In a randomised, double-blind, placebo-controlled phase III study, the Japanese investigators assessed the efficacy and safety of adding olanzapine, a neurokinin-1 (NK1) receptor antagonist (RA), to standard triple antiemetic therapy with aprepitant, a 5-hydroxytryptamine-3 (5-HT3) RA, and dexamethasone in patients who received carboplatin-containing chemotherapy. The rate of complete response (CR) in the overall phase was excellent, and it tended to be higher in the olanzapine group (86.9%), albeit without significance.
However, olanzapine significantly improved nausea prevention in the overall and delayed phases in patients who received carboplatin. The addition of olanzapine did not cause any serious adverse events. Further comparative studies are warranted to determine the benefits of this strategy according to Dr. Naoki Inui of the Second Division, Department of Internal Medicine and Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine in Hamamatsu, Japan and colleagues who reported the findings on 4 June 2024 in the JCO.
Previously, carboplatin had been classified as a moderately emetogenic chemotherapy agent that necessitated double antiemetic therapy with a 5-HT3 RA and dexamethasone. Currently, for carboplatin antiemetic guidelines recommend the prophylactic administration of a NK1 RA, a 5-HT3 RA, and dexamethasone. This triple antiemetic therapy for carboplatin-containing chemotherapy provided a 60-80% of CR rate in the overall phase. However, the control of chemotherapy-induced nausea and vomiting, especially nausea, remains suboptimal despite prophylactic treatment with these antiemetic agents.
Olanzapine is an antipsychotic drug that inhibits signalling via multiple neurotransmitter receptors and these receptors, particularly the dopaminergic D2, 5-HT2c, and 5-HT3 receptors, are considered to be involved in vomiting and nausea. Therefore, the effect of olanzapine on these receptors provides a pharmacologic rationale for its use in chemotherapy-induced nausea and vomiting prevention. Several studies demonstrated that adding olanzapine to triple therapy in highly emetogenic chemotherapy regimens improved chemotherapy-induced nausea and vomiting control.
The study team hypothesized that adding olanzapine would be useful for patients receiving carboplatin-containing chemotherapy. They previously conducted a pilot phase II study to evaluate antiemetic therapy with olanzapine 5 mg, aprepitant, 5-HT3 RA, and dexamethasone in patients who received carboplatin. The overall CR rate was 93.3%. At present, triple therapy is standardised for carboplatin-containing chemotherapy, and a placebo-controlled comparative study between triple therapy and olanzapine-added therapy was warranted.
In this phase III study, the investigators examined the efficacy and safety of adding olanzapine 5 mg once daily to triple antiemetic therapy for chemotherapy-induced nausea and vomiting prevention in patients receiving carboplatin-containing chemotherapy. This multicentre, prospective, randomised, double-blind, placebo-controlled phase III study was conducted at 16 hospitals in Japan.
Chemotherapy-naïve patients scheduled to receive carboplatin (AUC ≥5) were randomly assigned to receive either olanzapine 5 mg once daily (olanzapine group) or placebo (placebo group) in combination with aprepitant, a 5-HT3 RA, and dexamethasone. The primary endpoint was the CR rate, defined as no vomiting and no rescue therapy, in the overall phase (0-120 hours). Secondary endpoints included the proportion of patients free of nausea and safety.
A total of 355 patients were evaluated, 175 in olanzapine and 180 in placebo group; 78.6% were male, median age was 72 years. The overall CR rate was 86.9% in the olanzapine group versus 80.6% in the placebo group. The intergroup difference in the overall CR rate was 6.3%. The proportions of patients free of chemotherapy-induced nausea in the overall (88.6% in olanzapine group versus 75.0% in placebo group) and delayed (89.7% versus 75.6%) phases were significantly higher in olanzapine group than in placebo group (both p < 0.001).
Somnolence was observed in 43 (24.6%) and 41 (22.9%) patients in olanzapine and placebo groups, and no events were grade ≥3 in severity. The incidence of daytime sleepiness and the degree of associated difficulty experienced in daily life did not differ between the olanzapine and placebo groups. Somnolence is a significant problem that requires attention. In general, patients who receive 10 mg of olanzapine once daily more commonly experience drowsiness, particularly on day 2. The time to the maximum concentration of olanzapine is 4.8 hours, and administration after an evening meal might cause olanzapine levels to peak during sleep.
The authors commented that all patients in this study had thoracic cancers. Olanzapine might have greater benefits in patients with other cancers such as gynaecologic cancers. They concluded that addition of olanzapine was not associated with a significant increase in the overall CR rate. Regarding the prevention of nausea, adding olanzapine provided better control in patients receiving carboplatin-containing chemotherapy, which needs further exploration.
The study was supported in part by a Grant-in-Aid from the Japan Research Foundation for Clinical Pharmacology.
Reference
Inui N, Suzuki T, Tanaka K, et al. Olanzapine Plus Triple Antiemetic Therapy for the Prevention of Carboplatin-Induced Nausea and Vomiting: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial. JCO; Published online 4 June 2024. DOI: https://doi.org/10.1200/JCO.24.00278