Effect of esomeprazole on the pharmacokinetics of vepdegestrant, a PROteolysis TArgeting Chimera oestrogen receptor degrader, in healthy participants

Abstract

Aims

The aim of this study is to evaluate the effects of multiple doses of esomeprazole, a strong proton pump inhibitor and acid‐reducing agent, on the pharmacokinetics and safety of vepdegestrant, a PROteolysis TArgeting Chimera oestrogen receptor degrader.

Methods

This was a Phase 1, open‐label, two‐period, crossover, single‐dose study in healthy adult participants. During Period 1, on Day 1, a single oral dose of vepdegestrant 200 mg was administered with a moderate‐fat meal following overnight fasting. During Period 2, esomeprazole 40 mg was administered once daily on Days 1–5; a single dose of vepdegestrant 200 mg was given with a moderate‐fat meal on Day 5 following esomeprazole 40 mg. Serial blood samples for vepdegestrant pharmacokinetics and safety laboratory analyses were collected predose and up to 168 h after vepdegestrant dosing in each period. Safety was monitored throughout the study.

Results

Twelve participants were enrolled and treated. Following administration of vepdegestrant with (test) and without (reference) esomeprazole, test/reference ratios (90% CIs) of the adjusted geometric means for vepdegestrant area under the plasma concentration–time curve from time 0 to infinity and maximum plasma concentration were 83.73% (76.32, 91.86) and 74.11% (63.47, 86.52), respectively. Similar decreases in ARV‐473 (vepdegestrant epimer) plasma exposure were observed. All 12 treatment‐emergent adverse events experienced by seven participants were mild in severity.

Conclusion

Coadministration of multiple daily doses of esomeprazole 40 mg with vepdegestrant 200 mg under fed conditions in healthy adult participants resulted in mild decreases in vepdegestrant plasma exposure. Vepdegestrant 200 mg was well tolerated in healthy adult participants.

What is already known about this subject

• Vepdegestrant is an orally administered, investigational PROTAC ER degrader in development for the treatment of advanced breast cancer

• In vitro data indicate that vepdegestrant exhibits pH‐dependent solubility

What this study adds

• Coadministration of multiple daily doses of esomeprazole, a strong PPI and acid‐reducing agent, with a single dose of vepdegestrant resulted in mild decreases in vepdegestrant plasma exposure

1. INTRODUCTION

Vepdegestrant is an oral PROteolysis TArgeting Chimera (PROTAC) oestrogen receptor (ER) degrader composed of an ER‐binding domain linked to an E3 ligase–binding domain. This forms a trimer complex triggering ubiquitination and subsequent proteasomal degradation of ER. ¹ , ² , ³ , ⁴ , ⁵ Vepdegestrant is the first PROTAC compound to demonstrate clinical benefit in patients with breast cancer. ⁶ In a first‐in‐human Phase 1/2 study (NCT04072952), vepdegestrant showed promising clinical activity and a favourable safety profile among patients with ER–positive (ER+)/human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer. ⁷ , ⁸ , ⁹ As a result of the Phase 1/2 study, vepdegestrant 200 mg once daily (QD) was selected as the dose in the pivotal Phase 3 study VERITAC‐2 (NCT05654623), which showed significantly prolonged progression‐free survival compared with fulvestrant in patients with ER+/HER2− advanced breast cancer whose tumours harboured mutations in the oestrogen receptor 1 gene (ESR1). ¹⁰ , ¹¹ , ¹²

In vitro studies indicate that vepdegestrant exhibits pH‐dependent solubility and is classified as a Biopharmaceutical Classification System (BCS) class IV agent (unpublished data on file; Pfizer, Inc., La Jolla, CA, United States). Therefore, systemic vepdegestrant exposure may be subject to pH‐dependent drug interactions when coadministered with acid‐reducing agents such as antacids and proton pump inhibitors (PPIs). Notably, the use of PPIs to combat gastroesophageal reflux disease is common among patients with cancer. ¹³ , ¹⁴

Esomeprazole is a strong PPI and acid‐reducing agent that is commonly used and recommended by the US Food and Drug Administration (FDA) for evaluating the pH‐dependent drug interactions of investigational agents. ¹⁵ To evaluate the potential clinical drug–drug interactions (DDIs) and pH‐dependent effects on vepdegestrant plasma concentrations, esomeprazole was selected based on the prolonged gastric acid suppression achieved with treatment and its well‐characterized pharmacokinetic (PK) profile. ¹⁶ , ¹⁷ ARV‐473 is a pharmacologically inactive epimer of vepdegestrant and has been identified as a major vepdegestrant metabolite, accounting for >10% of total drug‐related exposure in plasma.

Here, we report the results of a Phase 1 study (NCT06275841) evaluating the effect of esomeprazole on the PK of vepdegestrant and ARV‐473 in healthy adult participants.

2. METHODS

2.1. Study design

This was a Phase 1, open‐label, two‐period, crossover, single‐dose study to estimate the effects of multiple doses of esomeprazole on the PK of vepdegestrant and ARV‐473 in healthy adult participants (Figure 1). This study was performed at the Pfizer Clinical Research Unit (PCRU) in New Haven, Connecticut, United States, in accordance with the ethical principles of the Declaration of Helsinki and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice. All molecular target nomenclature conforms to the IUPHAR/BPS Guide to PHARMACOLOGY nomenclature classification. Approval was obtained from a local independent ethics committee (Advarra Institutional Review Board; Approval Number: Pro00077187), and all local regulatory requirements were followed. All participants provided written informed consent at the time of enrolment.

FIGURE 1.

Study design. Participants were admitted to the PCRU on the day before initiating treatment and were required to remain there until the completion of the last scheduled activity on Day 12 of Period 2, except for the washout periods at the discretion of the clinical investigator. ^aFor each treatment with vepdegestrant, after an overnight fast of at least 10 h and after the collection of the predose vepdegestrant PK sample on Day 1, participants received a moderate‐fat breakfast (approximately 700 cal and 35% fat content) approximately 30 min prior to dosing. ^bFor each treatment with esomeprazole on Days 1–4 of study Period 2, participants fasted overnight for at least 10 h prior to dosing and for at least 1 h after dosing. PCRU, Pfizer Clinical Research Unit; PK, pharmacokinetics; QD, once daily.

Participants were admitted to the PCRU 1 day prior to the start of the study and remained onsite until the completion of the last scheduled activity on Day 12 of Period 2. On Day 1 of Period 1, following an overnight fast of ≥10 h, participants consumed a moderate‐fat meal (approximately 700 cal with an approximate fat content of 35%) approximately 30 min prior to receiving vepdegestrant 200 mg (2 × 100 mg tablets). On Days 1–5 of Period 2, following an overnight fast of ≥10 h, participants received esomeprazole 40 mg (1 capsule) QD with approximately 100 mL of water; no food was allowed for ≥1 h after esomeprazole dosing. On Day 5 of Period 2, participants consumed a moderate‐fat meal 1 h after receiving the esomeprazole dose and approximately 30 min before receiving a single dose of vepdegestrant 200 mg (2 × 100 mg tablets). The washout period between two successive single doses of vepdegestrant was ≥14 days.

2.2. Participants

Eligible participants included healthy adult (aged ≥18 years) female participants of non‐childbearing potential and healthy adult males with a body mass index of 16–32 kg/m² and total body weight >45 kg (99.2 lb). Participants were required to be of good health as determined by medical examination including medical history, physical examination, laboratory tests, vital signs, and standard 12‐lead electrocardiograms (ECGs).

Exclusion criteria included evidence or history of clinically significant medical or psychiatric conditions, any condition possibly affecting drug absorption, or a known history or sensitivity to vepdegestrant, esomeprazole, or any of the formulation components of either drug (Table S1). Additional exclusion criteria included previous administration of an investigational product within 30 days or five half‐lives and use of medication, drugs, or supplements within 7 days or five half‐lives (whichever is longer) prior to the first dose of the study drug. A longer washout period was required for acid‐reducing agents, such as PPIs, which had to be discontinued at least 14 days prior to the first study dose. Moderate or strong cytochrome P450 (CYP)3A inducers were prohibited within 14 days plus five half‐lives prior to the first study dose. Moderate or strong CYP3A inhibitors were prohibited within 14 days or five half‐lives (whichever is longer) prior to the first study dose.

2.3. Sample collection

Serial blood samples for vepdegestrant and ARV‐473 PK and safety analyses were collected predose and at 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144 and 168 h after vepdegestrant dosing in each period.

2.4. Bioanalytical methods

Vepdegestrant and ARV‐473 plasma concentrations were determined using a validated, sensitive and specific high‐performance liquid chromatography–tandem mass spectrometric (LC‐MS/MS) method at LabCorp Development (Asia) Pte. Ltd. (Singapore). Chromatographic separation of extracted plasma samples spiked with a stable isotope–labelled internal standard (ARV‐471‐d8) was achieved by isocratic elution on an Astec Chirobiotic V2 column (Supelco, Bellefonte, PA, United States). Analytes were subject to electrospray ionization in positive ion mode. The calibration curve was validated using linear regression with 1/X² weighting. The lower limit of quantitation was 2.50 ng/mL, and the upper limit of quantitation was 2500 ng/mL.

2.5. PK analysis

Plasma PK parameters for vepdegestrant and ARV‐473 were estimated using non‐compartmental analysis of plasma concentration–time data (oNCA, version 2.7.8; Pfizer, NY, United States). Primary endpoints included maximum observed plasma concentration (C _max ), area under the plasma concentration–time curve (AUC) from time zero extrapolated to infinity (AUC _inf ), and AUC from time zero to the time of the last quantifiable concentration (AUC _last ), if AUC _inf could not be reliably estimated. Additional endpoints included the time to reach C _max (T _max ), the last quantifiable concentration (C _last ), terminal elimination half‐life (t _1/2), apparent oral clearance (CL/F), and apparent volume of distribution (V _z /F).

2.6. Safety assessment

Safety and tolerability were assessed by the incidence of treatment‐emergent adverse events (TEAEs), serious adverse events (SAEs) and treatment‐related adverse events (TRAEs). Additional assessments included physical examinations, clinical laboratory values, vital signs and ECGs.

2.7. Statistical analyses

Sample size was determined to achieve 90% CIs for the difference between the reference treatment (Period 1, vepdegestrant 200 mg alone) and the test treatment (Period 2, QD dosing of esomeprazole 40 mg on Days 1–5 and vepdegestrant 200 mg on Day 5), with margins of ±0.2335 and ±0.2750 on the natural log scale for AUC _inf and C _max , respectively, and an 80% coverage probability. AUC _inf , AUC _last , C _max , C _last , CL/F and V _z /F were reported as geometric mean (percent coefficient of variation). T _last and T _max were reported as median (range), and t _1/2 was reported as arithmetic mean ± standard deviation. Natural log–transformed AUC _inf and C _max data were analysed using a mixed effect model with treatment as a fixed effect and participant as a random effect. Estimates of the adjusted mean differences of the test treatment and the reference treatment and corresponding 90% CIs were obtained from the model and exponentiated to provide estimates of the ratio of the adjusted geometric means (test/reference; expressed as a percentage) and corresponding 90% CIs. All statistical analyses were conducted using SAS® software (Version 9.4).

2.8. Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in https://www.guidetopharmacology.org/ and are permanently archived in the Concise Guide to PHARMACOLOGY 2021/22. ¹⁸ , ¹⁹

3. RESULTS

3.1. Participants

A total of 12 healthy adult male and female participants were enrolled, received both treatment regimens (vepdegestrant and vepdegestrant coadministered with esomeprazole) and completed the study. Most participants were male (66.7%; n = 8) and White (58.3%; n = 7). The median (range) age was 46.5 (28–69) years. The median (range) body weight was 79.8 (75.0–91.4) kg (Table 1). All participants were included in the PK and safety analyses.

TABLE 1.

Participant demographics and baseline characteristics.

Characteristic	Participants (N = 12)
Age, years, median (range)	46.5 (28–69)
Sex, n (%)
Male	8 (66.7)
Female	4 (33.3)
Race, n (%)
White	7 (58.3)
Black or African American	4 (33.3)
Asian	1 (8.3)
Ethnicity, n (%)
Not Hispanic or Latino	6 (50.0)
Hispanic or Latino	6 (50.0)
Height, cm, median (range)	172.5 (163–180)
Weight, kg, median (range)	79.8 (75.0–91.4)
BMI, kg/m2, median (range)	26.9 (25.1–30.2)

Abbreviation: BMI, body mass index.

3.2. Pharmacokinetics

3.2.1. Vepdegestrant PK

The median plasma concentration–time profiles of vepdegestrant were slightly higher following administration of a single dose of vepdegestrant 200 mg compared with coadministration of vepdegestrant 200 mg with esomeprazole 40 mg QD (Figure 2A,B). Compared with a single dose of vepdegestrant 200 mg alone (reference), coadministration of esomeprazole 40 mg QD with a single dose of vepdegestrant 200 mg (test) decreased vepdegestrant plasma exposure (AUC _inf by 16% and C _max by 26%). Test/reference ratios (90% CIs) of the adjusted geometric means for vepdegestrant AUC _inf and C _max were 83.73% (76.32, 91.86) and 74.11% (63.47, 86.52), respectively (Table 2 and Figure 3A,B). When receiving a single dose of vepdegestrant alone, the median T _max was 6.0 h and was delayed by approximately 1 h with coadministration of esomeprazole. The mean t _1/2 was 59.1 h when vepdegestrant was administered alone and 63.1 h when coadministered with esomeprazole (Table 2). When vepdegestrant was administered alone, the mean CL/F of vepdegestrant was 8.3 L/h, and it was 9.9 L/h when coadministered with esomeprazole (Table 2). The mean V _z /F of vepdegestrant was 697.3 L when administered alone and 888.6 L when coadministered with esomeprazole (Table 2).

FIGURE 2.

Median plasma vepdegestrant (A, B) and ARV‐473 (C, D) concentrations versus time on linear (A, C) and semi‐log scales (B, D). Data are for enrolled participants who received ≥1 dose of study intervention and had ≥1 measurable vepdegestrant or ARV‐473 concentration (N = 12). The lower limit of quantification was 2.5 ng/mL.

TABLE 2.

Plasma PK parameters of vepdegestrant and ARV‐473.

PK parameter, units	n	Vepdegestrant 200 mg (N = 12) reference	n	Esomeprazole 40 mg + vepdegestrant 200 mg (N = 12) test	Ratio of adjusted geometric means (90% CI) a test/reference
Vepdegestrant
AUC inf , ng*h/mL	12	24 210 (25)	12	20 270 (33)	83.73 (76.32, 91.86)
AUC last , ng*h/mL	12	21 750 (27)	12	17 760 (36)	81.65 (74.07, 90.00)
C max , ng/mL	12	509.4 (29)	12	377.5 (37)	74.11 (63.47, 86.52)
C last , ng/mL	12	28.17 (24)	12	26.98 (31)	–
CL/F, L/h	12	8.3 (25)	12	9.9 (33)	–
t 1/2, h	12	59.1 ± 8.7	12	63.1 ± 9.4	–
T last , h	12	168 (168–168)	12	168 (168–168)	–
T max , h	12	6.0 (6.0–12.0)	12	7.0 (6.0–12.0)	–
V z /F, L	12	697.3 (39)	12	888.6 (45)	–
ARV‐473
AUC inf , ng*h/mL	10	8438 (32)	8	7193 (40)	81.80 (71.21, 93.95)
AUC last , ng*h/mL	12	7096 (31)	12	5684 (45)	80.11 (72.19, 88.90)
C max , ng/mL	12	75.71 (23)	12	57.64 (42)	76.14 (65.63, 88.33)
C last , ng/mL	12	14.42 (41)	12	13.26 (51)	–
t 1/2, h	10	52.2 ± 6.1	8	54.3 ± 6.87	–
T last , h	12	168 (168–168)	12	168 (168–168)	–
T max , h	12	24.0 (12.0–48.0)	12	24.0 (12.0–48.0)	–

Note: PK parameters are presented as geometric mean (CV%) unless otherwise specified. T _last and T _max are presented as median (range); t _1/2 is presented as arithmetic mean ± SD. Data are for participants who received ≥1 dose of study intervention and had ≥1 measurable vepdegestrant or PK parameters of interest.

Abbreviations: AUC, area under the plasma concentration–time curve; AUC _inf , AUC from Time 0 extrapolated to infinity; AUC _last , AUC from Time 0 to the time of the last quantifiable concentration; CL/F, apparent oral clearance; C _last , last quantifiable concentration; C _max , maximum observed plasma concentration; CV%, percent coefficient of variation; PK, pharmacokinetic; SD, standard deviation; t _1/2, terminal elimination half‐life; T _last , time to last observable concentration; T _max , time to reach C _max ; V _z /F, apparent volume of distribution.

^a Ratios and 90% CIs are expressed as percentages.

FIGURE 3.

Individual and geometric mean (A) AUC _inf and (B) C _max of vepdegestrant and (C) AUC _inf and (D) C _max of ARV‐473 by treatment. Data are for enrolled participants who received ≥1 dose of study intervention and had ≥1 measurable vepdegestrant or ARV‐473 PK parameter of interest (N = 12). Black circles and lines within each plot represent the AUC _inf or C _max of vepdegestrant or ARV‐473, after administration of vepdegestrant alone vs. vepdegestrant combined with esomeprazole for each participant. The red diamonds with connecting red lines represent the geometric means. AUC _inf , area under the plasma concentration–time profile from time zero extrapolated to infinity; C _max , maximum observed plasma concentration; PK, pharmacokinetics.

3.2.2. ARV‐473 PK

The median plasma concentration–time profiles of ARV‐473 were slightly higher following administration of a single dose of vepdegestrant 200 mg compared with coadministration of vepdegestrant 200 mg with esomeprazole 40 mg QD (Figure 2C,D). Coadministration of esomeprazole 40 mg QD with a single dose of vepdegestrant 200 mg (test) decreased ARV‐473 plasma exposure (AUC _inf by 18% and C _max by 24%) compared with a single dose of vepdegestrant 200 mg (reference). The test/reference ratios (90% CIs) of the adjusted geometric means for ARV‐473 AUC _inf and C _max were 81.80% (71.21, 93.95) and 76.14% (65.63, 88.33), respectively (Table 2 and Figure 3C–D). Median T _max was 24.0 h for both a single dose of vepdegestrant alone and coadministration with esomeprazole. The mean t _1/2 was 52.2 h when vepdegestrant was administered alone and 54.3 h when coadministered with esomeprazole (Table 2).

3.3. Safety

A total of seven participants experienced 12 TEAEs, all of which were mild in severity (Table S2). In Period 1, following a single dose of vepdegestrant alone, one (8.3%) participant reported a TRAE of hunger. On Days 1–4 of Period 2, one TRAE of abdominal pain and two TRAEs of headache related to treatment with esomeprazole were reported in one (8.3%) and two (16.7%) participants, respectively. Following coadministration of vepdegestrant and esomeprazole in Period 2, one (8.3%) participant reported one TRAE of hunger. There were no SAEs, adverse events of special interest, deaths or events leading to treatment interruption and/or discontinuation reported in this study. No clinically relevant findings were observed for laboratory measurements, ECGs, vital sign assessments or physical examinations. No new safety signals were identified with coadministration of vepdegestrant and esomeprazole.

4. DISCUSSION

Vepdegestrant is an orally administered PROTAC ER degrader that is currently being evaluated for the treatment of ER+/HER2− advanced breast cancer. In vitro studies have shown that vepdegestrant exhibits pH‐dependent solubility and is classified as a BCS class IV agent. Thus, there is a potential risk for DDIs when vepdegestrant is administered with acid‐reducing agents, such as PPIs (e.g., esomeprazole), that could impact the solubility of vepdegestrant and impair the absorption and plasma exposure of vepdegestrant and its epimer, ARV‐473. Because PPIs are frequently used by patients undergoing cancer treatment to alleviate gastrointestinal symptoms, this Phase 1 study evaluated the impact of esomeprazole on the PK of vepdegestrant and its epimer, ARV‐473, in healthy adult participants. ²⁰

In general, PPIs are considered the most impactful among acid‐reducing agents for DDI studies. ¹⁵ Instead of other acid‐reducing agents such as H₂ receptor agonists and antacids, regulatory guidance recommends selecting commonly used PPIs, such as esomeprazole, to determine the maximum potential effects of pH‐dependent DDIs for investigational agents. ¹⁵ Esomeprazole, at its highest oral dose used in clinical practice (40 mg QD), was selected due its ability to provide prolonged gastric acid suppression and its well‐characterized PK profile. ¹⁶ , ¹⁷ , ²¹ , ²² Esomeprazole weakly inhibits CYP3A, which is not a predominant elimination pathway for vepdegestrant. ²³ , ²⁴ , ²⁵ In order to reach the pharmacodynamic steady state of PPIs, esomeprazole was administered daily during a 4‐day pretreatment period (Days 1–4) prior to coadministration with vepdegestrant on Day 5 of the test period. ¹⁶ Food improves the absorption of vepdegestrant (data on file), and vepdegestrant must be administered to patients under fed conditions. Vepdegestrant 200 mg QD was selected as the recommended Phase 3 dose and evaluated in the Phase 3 VERITAC‐2 clinical study (NCT05654623) for the treatment of patients with ER+/HER2− advanced breast cancer. ⁹ , ¹⁰ , ¹¹

This study provides a robust evaluation of the potential clinical DDI and pH‐dependent effects of esomeprazole on vepdegestrant exposure. The DDI risk of esomeprazole and vepdegestrant was low, given that coadministration of esomeprazole 40 mg QD with a single dose of vepdegestrant 200 mg resulted in mild decreases in plasma vepdegestrant (AUC _inf by 16% and C _max by 26%) compared with administration of vepdegestrant alone. Similar findings were also observed for plasma ARV‐473 (decreases in AUC _inf by 18% and C _max by 24%). Additionally, coadministration of esomeprazole delayed T _max by approximately 1 h compared with vepdegestrant alone. The mild decreases in C _max and AUC _inf (<20%), together with the delay in T _max , suggest that coadministration with esomeprazole primarily affects the absorption phase of vepdegestrant, with a minor impact on the extent of absorption but no clinically meaningful change in overall systemic exposure. These changes are consistent with pH‐solubility and absorption kinetics and do not lead to any meaningful reduction in overall vepdegestrant exposure. ¹⁵ Given the once‐daily dosing regimen of esomeprazole, a 1‐h shift in T _max is not expected to have any clinically significant impact. The decrease in C _max observed following coadministration of esomeprazole and vepdegestrant (26%) was also within the range of variability in C _max reported for several oncology drugs, suggestive of a minimally clinically significant impact. ²⁶

The PK sample collection schedule of up to 168 h was sufficient as AUC _inf was successfully calculated for vepdegestrant in all 12 participants and for ARV‐473 in the majority of participants. This indicates that drug elimination was adequately characterized and allowed for reliable PK assessment for both periods, with acceptable interparticipant variability in AUC_inf and C_max, ranging from 25% to 42% across both periods and analytes (Table 2). The washout period of a minimum of 14 days was also sufficient, as evidenced by the residual plasma concentration being below the lower limit of quantification in the predose sample on Day 1 of the second period (Figure 2).

Vepdegestrant 200 mg was well tolerated, with a safety profile consistent with previous clinical studies in healthy participants. No new safety signals were identified with coadministration of esomeprazole.

5. CONCLUSION

Coadministration of multiple doses of the PPI esomeprazole with a dose of vepdegestrant given with a moderate‐fat meal had minimal impact on the plasma exposure of vepdegestrant in healthy adult participants. Coadministration of esomeprazole with vepdegestrant decreased AUC_inf by 16% and C_max by 26%. Similar changes were observed for the vepdegestrant epimer, ARV‐473.

CONFLICT OF INTEREST STATEMENT

L.T., N.C., J.A.W., K.T.M., S.P.G., K.C.L. and W.T. are employees of Pfizer, Inc., and own stock/options in Pfizer, Inc. Y.Z. is an employee of Arvinas Operations, Inc.

Supporting information

Table S1. Eligibility criteria.

Table S2. AEs in the safety analysis set.

Tran L, Chen N, Winton JA, et al. Effect of esomeprazole on the pharmacokinetics of vepdegestrant, a PROteolysis TArgeting Chimera oestrogen receptor degrader, in healthy participants. Br J Clin Pharmacol. 2026;92(10):3477‐3484. doi: 10.1002/bcp.70636

DATA AVAILABILITY STATEMENT

Requests for data should be directed to the corresponding author. Scientifically sound proposals will be reviewed and approved at the discretion of the study sponsors (Pfizer, Inc., and Arvinas Estrogen Receptor, Inc.). Any patient‐level data will be anonymized, and study documents will be redacted to protect the privacy of trial participants.