Abstract PS3-10-28: Randomized phase II trial evaluating three anti-diarrheal prophylaxis strategies in patients (pts) with HER2+/HR+ early breast cancer (EBC) treated with extended adjuvant neratinib (dianer geicam/2018-06)

Abstract Background: In the ExteNET clinical trial, extended adjuvant treatment with neratinib (NER), reduced theabsolute risk of recurrence or death by 5.1% at 5 years versus (vs.) placebo in HR+/HER2+ EBC pts whoinitiated treatment ≤1 year post trastuzumab (T) (Chan 2021). Diarrhea was the main reason for NERdiscontinuation in the first 3 cycles (c) (1 c=28 days d). DIANER further studied 3 previously reportedstrategies for managing diarrhea (CONTROL: Chan 2023) in pts receiving NER. Methods: DIANER is a European, controlled, randomized, phase II study in pts with HER2+/HR+ EBC (stageIB-IIIC) who completed prior neo/adjuvant T-based therapy within 1 year. Pts were randomized 1:1:1 toArm A: NER (240 mg/d x 1 year) + loperamide (LP) (12 mg/d x 14 d → 8 mg/d till end of c 2 → as neededPRN), Arm B: NER dose escalation (120 mg/d x 7 d → 160 mg/d till d 14 → 240 mg/d x 13 c) + LP PRN,or Arm C: NER (like Arm A) + LP (12 mg/d x 14 d → 8 mg/d x 14 d → PRN) + colesevelam (3,750 mg/d x 28d). Pts were stratified by menopausal status and prior anti-HER2 therapy (T vs. T + pertuzumab). Theprimary endpoint was the rate of early (in the first 3 c) NER discontinuations due to diarrhea. Simon’soptimal two-stage design was used with a target of 5% (H1) vs. 13% (H0). In the first stage, up to 36 ptsper arm were to be enrolled. Arms with ≥ 4 early discontinuations due to diarrhea were planned to beclosed, otherwise recruitment would continue up to 105 pts per arm. Secondary endpoints were the rateof NER discontinuations (any reason); AEs and hospitalizations; duration, severity, and treatments fordiarrhea; NER exposure. Results: From Sept 2022 to Oct 2024, 177 pts were randomized (41 arm A, 107 arm B, 29 arm C) at 47sites. Median age was 51 years (range: 30-80), 50.3% of pts were postmenopausal, and 39.0%, 28.8% and15.3% had stage IIA, IIB and IIIA disease, respectively. Prior pertuzumab and T-DM1 were received by76.3% and 43.5% of pts, respectively. Arms A and C were closed due to 5 and 4 pts with earlydiscontinuation due to diarrhea, respectively. Early discontinuations due to any reason/diarrhea were25.6%/17.9% in arm A, 13.3%/8.6% in arm B and 27.6%/13.8% in arm C. For the first 3 c, mean (standarddeviation)/median (range) duration of NER exposure was 67 d (32)/84 d (4-101) in arm A, 78 d (19)/84 d(12-105) in arm B and 65 d (34)/84 d (1-91) in arm C. Median (range) relative NER dose intensity was 98%(14-107) in arm A, 99% (28-109) in arm B and 95% (4-105) in Arm C. Most common TEAEs within the first3 c are shown in Table 1. Conclusions: Although none of the 3 strategies for reducing the impact of NER-associated diarrheaassessed in DIANER reduced early treatment discontinuation due to diarrhea to ≤5%, the incidence ofearly NER discontinuation observed in the study suggests that NER dose escalation is the best strategy formanaging diarrhea and other AEs. Citation Format: J. Gil-Gil, M. Ruíz-Borrego, E. Carrasco, Y. Izarzugaza, C. Martínez-Vila, E. Galve, B. López-Barajas, E. Adrover, T. Silovski, M. Valero-Arbizu, Á. Guerrero-Zotano, S. González-Santiago, M. Echarri, A. Cano-Jiménez, A. Vethencourt-Casado, M. De Laurentis, C. Bueno-Muiño, B. Adamo, R. Andrés, C. Villanueva, F. Rojo, M. Casas, P. Wilson, J. Suissa, V. Adams, M. Martin. Randomized phase II trial evaluating three anti-diarrheal prophylaxis strategies in patients (pts) with HER2+/HR+ early breast cancer (EBC) treated with extended adjuvant neratinib (dianer geicam/2018-06) 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 PS3-10-28.