Abstract P2-03-07: Neoadjuvant (Z)-endoxifen for Premenopausal Estrogen Receptor (ER)+, Human Epidermal Growth Factor Receptor 2 (HER2)- Breast Cancer (BC): Evaluation of Quality of Life (QOL) measures in the EVANGELINE Study

Abstract Background: Premenopausal women (PrW) with ER+, HER2- breast cancer (BC) are commonly treated with aromatase inhibitors (AI) with ovarian function suppression (OFS) or tamoxifen (tam) +/- OFS. Common adverse effects (AE) include musculoskeletal symptoms, hot flashes, night sweats, mood changes, and sexual side effects that may seriously impact quality of life (QOL). In SOFT, compared to tam alone, pts treated with tam + OFS had more hot flashes, loss of sexual interest, sleep disturbances, and vaginal dryness. In the combined SOFT/TEXT analysis, pts receiving exemestane + OFS had greater bone/joint pain, vaginal dryness, and loss of sexual interest, whereas pts receiving tam + OFS had more hot flushes and sweats. In the premenopausal setting, E1/E2 levels differ based on type of endocrine therapy regimen, with menopausal E1/E2 levels following OFS, but increases with tam monotherapy. EVANGELINE (NCT05607004) is an ongoing phase 2 multicenter neoadjuvant study assessing (Z)-endoxifen (ENDX), a potent tam metabolite that dually targets ERα and PKCβ, in PrW with ER+/HER2- BC. Prior to the randomized phase II, a PK run-in was designed to identify a dose wherein 28-day ENDX Css > 500 ng/ml in ≥ 5/6 pts and to assess antitumor activity and toxicity when ENDX is dosed at 40 mg/day (monotherapy) and 80 mg/day (+/- OFS). Pts with endocrine sensitive disease (ESD) defined as 4-week Ki67 ≤ 10% continue treatment (tx) for 24 weeks followed by surgery. Here, we report the menopausal symptoms for pts enrolled onto 40 mg/day cohort. Methods: All eligible pts who completed baseline and at least one tx questionnaire or toxicity evaluation are included. Data captured by the medical team using Common Terminology Criteria for Adverse Events (CTCAE) and self-reported symptoms are reported in pts menstrual diary or on the Menopause-Specific Quality of Life (MENQOL) questionnaire administered at baseline, end of week 4, 12, and 24. MENQOL bothersomeness level was categorized as mild (score 0-1), moderate (2-4), and high (5-6). Estradiol and estrone levels were assessed for the 40 mg/day dose at week 4 and 24. Results: For the 40 mg/day cohort, 7 PrW (6 White, 1 Asian) aged 28-51 (median 46) received ENDX. One pt discontinued due to week 4 Ki-67 > 10%. The remaining 6 had ESD, and after 24 weeks underwent surgery. Over the course of tx, relevant AEs reported as possibly, probably or definitely attributed to ENDX included: amenorrhea (G2-n=5); dysmenorrhea (G2-n=1; G1-n=1), hot flashes (G2-n=1; G1-n=5), hyperhidrosis (G1-n=1), hypomenorrhea (G1-n=1), irregular menstruation (G1-n=2), and libido decrease (G2-n=1). Menses did not occur on tx for 4 pts. No dose reductions occurred. Among the remaining 3 pts, dysmenorrhea was described as mild/moderate. MENQOL after 4 wks of tx revealed that hot flashes developed in 4 pts (moderately bothersome -3 pts, not bothersome -1 pt). One pt began venlafaxine for hot flashes. Three pts reported ‘being impatient with others’ as moderately bothersome. The median (range) baseline estrone (n=5) was 54 pg/mL (19-114) with median (range) fold increase from baseline of 9.0 (1.3-23.2 pg/mL) at wk4 and 4.7 (0.4 - 25.9 pg/mL) at wk24. The median baseline estradiol level (n=5) was 29 pg/mL (19-209) with median fold increases from baseline of 17.9 (0.4-57.0 pg/mL) at wk4 and 8.1 (0.04 - 56.6 ng/mL) at wk24. Currently, 12 pts are enrolled to either 80 mg/day monotherapy or 80 mg/day + OFS. Conclusions: This is the first report of menopausal side effects in PrW women treated with ENDX 40 mg/day without OFS. Most side effects were low grade and amenorrhea was common. ENDX induced marked increases in E1/E2 levels that peaked at 4 weeks and then declined. MENQOL data from the 80 mg/day monotherapy and 80 mg/day + OFS cohort will be reported at the meeting. Citation Format: Sarah K. Premji, Vera J. Suman, Lida A. Mina, Pooja P. Advani, Arezoo Mirad, Roberto Leon-Ferre, Karthik V. Giridhar, Felipe Batalini, Swaathi Jayaraman, Patricia Cronin, Mara Piltin, Amy Degnim, James N. Ingle, Tufia C. Haddad, Amye J. Tevaarwerk, Jason M. Jones, Daniel Flora, Harjinder Singh, Nusayba A. Bagegni, Katie N. Hunt, Judy C. Boughey, Joel M. Reid, Matthew Schellenberg, John R. Hawse, Steven Carl Quay, Matthew P. Goetz. Neoadjuvant (Z)-endoxifen for Premenopausal Estrogen Receptor (ER)+, Human Epidermal Growth Factor Receptor 2 (HER2)- Breast Cancer (BC): Evaluation of Quality of Life (QOL) measures in the EVANGELINE Study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-03-07.