Clark, A. S.

Abstract As shown by the TAILORx and RxPONDER trials, recurrence score (RS) identifies many postmenopausal pts who do not benefit from addition of ACT to endocrine therapy (ET); however, it also identifies certain subsets of premenopausal pts who do benefit (node-neg/high clinical risk/RS 16-20, node-neg/RS 21-25, and node-pos/RS ≤25). Most premenopausal pts in these trials did not receive ovarian function suppression (OFS) as part of their ET regimen. Given the observed benefit from OFS in high-risk premenopausal pts with HR+/HER2- BC in the SOFT/TEXT trials, we question whether the noted ACT benefit in TAILORx/RxPONDER may have been the result of chemotherapy-induced OFS. To address this, we developed OFSET, a phase III clinical trial comparing OFS+ET v ACT+OFS+ET. We hypothesize that addition of ACT to OFS+ET is superior to OFS+ET in improving invasive breast cancer-free survival (IBCFS) among premenopausal, early-stage BC pts with HR+/HER2- tumors and a 21-gene RS between 16-25 (for pN0 pts) and 0-25 (for pN1 pts). Secondary objectives include invasive disease-free survival, overall survival, distant recurrence-free interval, breast cancer-free interval, and health-related quality of life (HRQOL). Pts must be node-neg with RS 16-20 (plus high clinical risk), or RS 21-25, or have 1-3 positive nodes with RS ≤25. Stratification is by nodal status/RS status (pN0 RS 16-25 v pN1 RS 0-15 and pN1 RS 16-25), intent to receive CDK4/6 inhibitor (yes; no), and age (18-39 v ≥40). Pts are randomized after surgery to either OFS+ET or ACT+OFS+ET. ET is an aromatase inhibitor (AI) per physician discretion; or tamoxifen if AI is not tolerated or if OFS is incomplete. Radiotherapy will be administered per protocol guidelines. The HRQOL substudy will assess differences between arms in severe menopausal symptoms (measured by FACT ESS-19) and pain severity (PROMIS). Blood and tumor specimens will be collected for future research. We anticipate accrual of 3,960 pts in 7 yrs, 7 mos. Per NSABP B-28/RxPONDER data, 5-yr IBCFS of pN1 pts on the ACT+OFS+ET arm is estimated at 92.3%. Based on TAILORx data, 5-yr IBCFS of pN0 pts on the ACT arm is ∼95%. Assuming 56% of pts to be pN0 and 44% pN1, and a 0.5% annual loss-to-follow-up rate, the definitive analyses to detect a hazard ratio: 0.75 with ACT+OFS+ET v OFS+ET, with 1-sided α of 0.025 and 80% power, will require 380 IBCFS events, expected to occur ∼11 yrs after study initiation. Accrual is 292/3,960 (from 8/2023 to 5/2025). Among 148 pts with OFS data available, 79 (53.4%) were prescribed goserelin and 69 (46.6%) leuprolide. A monthly dosing schedule was prescribed for 86.1% of pts receiving goserelin and 73.5% of those receiving leuprolide; the remaining received a 3-monthly schedule. NCT05879926 Support: U10 CA180868, -80822, UG1 CA189867, U24 CA196067 Citation Format: S. Swain, G. Tang, S. L. Puhalla, P. A. Ganz, N. L. Henry, R. S. Cecchini, S. A. Reid, P. Rastogi, C. E. Geyer, Jr., J. R. White, A. S. Clark, T. C. Haddad, G. A. Vidal, N. Wolmark, E. P. Mamounas. NRG-BR009: A phase III trial evaluating addition of adjuvant chemotherapy to Ovarian Function Suppression + Endocrine Therapy in premenopausal women with pN0-1, HR+/HER2- breast cancer and recurrence score ≤25 (OFSET) [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 PS5-07-04.

Abstract BACKGROUND: EOP is an I-SPY2 sub-study designed to test novel endocrine-based strategies in patients (pts) predicted to have modest benefit from chemotherapy. Vepdegestrant is a selective oral PROTAC estrogen receptor (ER) degrader that has demonstrated efficacy in mutant ER+ HER2-negative MBC. METHODS: EOP eligibility included pts with Stage 2/3 HR+ HER2-negative, MammaPrint (MP) Low Risk BC. Patients with MP High1 signatures were eligible if clinically node-negative or SET 2,3 High. Pts were randomized to one of 3 oral treatment (tx) arms: vepdegestrant 200 mg/d (V), vepdegestrant 200 mg/d +letrozole (VL), vepdegestrant 200 mg/d + abemaciclib 150 mg bid (VA). Pts received tx for six 28-day cycles followed by surgery. Premenopausal (PreMN) pts received ovarian function suppression (OFS) starting C1D1 in the VL arm, and C2D1 in the V and VA arms. The primary endpoint was feasibility, defined as >75% of pts completing >75% of study therapy. Breast MRI functional tumor volume (FTV) and ctDNA (tumor-informed assay) were assessed at baseline (T0), 3 weeks (T1), 12 weeks (T2), and 6 months (T3). Ki67 and ER/PR by IHC were centrally assessed from tumor biopsies at T0, T1, and the surgical specimen. Results: Between 4/2023 and 1/2025, 121 pts were enrolled: 40 in V, 41 in VL, and 40 in VA. Median age was 54 years, 50% preMN. 60% of pts had ductal, 35% lobular, 5% mixed histology. 55% were cN+, and 59% were not breast conservation surgery (BCS) candidates at baseline. Mean baseline Ki67 was 12.5%, 85.1% had MP Low Risk signature, 79.3% were SET 2,3 High. All 3 tx arms met the primary endpoint with 88%, 88%, and 83% completing > 75% study therapy in V, VL, and VA (thus far), respectively. Most common all grade (AG) TRAEs in V and VL arms include fatigue (53% V, 71% VL), hot flashes (48% V, 71% VL), arthralgias (33% V, 49% VL), all G1 or G2 except for 1 G3 fatigue in VL arm. G2 and G3 neutropenia was seen in 1 pt each in V and VL arms. The most common AG TRAEs in VA include diarrhea (80%), fatigue (65%), nausea (58%), hot flashes (50%), neutropenia (43%). High grade TRAEs in VA include neutropenia (23% G3, 5% G4), ovarian cyst requiring surgery (5% G3), diarrhea (15% G3), nausea (3% G3), transaminitis (3% G3), thromboembolic event (8% G3), acute kidney injury (3% G3). Table 1 summarizes key response endpoints by tx arm. CONCLUSION: Six months of neoadjuvant vepdegestrant, alone or in combination with letrozole or abemaciclib, is feasible and demonstrates robust ER/PR degradation. Encouraging anti-tumor activity through reduction of Ki67 and MRI FTV, ctDNA clearance, and achievement of BCS was seen in pre- and postMN women. The neoadjuvant setting provides a rich platform to identify the dynamic range of response and non-response using a multi-modal approach and can be leveraged to inform future trial design and adjuvant therapy. Citation Format: J. Chien, R. M. Mukhtar, C. Yau, A. D. Elias, A. M. Wallace, N. Chan, C. Omene, N. Chen, J. Tseng, M. S. Trivedi, E. Stringer-Reasor, D. Yee, A. S. Clark, A. Thomas, H. Han, M. Arora, C. Nangia, K. Albain, C. Falkson, C. Isaacs, A. Zimmer, M. Rozenblit, L. van't Veer, L. Brown Swigart, G. Hirst, W. Symmans, A. D. Borowsky, N. Onishi, N. Hylton, S. Alkhafaji, K. V. Giridhar, C. Vaklavas, M. Wei, M. P. Goetz, O. Olopade, L. Huppert, C. Wu, L. J. Esserman. I- SPY2 Endocrine Optimization Pilot (EOP): Neoadjuvant vepdegestrant monotherapy or in combination with letrozole or abemaciclib in molecularly selected patients with stage 2/3 HR+ HER2-negative breast cancer (BC) [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 PD10-02.