Abstract PD1-09: Nausea as a Mediator of Olanzapine’s effect on Quality-of-Life Improvement in Patients Receiving Highly or Moderately Emetogenic Chemotherapy Insights from a Phase III NCORP RCT

Abstract Background: Despite guideline-based antiemetics, refractory nausea remains common and significantly impairs quality of life (QOL) in patients receiving emetogenic chemotherapy. In this secondary analysis of a Phase III NCORP trial, we assessed whether olanzapine’s (OLZ) effects on QOL were mediated by reductions in nausea, using a moderated mediation model. We also evaluated subgroup differences by chemotherapy emetogenicity (HEC vs. MEC). Methods: In the parent RCT (NCT03367572), 1,363 chemotherapy-naïve breast cancer patients were screened across 21 NCORP sites while initiating highly (HEC) or moderately emetogenic chemotherapy (MEC). All received ASCO-recommended antiemetics. Three timepoints were defined: baseline prior to chemotherapy initiation (T1); immediately following Cycle 1 and prior to randomization (T2); and immediately prior to Cycle 2, post-randomization (T3). After Cycle 1 (T2), 310 patients with moderate nausea (≥3 on a 1-7 scale) were randomized 1:1:1 to receive olanzapine (OLZ), prochlorperazine (PC), or placebo, in addition to the standard regimen. This secondary analysis focused on the OLZ arm due to its superior QOL effects in the parent trial. Nausea was assessed using a 4-day home diary, with the maximum reported score across all diary entries used for analysis. QOL was measured via the FACT-G. We applied structural equation modeling (SEM) to evaluate whether OLZ’s effect on QOL at T3 was mediated by reductions in nausea, with moderation by time and treatment. Subscale analyses emphasized physical well-being (PWB). Clinically meaningful changes were defined as ≥5 points for FACT-G and ≥2 for subscales. Bonferroni correction (α = 0.00625) adjusted for multiple comparisons. Results: OLZ significantly improved QOL at T3, with 50.5% of the total FACT-G effect (Mean Difference [MD] = 4.67; p=0.002) mediated by reduced nausea (MD=2.36; p=0.001). In the HEC subgroup, the total FACT-G improvement was clinically meaningful (MD=6.50; p=0.001), with 3.82 points (58.8%) mediated (p<0.001). For PWB, OLZ led to a 2.53-point increase (p=0.001), with 59.4% (1.50 points) mediated by nausea reduction (p<0.001); in HEC patients, PWB increased by 3.20 points, with 72.2% (2.30 points) mediated (p<0.001). No significant effects were observed in the MEC group. A significant time-by-arm interaction (p<0.001) indicated greater improvement in nausea for OLZ compared to other arms between T2 and T3, the period during which OLZ was administered. Conclusions: In this secondary analysis, over half of OLZ’s benefit on overall QOL, and up to 72% of its benefit on physical well-being, was mediated by reductions in nausea. While effects were most pronounced in patients receiving HEC, clinically meaningful improvements were also observed in the MEC group, underscoring olanzapine’s broad utility across emetogenic risk levels. These findings highlight the critical role of nausea control in enhancing QOL and patient-reported outcomes, while supporting the integration of OLZ into standard antiemetic regimens for patients undergoing emetogenic chemotherapy. Citation Format: K. Spath, C. Fung, J. Guido, G. Morrow, M. Janelsins, C. Kamen, J. McGuire, L. Mattick, P. Kumar, J. Fukui, D. Doster, L. J. Peppone. Nausea as a Mediator of Olanzapine’s effect on Quality-of-Life Improvement in Patients Receiving Highly or Moderately Emetogenic Chemotherapy Insights from a Phase III NCORP RCT [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD1-09.