Add-on parsaclisib for patients with myelofibrosis and suboptimal response to ruxolitinib: a randomized phase 3 study

Background: Ruxolitinib (JAK1/JAK2 inhibitor) is indicated for adults with intermediate or high-risk myelofibrosis; however, a subset of patients may exhibit a suboptimal response due to persistent PI3K/AKT activation. The phase 3, randomized, double-blind, placebo-controlled LIMBER-304 study (NCT04551053) investigated the efficacy and safety of add-on parsaclisib (highly selective PI3Kδ inhibitor) in patients with myelofibrosis and suboptimal or declining response to stable ruxolitinib monotherapy. Patients and Methods: Adults with primary or secondary myelofibrosis who received ruxolitinib with palpable spleen and Myelofibrosis Symptom Assessment Form (MFSAF) total symptom score (TSS) ≥10 were eligible. Primary end point was proportion of patients achieving ≥25% spleen volume reduction (SVR; baseline to week 24); key secondary end point was proportion of patients with ≥50% MFSAF-TSS reduction (baseline to week 24). Results: In total, 90 patients received parsaclisib/ruxolitinib; 87 received placebo/ruxolitinib. At week 24, 16.7% of patients receiving parsaclisib/ruxolitinib achieved ≥25% SVR vs 9.7% for placebo/ruxolitinib; this difference was not statistically significant. By week 24, ≥50% reduction in MFSAF-TSS was observed in 17.1% of patients receiving parsaclisib/ruxolitinib vs 14.1% for placebo/ruxolitinib. Higher rates of infections (including cytomegalovirus) and gastrointestinal disorders were observed with parsaclisib/ruxolitinib. Grade ≥3 treatment-emergent adverse events occurred in 60.0% of patients receiving parsaclisib/ruxolitinib vs 42.5% with placebo/ruxolitinib. The study was terminated early based on efficacy findings. Conclusions: Study results suggested adding parsaclisib to stable-dose ruxolitinib was unlikely to offer clinically meaningful benefits. Further research is needed on the potential of JAK and PI3K inhibitor-based combination therapy for patients with myelofibrosis.