Abstract PO4-04-11: 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

Abstract BACKGROUND Giredestrant (GIR) is a highly potent, nonsteroidal, oral, selective estrogen receptor antagonist and degrader (SERD). The Phase Ia/b GO39932 study (NCT03332797) investigated GIR ± palbociclib (palbo) and ± a luteinizing hormone-releasing hormone agonist for 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. Results showed that GIR was well tolerated and potentially clinically active as a single agent and in combination with palbo, including in patients with ESR1-mutated tumors. 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. METHODS 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, selected AEs of interest [sAEIs], including all-grade hepatotoxicity, and bradycardia) were evaluated. RESULTS Data cutoff was September 17, 2021. A total of 111 patients were enrolled in the single-agent GIR cohort. Of these 111 patients, 107 were pharmacokinetic-evaluable and included in the analysis. ORR in patients with measurable disease at baseline was 20% (16/81 patients) and CBR was 49% (54/111). 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). There were 92/107 patients (86%) with AEs of any grade, overall. Seventy-two (67%) had sAEIs, 19 (18%) experienced hepatotoxicity (all events were reported as liver function test abnormalities), 11 (10%) had bradycardia, and 20 (19%) had Grade ≥ 3 AEs. Increasing exposure did not significantly increase the incidence of all AEs, Grade ≥ 3 AEs, sAEIs, or bradycardia at the dose range of 10 to 250 mg (p > 0.05). For hepatotoxicity, 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 hepatotoxicity was low and the predicted exposures were at the shallower slope of the relationship. CONCLUSIONS 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, indicating that the efficacy of GIR might have reached a plateau at low dose levels. At the clinically relevant exposure range of the 30 mg dose, GIR exposure was not associated with an appreciable increase in the incidence of AEs. The Phase Ia/b study design and subsequent E–R results enabled dose selection to be based on risk–benefit considerations, rather than the traditional maximum tolerated dose paradigm, in line with the United States Food and Drug Administration’s oncology dose optimization recommendations. 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. Citation Format: 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.