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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]

Population pharmacokinetic models for amlodipine and olmesartan were developed using data collected from 4 phase I studies in healthy volunteers and 1 phase III study in subjects with mild to severe hypertension. A 2‐compartment and a 1‐compartment model best described the pharmacokinetics of olmesartan and amlodipine, respectively; both agents were characterized by first‐order elimination/absorption and an absorption time lag. The analysis shows that neither agent had a clinically significant impact on the clearance of the other. The impact of covariates on the clearance of olmesartan and amlodipine was similar after coadministration of amlodipine besylate and olmesartan medoxomil as separate entities or as a fixed‐dose combination compared with monotherapy. The effect of exposure to amlodipine and olmesartan on the change in trough seated diastolic blood pressure was best described by linear and maximum effect (Emax) models, respectively. Black race was the most important covariate in the exposure‐response model, decreasing the maximal possible effect of olmesartan on blood pressure while increasing the effect of amlodipine, without influencing pharmacokinetic parameters. The drug effect of combination therapy was defined on the basis of exposure to both compounds and was greater than the effect of monotherapy with either agent.