A phase 3 randomized, double-blind, placebo-controlled trial has demonstrated that adding 5 mg olanzapine to standard triplet antiemetic therapy significantly improves control of chemotherapy-induced nausea and vomiting in breast cancer patients receiving anthracycline plus cyclophosphamide-based chemotherapy. The study, published in Lancet Oncology, represents the first trial of its kind to show significant overall antiemetic efficacy of post-chemotherapeutic olanzapine administration at this dosage.
Study Design and Patient Population
The multicenter Japanese trial enrolled 500 patients with stage I to III breast cancer who were chemotherapy-naive or had never received moderately to highly emetogenic chemotherapy. Patients were randomly assigned in a 1:1 ratio to receive either olanzapine (n = 251) or placebo (n = 249) in addition to standard triplet antiemetic therapy consisting of dexamethasone, palonosetron, and aprepitant or fosaprepitant.
The median age was 52 years in the olanzapine group and 51 years in the placebo group. Nearly all patients (99-100%) had an ECOG performance score of 0. The most commonly administered chemotherapy regimens included epirubicin plus cyclophosphamide (37% vs 34%), dose dense epirubicin plus cyclophosphamide (27% vs 32%), and doxorubicin plus cyclophosphamide (28% vs 25%).
Treatment Protocol
All patients received standard triplet antiemetic therapy including 0.75 mg of palonosetron 30 minutes before chemotherapy, oral aprepitant at 125 mg one hour before chemotherapy and 80 mg on days 2 and 3, or 150 mg of intravenous fosaprepitant, plus 9.9 mg of intravenous dexamethasone. Patients in the experimental arm received 5 mg of oral olanzapine within 5 hours of chemotherapy on day 1 and after evening meals on days 2-4, while control patients received matching placebo.
Primary Efficacy Results
After a median follow-up of 168 hours, the complete response rate for the overall treatment duration (0-120 hours) was significantly higher in the olanzapine group at 58.1% compared to 35.5% with placebo, showing a difference of 22.7% (95% CI, 14.0%-31.4%; P <.0001).
The benefit was observed across different phases of treatment. In the acute phase (first 24 hours), complete response rates were 76.4% versus 55.6%. During the extended delayed phase (24-168 hours post-treatment), rates were 62.9% versus 41.5%.
Time to Treatment Failure
The time to treatment failure was significantly longer in the olanzapine arm, with the median not being reached compared to 37.3 hours (95% CI, 22.2-49.5) in the placebo arm (stratified HR, 0.495; 95% CI, 0.385-0.635; P <.0001). Only 3 patients (~1%) in the placebo group versus 0 patients in the olanzapine group were censored before 168 hours.
Safety Profile
The treatment demonstrated an acceptable safety profile. The most common severe adverse events in the olanzapine versus placebo groups included anorexia (13% vs 38%) and constipation (12% vs 16%). Severe concentration impairment was reported in 10% versus 14% of patients, respectively.
Grade 3 to 4 adverse events specifically related to olanzapine included somnolence (2% vs 0%) and concentration impairment (1% vs 0%). No grade 5 adverse events or treatment-related deaths were observed. Three patients in the placebo arm discontinued treatment due to drug-related toxicities.
Clinical Significance
"To our knowledge this is the first double-blind, randomised, placebo-controlled phase 3 trial to show the significant overall antiemetic efficacy of post-chemotherapeutic administration of 5 mg olanzapine added to a triplet antiemetic regimen, including NK-1 receptor antagonists, palonosetron, and dexamethasone, in patients at high risk of emesis receiving anthracycline plus cyclophosphamide-based chemotherapy without severe sedative adverse effects," stated Dr. Mitsue Saito from the Department of Breast Oncology at Juntendo University Hospital in Tokyo.
The investigators concluded that the findings "represent a substantial advancement in managing chemotherapy-induced nausea and vomiting in patients with breast cancer and provide assurance that the safe and effective administration of olanzapine can be achieved at a dosage of 5 mg."
Patient satisfaction with antiemetic therapy was also higher on a 7-point scale in the olanzapine group compared to the placebo group, further supporting the clinical benefit of this approach.
