Clinical Summary:

• Design/Population: The double-blind, placebo-controlled RINGSIDE Part B trial evaluated varegacestat in patients with progressing desmoid tumors. This prespecified exploratory analysis assessed patient-reported outcomes through 48 weeks.
• Key Outcomes: Varegacestat demonstrated greater improvements in patient-reported pain, desmoid-related symptoms, physical function, and quality of life compared with placebo, with benefits evident as early as week 4 and sustained through week 48. Longitudinal analyses consistently favored varegacestat across evaluated measures. 
• Clinical Relevance: These findings reinforce the clinical benefit of varegacestat in progressing desmoid tumors, demonstrating improvements in symptoms and functional outcomes that complement the previously reported progression-free survival and objective response benefits. 

Results from a prespecified exploratory analysis of the RINGSIDE Part B trial demonstrated that varegacestat provided rapid and sustained improvements in patient-reported pain, desmoid tumor-related symptoms, physical function, and quality of life compared with placebo in patients with progressing desmoid tumors, reinforcing the clinical benefits observed in the trial’s primary efficacy analysis. 

These findings were presented by Winette T.A. Van der Graaf, MD PhD, Netherlands Cancer Institute, Amsterdam, The Netherlands, at the European Society for Medical Oncology (ESMO) Congress in Madrid, Spain.

In this double-blind, placebo-controlled trial,  patients with progressing desmoid tumors were randomized 1:1 to receive either varegacestat or placebo. 

The primary RINGSIDE analysis previously demonstrated that varegacestat significantly improved progression-free survival, reducing the risk of a progression-free survival event by 84% compared with placebo. The confirmed objective response rate was 56% in the varegacestat arm and 9% in the placebo arm.

The current prespecified exploratory analysis evaluated patient-reported outcomes using desmoid-specific and general health measures to assess changes in symptoms, physical function, and quality of life. 

Patient-reported outcomes were assessed at baseline and every 4 weeks thereafter using the Gounder/Desmoid Tumor Research Foundation Desmoid Symptom/Impact Scale (GODDESS DTSS/DTIS) and the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function Short Form 10a. 

Desmoid tumor symptom scores were collected through daily questionnaires. Changes from baseline were evaluated descriptively and using longitudinal mixed models with data collected through week 48.

Across all evaluated time points through week 48, varegacestat demonstrated consistently greater improvements from baseline in patient-reported outcomes compared with placebo. 

Sustained reductions in pain and desmoid-related symptoms were observed across the GODDESS Desmoid Tumor Symptom Scale measures, including the Pain Domain, Total Symptom Score, and 5-item Total Symptom Score. 

 Improvements were evident as early as the first post-baseline assessment at week 4 and were sustained throughout week 48, while patients receiving placebo experienced minimal change over time.

Improvements with varegacestat were also observed in the GODDESS Desmoid Tumor Impact Scale physical function measure and PROMIS Physical Function scores, indicating improvements in physical function and health-related quality of life.

Longitudinal analyses confirmed improvements favoring varegacestat across all evaluated measures through week 48.

At week 48, the least-squares mean change in the GODDESS Pain Domain score was –2.48 with varegacestat and 0.22 with placebo. Similarly, the least-squares mean change in the 5-item Total Symptom Score was –1.50 with varegacestat and 0.59 with placebo. 

For PROMIS Physical Function, the least-squares mean change was 3.90 with varegacestat compared with –3.04 with placebo, demonstrating improved physical function with varegacestat compared with a decline in the placebo arm. 

“Overall, varegacestat demonstrated rapid, sustained, and clinically meaningful improvements in patient-reported pain, symptoms, physical functioning, and quality of life compared to placebo in patients with progressing desmoid tumors,” concluded Dr Van der Graaf et al. “These findings are consistent with and further support the benefit of varegacestat demonstrated by the RINGSIDE efficacy end points.” 

Source:

Van der Graff WT, Gounder M, Basu-Mallick A, et al. Patient reported outcomes (PROs) with varegacestat versus placebo (PBO) in progressing desmoid tumors: Results from RINGSIDE Part B. Presented at ESMO Congress. October 23–27, 2026; Madrid, Spain. Abstract 3724RO.