Olanzapine or prochlorperazine added to antiemetic therapy for persistent chemotherapy-induced nausea: an NCORP phase 3 RCT

BACKGROUND: Despite guideline-consistent antiemetic prophylaxis, persistent chemotherapy-induced nausea remains common, and comparative phase 3 evidence for olanzapine versus prochlorperazine is limited. We evaluated whether adding olanzapine or prochlorperazine to standardized Cycle 2 antiemetic prophylaxis reduces persistent nausea compared with placebo. METHODS: In this multicenter, randomized, double-blind, placebo-controlled phase 3 trial at 23 NCORP community oncology sites (April 2018-January 2024), women 18 years or older with breast cancer receiving moderately or highly emetogenic chemotherapy who recorded a Cycle 1 nausea score of 3 or greater (1-7 scale) were randomized 1:1:1 during Cycle 2 to placebo, prochlorperazine (10 mg every 8 hours, Days 1-4), or olanzapine (10 mg once daily, Days 1-4), added to netupitant/palonosetron plus dexamethasone. The primary outcome was change in average nausea from Cycle 1 to Cycle 2; the key secondary outcome was change in maximum nausea. RESULTS: Among 1363 screened patients, 310 comprised the intention-to-treat population (placebo, 91; prochlorperazine, 110; olanzapine, 109). Compared with placebo, average nausea improved with prochlorperazine (between-group difference, -0.44; P=.01) and olanzapine (-0.57; P=.001). Olanzapine reduced maximum nausea more than prochlorperazine (difference, -0.59; P=.02) and improved FACT-G quality-of-life scores over placebo (difference, 4.91; P=.006) and prochlorperazine (5.80; P=.001). Adverse events were primarily grade 1-2, with no toxicity-related discontinuations. CONCLUSIONS: Adding olanzapine or prochlorperazine to standardized Cycle 2 antiemetic prophylaxis reduced persistent chemotherapy-induced nausea compared with placebo. Olanzapine produced greater improvement in maximum nausea and quality of life than prochlorperazine and is an effective escalation option, with prochlorperazine a reasonable alternative when olanzapine is unsuitable. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03367572.