12087 Background: Olanzapine is used as an adjunct antiemetic in oncology as salvage therapy and in four-drug prophylaxis. Growing literature supports its effectiveness in initial three-drug prophylaxis in highly emetogenic chemotherapy (HEC). Methods: This prospective, multi-centre, open-label study evaluated the feasibility of a large-scale randomized controlled trial comparing the effectiveness and tolerability of 5 mg olanzapine once daily for four days (starting the night before chemotherapy) versus standard dose aprepitant (in tritherapy with standard ondansetron and dexamethasone) in treatment-naive patients receiving the first cycle of a HEC. Secondary outcomes included: complete response (no nausea, no emesis, no use of rescue medication), complete remission (no emesis, no rescue medication), intensity of patient-reported nausea and emesis on a visual analog scale, quality of life (scored with the Functional Living Index Emesis [FLIE]), and incidence of adverse events. Results: We randomized 30 patients in an intent-to-treat analysis. The large-scale trial was deemed not feasible without support from a research centre. Complete response rates were significantly higher in the olanzapine group in the delayed phase (24-120h post-chemotherapy) (86,7% v 21,4%, p < 0,001) and overall phase (0-120h post-chemotherapy) (60,0% v 21,4%, p = 0,04). Similar results were observed for complete remission. Intensity of patient-reported nausea was significantly lower in the olanzapine group in the delayed phase (p = 0,001). FLIE scores were significantly lower for the nausea domain (mean 62,3 v 60,9, p = 0,004) and overall score (124,3 v 108,8, p = 0,006). Depression on the ESAS-R was more common in the aprepitant group (0% v 38%, p = 0,01). Other adverse events were not significantly different. Conclusions: Support from a research centre must be ensured for study feasibility. Tritherapy olanzapine significantly improved complete response and remission in the delayed and overall phases post-chemotherapy among patients receiving HEC. It was also associated with higher quality of life and a reassuring safety profile. This feasibility trial, despite its small sample size, is one of the first prospective randomised trials to suggest similar efficacy of 5 mg olanzapine to aprepitant and to measure a difference in patient quality of life with this regimen. Clinical trial information: NCT04075955 .