Abstract P5-18-07: Heart rate changes, cardiac safety, and exercise tolerance from a phase Ia/b study of giredestrant (GDC-9545) ± palbociclib in patients with estrogen receptor-positive, HER2-negative locally advanced/metastatic breast cancer
Authors: Neilan Tomas G , Villanueva-Vázquez Rafael , Bellet Meritxell , López-Miranda Elena , García-Estévez Laura , Kabos Peter , Bond John , Gates Mary R , Chang Ching-Wei , Boni Valentina 
Published: March 2022

Abstract
Background Targeting the activity of the estrogen receptor and/or estrogen synthesis is a standard primary treatment for eligible patients with estrogen receptor-positive breast cancer. Giredestrant is a highly potent, nonsteroidal oral selective estrogen receptor antagonist and degrader that achieves robust estrogen receptor occupancy. In animal models and early phase studies, giredestrant was associated with a dose-dependent reduction in heart rate. Therefore, we leveraged an ongoing nonrandomized, open-label, dose-escalation and -expansion phase Ia/b study (GO39932) to evaluate its cardiac safety. Methods Eligibility criteria for the main study are available at https://clinicaltrials.gov/ct2/show/NCT03332797. Additional relevant cardiac exclusion criteria included current treatment with medications known to decrease heart rate, e.g., beta blockers.100 mg giredestrant was given daily on Days 1-28 of each 28-day cycle (monotherapy for 14 days; patients then continued monotherapy or received combination treatment with 125 mg daily oral palbociclib for the study duration, per investigator decision). The 100 mg giredestrant dose for this arm (rather than the phase III 30 mg dose) was evaluated to increase the likelihood of observing relevant cardiac effects. Electrocardiograms were required on Day 1 of each cycle; 24-hour Holter data were collected and treadmill-exercise testing was completed at screening (prior to starting giredestrant), steady state (Day 8 [+3 days]), and as clinically indicated. Exercise testing evaluated baseline heart rate, exercise duration, maximal heart rate, and heart rate recovery. A standard Bruce protocol was followed. Results Clinical data cutoff was Apr 16, 2021. Twenty patients were enrolled and included in the current analysis; median age was 59 (range, 45-72); three patients (15%) had a history of hypertension at screening. During follow-up, no dysrhythmias were observed that required treatment or a change in study medication, and no patients were noted to have a resting heart rate of &lt;50 beats per minute based on routine heart rate monitoring. Two Grade 1 bradycardia events (&lt;60 beats per minute) were reported; both in patients receiving palbociclib. No other cardiac adverse events (AEs) were reported overall, nor any other serious AEs. Holter monitoring reports were available for 19 patients at screening and 20 on treatment. There were no episodes of second- or third-degree atrioventricular block. At screening, 2/19 patients (11%) had a paroxysmal supraventricular tachycardia event (SVT; ≤30 seconds). During the study, 4/20 patients (20%) had a paroxysmal SVT event and, of these, 1/4 had four episodes of an SVT event lasting &gt;30 seconds and 1/4 also experienced one episode of non-sustained ventricular tachycardia. No patients required any cardiac treatment or dose modification. Twenty patients underwent exercise testing. Exercise time was similar among patients before and after starting giredestrant (mean exercise time 7 min 10 sec before; 7 min 44 sec after). Exercise intensity was similar before and after starting treatment (mean metabolic equivalents expenditure 7.52 [standard deviation 2.81] and 8.68 [2.78], respectively). One patient had an abnormal heart rate recovery on exercise testing at screening and again while on treatment. Conclusions In a thorough cardiac safety analysis, applying routine electrocardiograms, 24-hour Holter monitoring, and exercise testing, no clinically relevant cardiac effects were observed with 100 mg giredestrant (a higher dose than the phase III 30 mg dose).
Citation Format: Tomas G Neilan, Rafael Villanueva-Vázquez, Meritxell Bellet, Elena López-Miranda, Laura García-Estévez, Peter Kabos, John Bond, Mary R Gates, Ching-Wei Chang, Valentina Boni. Heart rate changes, cardiac safety, and exercise tolerance from a phase Ia/b study of giredestrant (GDC-9545) ± palbociclib in patients with estrogen receptor-positive, HER2-negative locally advanced/metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-07.