Background: Chemotherapy induced nausea and vomiting (CINV) is a highly prevalent adverse event^1,2 that can result in decreased quality of life, dose reduction and interruptions of treatment.³ Four drug protocol including Olanzapine, 5-hydroxytryptamine type 3 receptor (5HT3) antagonist, a neurokinin 1 receptor (NK1) antagonist and dexamethasone is the current standard of care for highly emetogenic chemotherapy (HEC) ^2,4-6. Corticosteroids are associated with side effects like insomnia and weight gain. To our knowledge, total Dexamethasone omission has not been addressed previously. Methods: This is a prospective single arm phase II study designed to evaluate the efficacy of Olanzapine, Netupitant and Palonosetron in controlling nausea and vomiting induced by highly emetogenic chemotherapy. Eligible patients were women with histologic confirmed breast cancer, planned to start treatment with Doxorubicin and Cyclophosphamide. Exclusion criteria included use of opioids or antipsychotic medications, medical condition that could potentially cause vomiting or inability to take oral medications. Patients were assigned to take Olanzapine 5mg QD, days 1 – 5, Netupitant 300mg and Palonosetron 0.5mg on day one. No corticosteroid use was allowed. The null hypothesis considered that the scheme containing Olanzapine, Netupitant and Palonosetron could not effectively control nausea. Based on a previous phase III study with Olanzapine (Navari et al.), we set the control of nausea at 20% and the expected control rate at 40% for the present study. To reach 5% (two-sided) significance and 80% statistical power, we calculated that a minimum sample size of 50 patients was required, assuming a 5% dropout rate. We used the one-sample T-test of proportion to analyze the data, based on intent-to-treat (ITT) The primary endpoint was complete control of nausea in the first 5 days after chemotherapy administration. Secondary endpoints were complete emesis control (no emesis, no use of rescue medication) and complete control (no emesis, no rescue and no nausea) Results: Fifty patients were enrolled from January 2020 to December 2021. The median age was 47.6 years-old (range: 29 – 78 years) and 48 patients (96%) received chemotherapy with curative intent. For the primary endpoint, complete nausea control rate was 46% (IC 32 – 59%) and p < 0.0001. The emesis control rate was 68% (IC 55 – 80%) and overall control rate was 46% (IC 32 – 59%). One patient dropped out for dizziness and drowsiness following administration of Olanzapine. Conclusions: Omitting Dexamethasone for highly emetogenic chemotherapy is feasible and showed similar control of nausea and vomiting compared to standard four-drug protocol. This could be a potential prophylactic regimen of choice for patients who have a contraindication for Dexamethasone use. Clinical trial information: NCT04669132.