Background: Olanzapine (OLZ) 10 mg added to standard antiemetic therapy including aprepitant (APR), palonosetron (PALO), and dexamethasone (DEX) has been recommended for the prevention of chemotherapy-induced nausea and vomiting (CINV) caused by highly emetogenic chemotherapy (HEC). Guidelines suggest that a dose of 5 mg should be taken into consideration in patients at risk of sedation. OLZ 5 mg showed an equivalent activity and favorable toxicity to somnolence in several phase II studies. We conducted a randomized, double-blind, placebo-controlled phase III trial to evaluate OLZ 5 mg in addition to standard antiemetic therapy for the prevention of CINV in patients receiving cisplatin-based chemotherapy. Methods: Patients receiving cisplatin (≥ 50 mg/m²) were randomly assigned to either OLZ 5 mg or placebo on days 1–4, combined with APR, PALO and DEX. The primary endpoint was complete response (CR), defined as no vomiting and no rescue medications in the delayed phase (24–120 h). A total of 690 patients were required to detect a 10% increase in CR from 65% in the placebo to 75% in the OLZ, with a one-sided alpha of 2.5% and a power of 80%. Results: A total of 710 patients were enrolled (OLZ 356 and placebo 354). CR in the delayed phase was 79.1% (95% CI: 74.9–83.3) in the OLZ 5 mg and 65.8% (95% CI: 60.9–70.8) in the placebo (p< 0.001). Other efficacy results are summarized in Table. The most common treatment-related adverse events was somnolence (43.1% for OLZ vs. 33.0% for placebo). Conclusions: OLZ 5 mg combined with APR, PALO and DEX can be considered a new standard antiemetic therapy in patients receiving cisplatin-based chemotherapy. Clinical trial information: UMIN000024676.

*TC (total control): no vomiting, nausea and rescue medications