ORIC Pharmaceuticals (NASDAQ:ORIC) saw its shares fall about 27% on Tuesday after announcing the recommended Phase 3 dosing for rinzimetostat in combination with darolutamide for its global Himalayas-1 registrational trial targeting post-abiraterone metastatic castration-resistant prostate cancer.
The company selected rinzimetostat 400 mg once daily as the Phase 3 dose to be used alongside darolutamide. ORIC said the decision rested on Phase 1b dose optimization data showing that 400 mg and 600 mg delivered comparable efficacy measures, while exposure-response analyses identified statistically significant relationships between higher drug exposure and increased toxicities at the 600 mg dose.
At a median follow-up of approximately 5 months, the 400 mg cohort showed a landmark 5-month radiographic progression-free survival (rPFS) of 84% among 18 efficacy-evaluable patients. ORIC stated that this rPFS result was consistent with that reported for a competitor PRC2 inhibitor now in Phase 3.
Additional efficacy signals at the 400 mg level included a prostate-specific antigen 50 (PSA50) response in 47% of patients, with 33% of those responses confirmed. Circulating tumor DNA (ctDNA) measurements revealed that 71% of patients achieved greater than 50% reduction in ctDNA.
Safety findings at the recommended dose indicated that the vast majority of treatment-related adverse events were Grade 1 in severity. The most commonly observed adverse events were fatigue (39%), diarrhea (22%), and nausea (22%). There was one recorded Grade 3 treatment-related adverse event, and the company reported no Grade 4 or Grade 5 events attributed to the therapy. Dose modifications were infrequent, consisting of one treatment interruption and one discontinuation, and no dose reductions were required.
ORIC outlined the Himalayas-1 study design: approximately 600 patients will be enrolled across more than 250 sites in over 20 countries. Participants will be randomized 1:1 to receive rinzimetostat plus darolutamide versus physician's choice of an androgen receptor inhibitor or chemotherapy. The primary endpoint for the trial is radiographic progression-free survival, and initiation of the Phase 3 study is expected in the first half of 2026.
The market reaction to the dose selection was immediate, with the company's share price declining sharply following the announcement.