Preliminary Activity Seen with RAD51 Inhibitor

An investigational agent that inhibits RAD51-mediated homologous recombination DNA repair has shown preliminary signs of activity in patients with cancer. In a phase I trial, CYT-0851 elicited three responses in patients with relapsed/refractory hematologic malignancies and advanced solid tumors and was associated with only mild side effects. Results were presented on June 4 at the American Society of Clinical Oncology 2021 Annual Meeting,

CYT-0851 was chosen for development due to its ability to selectively target cancer cells that overexpress cytidine deaminase enzymes. These enzymes lead to increased rates of DNA damage, making cancer cells dependent on homologous recombination DNA repair. CYT-0851 inhibits RAD51, preventing the repairs and causing the cancer cells to die. In preclinical studies, the agent demonstrated broad antitumor activity and minimal off-target effects in hematologic and solid-tumor cell lines, and inhibited tumor growth in mouse models of lymphoma and pancreatic cancer.

Ryan Lynch, MD, of Fred Hutchinson Cancer Research Center in Seattle, WA, reported on the first 35 patients enrolled in the trial, who had received a median of 4 prior therapies. Most patients had non-Hodgkin lymphoma or soft-tissue sarcoma, although people with other cancers were included. Doses of CYT-0851 ranged from 15 to 300 mg per day.

Three of 21 evaluable patients had partial responses to the drug, and 10 more patients experienced stable disease. A patient with diffuse large B-cell lymphoma who responded remained on the drug for almost 8 months before his disease progressed into the central nervous system. A patient with follicular lymphoma experienced 46% tumor shrinkage on a dose of 90 mg per day, and a partial response and 68% tumor shrinkage when his dose was increased to 130 mg daily.

“While this is only one example so far, the increase in tumor shrinkage at the higher dose may translate into faster and deeper shrinkage in future cohorts at higher dose levels,” Ryan said. A patient with myxofibrosarcoma had significant tumor shrinkage that culminated in a partial response before his disease eventually worsened.

Overall, 13 patients (37.1%) experienced side effects—most commonly fatigue, nausea, or an increase in blood alkaline phosphatase. Only three patients experienced grade 3 adverse events, and no grade 4 or 5 adverse events occurred. None of the patients discontinued treatment due to side effects or experienced dose-limiting toxicities; four patients received the agent for 6 or more months without evidence of accumulating toxicity.

Now, investigators are attempting to determine the maximum tolerated dose, as well as the recommended dose for the phase II portion of the trial. As the trial continues, it will enroll patients who have already received a PARP inhibitor, providing insight into whether CYT-0851 is effective in patients who have developed PARP resistance. The researchers are also planning on testing various combinations. Gathering and analyzing genomic data will be essential, Ryan added, to investigate the alterations present in patients who respond.

“The importance of this single-agent phase I trial of a RAD51 inhibitor is that the early clinical trial is already showing efficacy [and an] impressive safety profile,” said Ulka Vaishampayan, MD, of the University of Michigan in Ann Arbor, who provided outside commentary on the results. In particular, she noted that CYT-0851 was not associated with cytopenia—a significant side effect of PARP inhibitors. Moreover, “now we are seeing … actual clinical efficacy in sarcoma and non-Hodgkin's lymphoma,” she said—diseases that are not dependent on homologous recombination DNA repair, and “have not typically been showing responses to PARP inhibitors.” –Catherine Caruso