Overall efficacy and safety of olanzapine 5 mg added to triplet antiemetics for an anthracycline-containing regimen in patients with breast cancer: a phase 3, double-blind, randomised, placebo-controlled trial.

BACKGROUND

The addition of 10 mg olanzapine to the standard triplet antiemetic therapy has shown superiority in controlling chemotherapy-induced nausea and vomiting compared with triplet therapy alone for highly emetogenic chemotherapy, albeit with sedative side-effects. We aimed to investigate if administering 5 mg of olanzapine at home after anthracycline plus cyclophosphamide chemotherapy, rather than before chemotherapy, can maintain efficacy in controlling chemotherapy-induced nausea and vomiting while minimising sedative side-effects and associated risks.

METHODS

This was a phase 3, double-blind, randomised, placebo-controlled trial, done in 15 hospitals and cancer centres in Japan. Eligible patients were female adults aged 20 years or older with stage I-III breast cancer and an Eastern Cooperative Oncology Group performance status of 0-1, who were scheduled to receive intravenous anthracycline plus cyclophosphamide-based chemotherapy, and were naive to chemotherapy or had never received moderately to highly emetogenic chemotherapy. Eligible patients were randomly assigned 1:1 to oral olanzapine 5 mg or placebo via the central registration system. Randomisation was performed using blocked stratification, with age (≥55 years vs <55 years) and institution as stratification factors and a block size of two. Allocation was concealed and masking was achieved by using tablets with identical appearance. Treatment was administered at home within 5 h after the end of anthracycline plus cyclophosphamide administration and before the patient's evening meal on day 1 to minimise the risk of sedation during hospital visits and transportation, and on the next 3 days after their evening meal, both with pre-chemotherapeutical application of intravenous dexamethasone 9·9 mg, intravenous palonosetron 0·75 mg, and oral aprepitant 125 mg on day 1 followed by an additional dose of aprepitant 80 mg on days 2 and 3 or intravenous fosaprepitant 150 mg as a premedication on day 1. The primary endpoint was the proportion of patients with a complete response, defined as no vomiting and no rescue medication during the overall phase (0-120 h after the initiation of anthracycline plus cyclophosphamide) based on patient diary. The primary analysis was done by modified intention-to-treat, including all patients who received at least one dose of the study treatment and had at least one efficacy evaluation. Safety was analysed in all patients who received any treatment. This trial was registered with the Japan Registry of Clinical Trials, jRCT1031200134, and is complete.

FINDINGS

Between Oct 26, 2020 and Nov 2, 2022, 500 female patients from 15 medical institutions in Japan were randomly assigned to receive olanzapine (n=251) or placebo (n=249). Median age at enrolment was 52 years (IQR 45-60) in the olanzapine group and 51 years (46-60) in the placebo group. Data on gender and race or ethnicity were not collected. The median follow-up was 168 h (IQR 168-168). 480 participants (246 in the olanzapine group and 234 in the placebo group) received at least one dose of study medication and were eligible for the efficacy analysis. The complete response rate in the olanzapine group (58·1%, n=143) was significantly higher than in the placebo group (35·5%, n=83; difference 22·7%, 95% CI 14·0-31·4%; p<0·0001) during the overall phase. The most frequently reported severe or very severe symptoms based on the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) version 1.0 were anorexia (33 [13%] of 246 patients in the olanzapine group vs 89 [38%] of 235 in the placebo group) and constipation (30 [12%] vs 37 [16%]). Severe or very severe concentration impairment was reported in 25 (10%) of 246 patients in the olanzapine group and 34 (14%) of 235 patients in the placebo group. Experimental drug-related grade 3-4 adverse events according to the Common Terminology Criteria for Adverse Events version 5.0 included somnolence (four [2%] of 246 patients in the olanzapine group vs none of 235 in the placebo group), and concentration impairment (two [1%] vs none). There were no deaths.

INTERPRETATION

Post-chemotherapy administration of 5 mg olanzapine in combination with triplet antiemetic therapy before anthracycline plus cyclophosphamide-based chemotherapy significantly improved the complete response rate for chemotherapy-induced nausea and vomiting during the overall phase compared with placebo in female patients with breast cancer receiving outpatient chemotherapy, with an acceptable level of safety. The findings represent a substantial advancement in managing chemotherapy-induced nausea and vomiting and provide assurance that the safe and effective administration of olanzapine can be achieved at a dosage of 5 mg.

FUNDING

The Capture of Outstanding Clinical Research and Evolution (CORE) project at Juntendo University.