Pathologic response and molecular correlates of giredestrant in patients with grade 1 clinical stage IA endometrioid endometrial cancer: the phase II endomERA study

Objective To evaluate the activity and safety of giredestrant, a next-generation oral selective full estrogen receptor antagonist and degrader, in patients with early-stage endometrioid endometrial cancer. Methods In the single-arm, phase II endomERA study (NCT05634499), patients with centrally confirmed grade 1, clinical stage IA endometrioid endometrial cancer received six 28-day cycles of oral giredestrant 30 mg/day, with endometrial sampling after cycles 3 and 6. Thereafter, patients could continue giredestrant for up to 24 cycles or undergo hysterectomy. Primary endpoints were the centrally reviewed 6-month pathologic regression rate and safety; the 6-month complete regression rate was a secondary endpoint. Results Between June 2023 and September 2024, 33 patients were enrolled and treated (median age 54 years, median body mass index 43 kg/m 2 ; 12% TP53 -mutated, 9% POLE -mutated, 3% mismatch repair-deficient by next-generation sequencing). The 6-month pathologic regression rate in 28 evaluable patients was 82% (95% confidence interval 63 to 94%), with complete regression in 39% (95% CI 22 to 59%); regression was observed in 9/10 premenopausal patients (90%), including complete regression in 6/10 (60%). Pathologic tumor regression was seen across molecular subtypes, and in all TP53 -mutated tumors. Only 2 patients had grade 3 treatment-related adverse events (1 with diarrhea, 1 with abnormal estradiol); the rest were grade ≤2, most commonly hot flushes (36%), ovarian cysts (27%), and fatigue (24%). Five patients (15%) discontinued giredestrant before cycle 6 (4 for treatment-related grade 2 ovarian cysts, 1 for treatment-unrelated grade 4 thrombocytopenia). No patients died. Twenty-one patients opted to continue giredestrant beyond the protocol-mandated 6 months. Conclusion Giredestrant demonstrated antitumor activity in patients with early-stage endometrioid endometrial cancer across molecular subtypes in this study, and in TP53 -mutated tumors, with acceptable toxicity in this proof-of-concept study. For patients who desire or require alternatives to hysterectomy, giredestrant may represent a novel therapeutic approach.