Exposure-response analyses of GO39932: a Phase Ia/b study of giredestrant in estrogen receptor-positive, HER2-negative, locally advanced or metastatic breast cancer
Authors: Lien Yi Ting (Kayla) , Jhaveri Komal , Turner Nicolas , Lim Elgene , Cannon Maureen , Anziano Richard , Langenhorst Jurgen , Yoshida Kenta , Malhi Vikram , Gates Mary , Eng-Wong Jennifer , Li Chunze , Shah Mona , Pérez-Moreno Pablo , Yu Jiajie , Bardia Aditya 
Published: February 2025

Giredestrant(GIR), an oral selective estrogen receptor antagonist and/ degrader(SERD), was studied in Phase Ia/b GO39932 study(NCT03332797). GIR was administered alone or with palbociclib(palbo) to patients with ER-positive, HER2-negative, locally advanced or metastatic breast cancer who had disease progression on prior endocrine therapies. In the single-agent dose-escalation stage, patients received 10, 30, 90, or 250 mg of once-daily(QD) GIR. In the dose-expansion stage, patients received 30, 100, or 250 mg of QD GIR. Safety and tolerability of 100 mg GIR+125 mg palbo was also explored in the dose-escalation and expansion stages. GIR was well tolerated and potentially clinically active alone and with palbo, independent of ESR1 mutation status. To inform the selection of the clinical dose for GIR late-stage development based on risk–benefit considerations, exposure–response(E–R) analyses for efficacy and safety endpoints were conducted using single-agent GIR data. _x000D_ _x000D_ Exposure metrics included maximum concentration at steady state and area under the concentration-time curve at steady state. The association between the exposure metrics and efficacy endpoints(objective response rate[ORR] and clinical benefit rate[CBR]) or safety endpoints(all adverse events[AEs], Grade ≥3 AEs, and selected AEs of interest[sAEI] were evaluated.Data cutoff was September 17, 2021. Of 111 patients enrolled in the GIR monotherapy cohort, 107 were pharmacokinetic-evaluable.ORR in patients with measurable disease at baseline was 20&#37; and CBR was 49&#37;. No significant associations were observed between exposure and ORR or CBR, including in patients with ESR1-mutated tumors and those with no mutation detected(p >0.05). 86&#37; of patients experienced AEs;67&#37; had sAEI, with 18&#37; experiencing hepatic events(all events were reported as liver function test abnormalities, and were not clinically significant), 10&#37; bradycardia, and 19&#37; Grade ≥3 AEs. Increasing exposure did not significantly increase the incidence of all AEs, Grade ≥3 AEs, sAEI, or bradycardia at the dose range of 10 to 250 mg. For hepatic events, the analysis suggested that higher exposure may lead to a higher probability of events (p=0.0065); however, at the clinically relevant exposure range for the 30 mg dose, the incidence of hepatic events was low and the predicted exposures were at the shallower slope of the relationship._x000D_ _x000D_ Single-agent GIR did not exhibit a significant association between exposure and efficacy endpoints at a dose range of 10 to 250 mg, regardless of ESR1 mutation status, suggesting that GIR’s efficacy might have reached a plateau at low dose levels. At the clinically relevant exposure range, GIR exposure was not associated with an appreciable increase in the incidence of AEs. The E–R results also indicate that GIR may have a relevant wide therapeutic window. Overall, these data support the 30-mg clinical dose of GIR that was selected, with a favorable risk–benefit profile, for further clinical studies.Citations: Komal Jhaveri, Yi Ting (Kayla) Lien, Nicholas Turner, Elgene Lim, Maureen Cannon, Richard Anziano, Jurgen Langenhorst, Kenta Yoshida, Vikram Malhi, Mary Gates, Jennifer Eng-Wong, Chunze Li, Mona Shah, Pablo Perez-Moreno, Jiajie Yu, Aditya Bardia. Exposure–response analyses of GO39932: a Phase Ia/b study of giredestrant in estrogen receptor-positive, HER2-negative, locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-04-11.