Safety and activity of single-agent giredestrant (GDC-9545) from a phase Ia/b study in patients (pts) with estrogen receptor-positive (ER+), HER2-negative locally advanced/metastatic breast cancer (LA/mBC).

Abstract

1017 Background: Targeting ER activity and/or E synthesis is a mainstay of ER+ BC treatment, but many pts relapse during/after adjuvant endocrine therapy (ET) or develop resistance via ESR1 mutations that drive E-independent transcription and proliferation. Most tumors remain ER signaling-dependent and pts may respond to second-/third-line ET after disease progression (PD) on prior therapies (Di Leo 2010; Baselga 2012). Giredestrant, a highly potent, nonsteroidal oral selective ER degrader, achieves robust ER occupancy, is active despite ESR1 mutations, and was well tolerated ± palbociclib with encouraging antitumor activity in the nonrandomized, open-label, dose-escalation and -expansion, phase Ia/b GO39932 study (NCT03332797; Jhaveri 2019; Lim 2020). We present updated interim data from the dose-escalation and -expansion single-agent giredestrant cohorts. Methods: Pts had ≤2 prior therapies in the LA/mBC setting with disease recurrence/PD while being treated with adjuvant ET for ≥24 mo and/or ET in the LA/mBC setting, and derived a clinical benefit (CB) from therapy (tumor response/stable disease [SD] ≥6 mo). Pts received 10, 30, 90/100, or 250 mg PO giredestrant QD on D1–28 of each 28-day cycle. Pts were postmenopausal (medical menopause on LHRH agonists was allowed with ≥100 mg giredestrant). Results: Clinical cutoff: Jul 31, 2020; median prior therapy lines in the LA/mBC setting: 1; mean dose intensity: 98%. Safety/activity: see the table below. No adverse events (AEs) led to study drug withdrawal. No dose-limiting toxicities (DLTs) occurred; maximum tolerated dose was not reached. Most common AEs in 107 pts: fatigue (22; 21%), arthralgia (18; 17%), and nausea (17; 16%); largely grade 1/2. Related grade 3 AEs were infrequent (5; 5%); none were grade 4/5 per investigator assessment (grade 5 duodenal perforation occurred with 90/100 mg after stopping giredestrant due to PD). 8 (7%) had bradycardia (none with 10 mg or the 30 mg phase 3 dose; all grade 1 except one grade 2 at 250 mg; no treatment interruptions/dose reductions were required). Objective responses and CB were observed at all doses. Conclusions: Single-agent giredestrant was well tolerated at all doses, with no DLTs. AEs were generally low grade and in keeping with expected AEs for ETs. Clinical activity was observed at all doses. Updated data, including biomarker and correlative data, will be presented. Clinical trial information: NCT03332797 .[Table: see text]

Next-generation selective estrogen receptor degraders and other novel endocrine therapies for management of metastatic hormone receptor-positive breast cancer: current and emerging role

“… 97 , 98 It is notable that only 21% of patients in this cohort received prior fulvestrant, less than other phase I novel SERD trials reviewed here. 98 As with camizestrant, grade 1–2 sinus bradycardia was seen on therapy, though it appears to be dose dependent with low frequency at 30 mg dose. 98 …”

“… 98 As with camizestrant, grade 1–2 sinus bradycardia was seen on therapy, though it appears to be dose dependent with low frequency at 30 mg dose. 98 …”

Accelerating drug access from advanced to early breast cancer: the special case of oral selective estrogen receptor degraders

“…Phase I NCT03332797 [10] enrolled patients with metastatic ER+ disease into two cohorts (Cohort A – Giredestrant ± luteinizing hormone releasing hormone [LHRH] if premenopausal, and Cohort B – Giredestrant plus Palbociclib ± LHRH if premenopausal). The clinical benefit rate from Giredestrant ± LHRH ranged from 33 to 53% depending on the dose used [11]. Importantly, the benefit was observed in patients with prior fulvestrant treatment, and in those with known ESR1 mutations.…”

“…However, several unique toxicities have emerged. In the phase I study of Giradestrant [10], grade 1 asymptomatic bradycardia was observed 7-13% of patients in various cohorts, though this appeared dose-dependent and occurring above the 30 mg dose being used in phase III [11]. In SERENA-1 [18], 53% of patients experienced visual disturbance (3% grade 3), and 45% experienced bradycardia (7% grade 2, no grade 3).…”

AMEERA-5: a randomized, double-blind phase 3 study of amcenestrant plus palbociclib versus letrozole plus palbociclib for previously untreated ER+/HER2– advanced breast cancer

“…The development of new oral SERDs that can potentially achieve greater bioavailability may improve outcomes for patients with advanced/metastatic ER+/HER2– breast cancer, including in those with ESR1 mutations. 30 – 35 …”