been tested in a significant fraction of patients, both in United States and in China. Before the results of the phase 3 VERONA trial [read out], we designed this GLORA-4 with the idea that this drug could also be a little bit more active [than venetoclax in MDS.”

Guillermo Garcia-Manero, MD, the interim chair of the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, discussed the rationale for investigating lisafotclax (APG-2575) in combination with azacitidine (Vidaza) in patients with high-risk myelodysplastic syndromes (MDS) in the phase 3 GLORA-4 trial (NCT06641414).

Although lisaftoclax functions similarly to the BCL-2 inhibitor venetoclax (Venclexta), Garcia-Manero noted that it possesses a distinct pharmacological profile, including a different half-life and fewer drug interactions. These properties suggest that the agent may be potentially safer than first-generation BCL-2 inhibitors, he added. The drug has already undergone extensive study in both China and the United States across several hematologic malignancies, including acute myeloid leukemia and chronic lymphocytic leukemia, in addition to MDS, he detailed.

The development of the GLORA-4 trial was influenced by the phase 3 VERONA trial (NCT04401748), which evaluated venetoclax plus azacitidine in a similar population, Garcia-Manero shared. Findings from VERONA presented at the 2025 SOHO Annual Meeting showed that the addition of a BCL-2 inhibitor to frontline therapy did not translate into a statistically significant overall survival (OS) improvement compared to azacitidine alone. However, a subgroup analysis shared at the 2025 ASH Annual Meeting suggested a possible signal in specific populations.

GLORA-4 has dual primary end points of complete remission rate and OS. Garcia-Manero explained that this design follows FDA mandates and allows for a potential regulatory strategy based on response data. The study is a randomized, double-blind trial that seeks to determine if this specific combination can improve outcomes in high-risk MDS, he concluded.