The first-in-class covalent Werner helicase inhibitor (RO7589831) demonstrated early signals of efficacy as well as general tolerability in patients with advanced solid tumors harboring certain genetic defects, according to results from a phase I trial. Agents in this class target the DNA repair enzyme, and they reportedly work similarly to other DNA damage–repair inhibitors such as PARP inhibitors. Early data from this trial were presented by Timothy Yap, MBBS, PhD, Professor of Investigational Cancer Therapeutics and Vice President and Head of Clinical Development in the Therapeutics Discovery Division of The University of Texas MD Anderson Cancer Center, at the 2025 American Association for Cancer Research (AACR) Annual Meeting (Abstract CT016).
Timothy Yap, MBBS, PhD
“These are encouraging early clinical data, especially because this is a patient population that currently has very limited treatment options,” stated Dr. Yap. “This also further validates Werner helicase as an actionable target, which is exciting because many cancers are highly dependent on it for survival.”
Though this targeted therapy is the first in a new class of drugs, it is part of a wider group of therapies targeting the DNA damage response for patients who have solid tumors with high microsatellite instability or mismatch repair deficiency. They can occur in many cancer types, and 40% to 70% of patients with these types of solid tumors either do not respond to immune checkpoint inhibitors or develop resistance during treatment.
Like other therapies targeting DNA damage response (such as PARP inhibitors), RO7589831 inhibits the function of a DNA repair enzyme—in this case, Werner helicase—to create a buildup of DNA damage within tumor cells, ultimately leading to cell death. Because normal cells do not have microsatellite instability, these treatments spare normal cells.
Results and Safety
Initial efficacy of the agent was evaluated in 37 patients. Five of these patients, representing multiple cancer types with high microsatellite instability or mismatch repair deficiency, had partial responses as determined by radiologic imaging, and 65.7% of all patients had lasting stable disease, according to the investigators. Specialized metabolic imaging showed that deeper metabolic responses were associated with both radiologic partial responses and longer-term disease control.
Safety was assessed in 44 patients, with the majority experiencing grade 1 or 2 adverse events, though higher doses appeared to be less tolerable than lower doses. Mild, manageable nausea, vomiting, and diarrhea were the most common adverse events, and no dose-limiting toxicities were observed. Three randomized dose-level cohorts are underway to establish the optimal recommended dose for a future phase II trial.
Disclosure: Funding for this study was provided by Roche. For full disclosures of all study authors, visit abstractsonline.com.
