Abstract PD5-10: A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader (SERD), GDC-0927, in postmenopausal women with estrogen receptor positive (ER+) HER2-negative metastatic breast cancer (BC)

Abstract

Background: Modulation of estrogen activity and/or synthesis is the mainstay therapeutic strategy in the treatment of ER+ BC. However, despite the effectiveness of available endocrine therapies, many patients ultimately relapse or develop resistance to these agents via estrogen-dependent and estrogen-independent mechanisms, including mutations in ESR1 affecting the ER ligand binding domain that drive ER-dependent transcription and proliferation in the absence of estrogen. ER antagonists that are efficacious against ligand-dependent and ligand-independent, constitutively active ESR1 mutant tumors may be of substantial therapeutic benefit. GDC-0927 (formerly known as SRN-927) is a novel, potent, non-steroidal, orally bioavailable, selective ER antagonist/ER degrader (SERD) that induces tumor regression in ER+ BC patient-derived xenograft models. Methods: A phase I dose escalation study with 3+3 design was conductedin postmenopausal women with ER+ (HER2-) metastatic BC (progressing ≥ 6 months on endocrine therapy and with ≤ 2 prior chemotherapies in the advanced or metastatic setting) to determine the safety, pharmacokinetics (PK) and the recommended Phase 2 dose (RP2D) of GDC-0927. Pharmacodynamic (PD) activity was assessed with [18F]-fluoroestradiol (FES)-PET scans. Plasma PK samples (after single dose and at steady state), CT scans, and when feasible, pre and on-study tumor biopsies were obtained Results: From March 16, 2015 to March 17, 2017 patients (pts) with a median age of 53 years (range 44-69) and a median number of prior therapies for MBC 4 (range 1-7) were enrolled at 3 total daily dose levels (600, 1000, 1400 mg) once daily (QD) given orally with fasting (n = 12). Increases in GDC-0927 exposure were approximately dose proportional. Treatment related adverse events (AEs) were all grade 1 or 2. The most common treatment-related AEs were nausea (54%, n = 7), diarrhea (46%, n = 6), elevated aspartate aminotransferase (39%, n = 5) and anemia, constipation, (each 31%, n = 4). Treatment interruption was required for 2 pts due to nausea and vomiting. Of those pts with FES-PET avid disease at baseline (9 of 12), all post-therapy scans showed complete or near complete (> 90%) suppression of FES uptake to background levels, including pts with ESR1 mutations. Evidence of reduced ER levels and Ki67 staining was observed in on-treatment biopsies. Five of 12 pts (1 at 600 mg and 4 at 1400 mg) were on study ≥ 24 weeks (CBR = 41.6 %) with the best overall response of stable disease with 1 patient (ESR1 mt+ D538G) on study for over 490 days. There were no dose limiting toxicities and no SAEs related to study drug. R2PD was 1400 mg and was selected for single arm dose-expansion which is now complete with last patient enrolled on March 17, 2017. Updated results from dose-escalation and dose-expansion will be presented at the meeting (N = 43). Conclusions: GDC-0927 appears well-tolerated to date with PK exposure supporting QD dosing, evidence of robust PD target engagement, and encouraging anti-tumor activity in heavily pretreated pts with advanced or metastatic ER+ BC, including pts with ESR1 mutations. Citation Format: Dickler MN, Villanueva R, Perez Fidalgo JA, Mayer IA, Boni V, Winer EP, Hamilton EP, Bellet M, Urruticoechea A, Gonzalez-Martin A, Cortes J, Martin M, Giltnane J, Gates M, Cheeti S, Fredrickson J, Wang X, Friedman LS, Spoerke JM, Metcalfe C, Liu L, Li R, Morley R, McCurry U, Chan IT, Mueller L, Milan S, Lauchle J, Humke EW, Bardia A. A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader (SERD), GDC-0927, in postmenopausal women with estrogen receptor positive (ER+) HER2-negative metastatic breast cancer (BC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD5-10.

Endocrine therapy-based treatments in hormone receptor-positive/HER2-negative advanced breast cancer: systematic review and network meta-analysis

“…Ongoing trials are testing new, orally administered selective oestrogen receptor degraders, alone or in combination with CDK4/6i or AI, which should change the treatment landscape in coming years. 81 In the future, it is expected that new genomic, proteomic, metabolomics and imaging biomarkers will be used to further tailor treatment to the individual patient. This is especially needed, not only to spare patients from the toxic effects of ineffective regimens, but also due to the potential 'financial toxicity' of these multiple ET-based treatments, given their potential impact on the individual patient and also on the sustainability of healthcare systems.…”

“…Ongoing trials are testing new, orally administered selective oestrogen receptor degraders, alone or in combination with CDK4/6i or AI, which should change the treatment landscape in coming years. 81 …”

The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells

“…However, its clinical efficacy is limited by poor solubility and oral bioavailability (Wardell et al, 2013a; van Kruchten et al, 2015). Consequently, new complete antiestrogens are being examined for their activities in breast cancers harboring Y537S and D538G ERα that all demonstrate improved oral bioavailability and pharmacokinetics, including G1T48, AZD9496, GDC-0927, RAD1901, SAR439859, and LSZ102 (Wardell et al, 2017; De Savi et al, 2015; Weir et al, 2016; Toy et al, 2017; Dickler et al, 2018; Wardell et al, 2015b; Bihani et al, 2017; Tria et al, 2018; Shomali et al, 2017). Other non-traditional ERα degraders including H3B 6545, which covalently binds to the ERα LBD, and an ER PROTAC from Arvinas are currently in development.…”

Computer-Aided Ligand Discovery for Estrogen Receptor Alpha

“…This SERD causes 97% degradation of ERα and is highly active in tam-resistant MCF-7 xenografts [ 268 ]. In Phase I trials, it was determined that the compound was safe and tolerable in metastatic ERα+/HER- BCa in post-menopausal women including patients harboring ESR1 mutations [ 269 ]. The structure of GDC-0927 in complex with ERα has been resolved but the H12 seems disordered in its packing to the rest of the ER as seen in Figure 10 a using MOE package [ 42 , 270 ].…”