Clinical Summary:

• Design/Population: The phase 3 RINGSIDE trial randomized adults with progressing desmoid tumors to receive either varegacestat or placebo.
• Key Outcomes: Varegacestat significantly improved progression-free survival, objective response rate, tumor volume reduction, and patient-reported pain compared with placebo. Toxicities were mostly low grade, although dose reductions were frequent and ovarian toxicity occurred in more than half of premenopausal women.
• Clinical Relevance: Varegacestat may provide a new systemic treatment option, offering meaningful antitumor activity and symptom relief. 

According to results from the phase 3 RINGSIDE trial, varegacestat significantly improved outcomes compared with placebo among patients with progressive desmoid tumors.

These results were presented by Mrinal Gounder, MD, Memorial Sloan Kettering Cancer Center, New York, New York, at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois. 

In this double-blind, placebo-controlled trial, 156 patients were randomized 1:1 to receive either 1.2 mg of once daily varegacestat (n = 79) or placebo (n = 77). The primary end point was progression-free survival (PFS). Alpha-controlled secondary end points included objective response rate (ORR), change in tumor volume, and change in patient-reported worst pain intensity.

At analysis, median treatment exposure was 20.3 months in the varegacestat arm and 11.1 months in the placebo arm. Median PFS was not reached in the varegacestat arm and was 24.9 months in the placebo arm (hazard ratio [HR], 0.16; 95% confidence interval [CI], 0.07 to 0.38; P < .0001). The 1-year PFS rates were 94.2% and 65.6%, respectively. The 2-year PFS rates were 88.9% and 56.7%, respectively. Confirmed ORR was 55.7% in the varegacestat arm and 9.1% in the placebo arm (P < .0001), with 3 complete responses in the varegacestat arm and 1 complete response in the placebo arm. Median duration of response was not reached in either treatment arm. 

Tumor volume decreased by at least a-squares mean of 109.6 cm³ in the varegacestat arm and an increase of 122.8 cm³ in the placebo arm (P < .0001). Median best percentage change in tumor volume was -83.4% and +11.3%, respectively. Mean worst pain intensity scores decreased by 2.24 points in the varegacestat arm and increased by 0.18 points in the placebo arm (P < .0001). 

Safety was consistent with prior findings and 95% of adverse events were grade 1/2 in nature. Grade 3/4 adverse events were reported in 57% of patients in the varegacestat arm and 17% in the placebo arm. The most common varegacestat-related adverse events included diarrhea (82%), fatigue (44%), and rash (43%). Ovarian toxicity was reported in 56% of premenopausal women in the varegacestat arm and resolved in 55% of affected patients. Adverse events led to dose reductions in 80% of patients in the varegacestat arm and 9% of patients in the placebo arm, and treatment discontinuations in 20% and 7% of patients, respectively. No treatment-related deaths were reported. 

“[Varegacestat] demonstrated statistically significant and clinically meaningful antitumor activity and pain relief, achieving the highest ORR reported in a phase 3 trial of systemic [desmoid tumor] therapy, with no new safety signals,” concluded Dr Gounder. 

Source:

Gounder MM, Rutkowski P, Jones RL, et al. RINGSIDE: A phase 3 randomized, placebo-controlled trial of varegacestat for treatment of progressing desmoid tumors. Presented at the ASCO Annual Meeting. May 29 - June 2, 2026. Chicago, Illinois. Abstract 11506.