Add-on olanzapine augments nausea, vomiting control during chemo cycles

Adding olanzapine to prophylactic antiemetic medications appeared to substantially improve nausea and vomiting control among patients receiving moderately emetogenic chemotherapy (MEC) regimens in a phase III randomized clinical trial.

Over the entire 120 hours of the first chemotherapy cycle, the rate of complete response (CR) with a prophylactic antiemetic combination of dexamethasone, aprepitant, and palonosetron was significantly higher among patients who received add-on olanzapine than among control participants who did not (91 percent vs 82 percent; p=0.005). CR was defined as the absence of vomiting, absence of significant nausea (score of <5 on a visual analogue scale of 1–100), and no use of rescue medications for nausea.  [JAMA Netw Open 2024;7:e2426076]

The same held true when CR was assessed during the later treatment period (25–120 hours: 92 percent vs 83 percent; p=0.001) but not during the early treatment period (0–24 hours: 96 percent vs 94 percent; p=0.53).

In terms of secondary endpoints, the olanzapine arm showed better nausea control (96 percent vs 87 percent; p<0.001) and chemotherapy-induced nausea and vomiting (CINV) control (96 percent vs 91 percent; p<0.02) compared with the control arm in the overall treatment period. Results for vomiting control did not differ between the treatment arms (95 percent vs 94 percent; p<0.67).

During the late treatment period, control rates for nausea and CINV were likewise higher in the olanzapine arm than in the control arm (96 percent vs 89 percent; p<0.001 and 95 percent vs 86 percent; p<0.001). No significant differences were observed during the early treatment period.

Overall, significantly fewer patients in the olanzapine arm than in the control arm received rescue medications (4 percent vs 11 percent; p=0.001). Aside from grade 1 somnolence, which occurred solely in the olanzapine arm (10 percent), no other adverse events deemed related to the medication were reported.

Finally, Functional Living Index–Emesis (FLIE) scale scores indicated reduced quality of life (QOL) in a significantly smaller proportion of patients in the olanzapine than in the control arm when assessed for CINV (6 percent vs 12 percent; p=0.03) and vomiting (3 percent vs 8 percent; p=0.01). No significant difference was observed in the proportion of patients with reduced nausea-related QOL (9 percent vs 12 percent; p=0.30).

“The effect of olanzapine appeared to predominantly occur in the delayed phase of CINV prevention, as evidenced by the improvement across endpoints (CR, CINV, and nausea) in the delayed phase,” the investigators said. 

“A key parameter that is commonly used by major guidelines as an assessment in improving antiemetic prophylaxis is whether an intervention improves an emesis-related endpoint by 10 percent or more. While the improvement in CR rates with the addition of olanzapine in this study fell marginally short of this conventional arbitrary margin, the improvement across endpoints, lesser use of rescue medications, negligible adverse effect profile, and improvement in QOL … support the addition of olanzapine as antiemetic prophylaxis in patients receiving oxaliplatin, carboplatin, or irinotecan,” they added.

CINV risk assessment

In an exploratory analysis that applied the CINV risk assessment model, patients who were classified as low risk were more likely to achieve CR with the addition of olanzapine (91 percent vs 84 percent; p=0.03)—a benefit that was not observed among patients classified as high risk (88 percent vs 82 percent; p=0.32). Similarly, patients in the olanzapine arm classified as low risk had significantly better CINV control rates compared with their counterparts in the control arm (94 percent vs 84 percent; p=0.002).

“Most patients in the study were classified as low risk as opposed to high risk for CINV, and this could be one of the reasons for the higher than expected overall CR rates in the study,” the investigators said.

As for why the additive effect of olanzapine in improving CR rates and reducing CINV rates was greater among patients at low risk than among those at high risk, the investigators pointed to variations in risk assessment methodologies.

“[It] could be that the [CINV risk] score recognizes the standard antiemetic regimen for non–carboplatin-containing MEC as a combination of a 5-HT3 antagonist and dexamethasone and calculates the baseline CINV risk based on the efficacy of this combination, whereas the current study used an additional NK-1RA as a baseline comparator,” they explained.

Study details

The trial included 560 chemotherapy-naïve patients (median age 51 years, 64 percent male) with solid tumours. Most of these patients were treated with oxaliplatin-based chemo regimen (61 percent), 29 percent received carboplatin-containing regimen, and the remaining 10 percent received irinotecan-containing regimen. For antiemetic prophylaxis, all patients received palonosetron (0.25 mg intravenously on day 1 of chemo), dexamethasone (12 mg intravenously on day 1), and aprepitant (125 mg orally on day 1 and 80 mg orally on days 2 and 3). In the olanzapine arm, patients additionally received olanzapine (10 mg per day orally once, taken at night) on days 1 through 3.

A total of 544 patients, including 274 in the olanzapine arm and 270 in the observation arm, had evaluable data and were included in the analysis.

Subgroup analysis defined by the type of chemotherapy showed that the benefit of add-on olanzapine for CR was pronounced among patients receiving oxaliplatin-based chemotherapy (odds ratio [OR], 0.36, 95 percent confidence interval [CI], 0.16–0.85) or carboplatin-based chemotherapy (OR, 0.23, 95 percent CI, 0.07–0.73) but not irinotecan-based therapy (OR, 2.36, 95 percent CI, 0.23–24.25).

“The use of the CINV risk score should be explored further when making treatment decisions for using antiemetic prophylaxis in these MEC regimens,” the investigators said.