Post-progression treatment (tx) analyses of evERA Breast Cancer (BC): A phase III trial of giredestrant (GIRE) + everolimus (E) in patients (pts) with estrogen receptor–positive, HER2-negative advanced BC (ER+, HER2– aBC) previously treated with a CDK4/6 inhibitor (i).

1016 Background: evERA BC (NCT05306340) is the first Phase III trial to demonstrate a statistically significant and clinically meaningful improvement in investigator-assessed progression-free survival (INV-PFS) with an all-oral, selective ER degrader and full ER antagonist combination (GIRE + E) compared with standard-of-care endocrine therapy combinations (SOC ET + E) in pts with ER+, HER2– aBC post-CDK4/6i + ET (Mayer ESMO 2025). Improvement in INV-PFS was seen in all pts (hazard ratio HR, 0.56) and in pts whose tumors had a detectable ESR1 mutation ( ESR1 m; HR, 0.38), with no unexpected safety findings. We report exploratory post-progression tx analyses. Methods: Pts with ER+, HER2– aBC who had disease progression (PD) or relapse during/post-CDK4/6i + ET were randomized 1:1 to once-daily oral 30 mg GIRE + 10 mg E or SOC ET (exemestane/ fulvestrant/tamoxifen) + E until PD/unacceptable toxicity. Exploratory analyses included PFS2 (time from randomization to PD on next-line tx, or death), chemotherapy-free survival (CFS; time to first subsequent chemotherapy and/or antibody–drug conjugate ADC, or death), and types of cancer tx following discontinuation from study tx. Results: Median PFS2 and CFS were longer with GIRE + E vs SOC ET + E in all pts (PFS2 HR, 0.69; CFS HR, 0.61), including in the ESR1 m (PFS2, 0.61; CFS, 0.46) and ESR1 m not detected populations (PFS2, 0.77; CFS, 0.80; Table). Of those receiving follow-up cancer therapy in all pts, and in the ESR1 m and ESR1 m not detected populations, 69.1%, 63.3%, and 73.8%, respectively, received chemotherapy in the GIRE + E arm vs 71.5%, 65.3%, and 79.0% in the SOC ET + E arm; 24.5%, 18.4%, and 29.5% received an ADC in the GIRE + E arm vs 31.4%, 25.3%, and 38.7% in the SOC ET + E arm. Conclusions: Delaying chemotherapy improves clinical and quality of life outcomes in ER+ aBC. These analyses further support the superior INV-PFS of GIRE + E over SOC ET + E observed in all pts and in the ESR1 m population. Improvements in PFS2 and CFS, regardless of ESR1 m status, suggest that the clinical benefit of GIRE + E is sustained beyond initial progression. Clinical trial information: NCT05306340 . All pts ESR1 m ESR1 m not detected GIRE + E (n = 183) SOC ET + E (n = 190) GIRE + E (n = 102) SOC ET + E (n = 105) GIRE + E (n = 81) SOC ET + E (n = 85) PFS2 Event, n (%) 81 (44.3) 108 (56.8) 39 (38.2) 57 (54.3) 42 (51.9) 51 (60.0) Median, mo (95% CI) 19.0(15.5, not evaluable NE) 13.2 (11.7, 15.9) 19.0 (15.5, NE) 12.9 (11.8, 17.6) 17.3(13.0, NE) 12.9 (9.8, 20.8) Stratified HR (95% CI) 0.69 (0.51, 0.92) 0.61 (0.40, 0.93) 0.77 (0.51, 1.17) CFS Event, n (%) 111 (60.7) 146 (76.8) 51 (50.0) 78 (74.3) 60 (74.1) <jats:td colspan="1