In ESR1-mutated, ER+/HER2- aBC or mBC following progression on ET ORSERDU: 2x longer mPFS vs fulvestrant or AI¹*

PRIMARY ENDPOINT¹

Primary endpoint in EMERALD: mPFS in patients with ESR1-Mutated mBC

Number of PFS events: 62 (54%) with ORSERDU vs 78 (69%) with fulvestrant or AI¹
A statistically significant PFS was observed in the ITT population and in the subgroup of patients with ESR1-mutated mBC. The exploratory PFS analysis in the 250 patients (52%) without ESR1 mutations showed an HR of 0.86 (95% CI: 0.63-1.19), suggesting that the improvement observed in the ITT population was primarily driven by outcomes in patients with ESR1-mutated mBC¹

*AI therapy included anastrozole, letrozole, or exemestane.¹ †Prespecified, descriptive analyses: PFS rates at 3, 6, 12, and 18 months were estimated using Kaplan–Meier methodology and were not powered to detect statistical difference at these time points. 3 months: ORSERDU 55.9% (95% CI: 45.8-66.1) vs fulvestrant or AI 39.6% (95% CI: 29.4-49.7); 6 months: ORSERDU 40.8% (95% CI: 30.1-51.4) vs fulvestrant or AI 19.1% (95% CI: 10.5-27.8); 12 months: ORSERDU 26.8% (95% CI: 16.2-37.4) vs fulvestrant or AI 8.2% (95% CI: 1.3-15.1); 18 months: ORSERDU 24.3% (95% CI: 13.7-35.0) vs fulvestrant or AI (NE).³

Female ESR1-mutated mBC patient treated with ORSERDU®

More than 16,000 patients with ESR1-mutated mBC have been treated with ORSERDU in the US³

aBC, advanced breast cancer; AI, aromatase inhibitor; CI, confidence interval; ER+, estrogen receptor-positive; ESR1, estrogen receptor 1; ET, endocrine therapy; HER2-, human epidermal growth factor receptor 2-negative; HR, hazard ratio; ITT, intent to treat; mBC, metastatic breast cancer; mPFS, median progression-free survival; NE, not estimable; PFS, progression-free survival.

About endpoints

In an exploratory post hoc analysis ORSERDU: 8.6 months mPFS in patients treated with prior ET + CDK4/6i for ≥12 months⁷

Results of exploratory post hoc analyses are descriptive but not conclusive of efficacy, are not controlled for type 1 error, and require cautious interpretation. Small patient numbers can be a limitation of subgroup analyses and could represent chance findings.

EXPLORATORY POST HOC ANALYSIS⁷

Exploratory post hoc analysis: mPFS in patients with prior ET + CDK4/6i FOR ≥12 months

An exploratory post hoc analysis of EMERALD suggests that patients treated with prior ET + CDK4/6i for ≥6 but <12 months may still benefit from ORSERDU⁸*

AI, aromatase inhibitor; CDK4/6i, cyclin-dependent kinase 4/6 inhibitor; CI, confidence interval; ET, endocrine therapy; HR, hazard ratio; mPFS, median progression-free survival; PFS, progression-free survival.

*4.14 months mPFS (95% CI: 2.20-7.79) for ORSERDU vs 1.87 (95% CI: 1.87-3.29) for fulvestrant or AI (HR=0.52 [95% CI: 0.36-0.74]).⁸

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In an exploratory post hoc analysisORSERDU: mPFS in clinically relevant patient types⁷

ORSERDU is NOT indicated to target PIK3CA mutations.

EXPLORATORY POST HOC ANALYSIS:
PATIENT SUBGROUPS TREATED WITH PRIOR ET + CDK4/6i FOR ≥12 MONTHS⁷

		mPFS, months
Patients with ESR1-mutated tumors	n (%)	ORSERDU (95% CI)	Fulvestrant or AI (95% CI)	HR (95% CI)
All patients with ESR1m	159 (100)	8.6 (4.14-10.84)	1.9 (1.87-3.68)	0.41 (0.26-0.63)
Liver and/or lung metastases*	113 (71)	7.3 (2.20-10.84)	1.9 (1.84-1.94)	0.35 (0.21-0.59)
PIK3CA- and ESR1-mutated tumors†	62 (39)	5.5 (2.14-10.84)	1.9 (1.84-3.94)	0.42 (0.18-0.94)
Bone and other sites of metastases^‡	136 (86)	9.1 (5.49-16.89)	1.9 (1.87-3.71)	0.38 (0.23-0.62)
HER2-low expression^§	77 (48)	9.0 (5.49-16.89)	1.9 (1.84-3.75)	0.30 (0.14-0.60)

In an exploratory post hoc analysis In patients with liver and/or lung metastases and prior ET + CDK4/6i for ≥12 months^||

72% of patients in the EMERALD trial had visceral metastases (54% liver and/or 25% lung)^3¶

In an exploratory post hoc analysis In the 39% of patients with both ESR1m and PIK3CAm and prior ET + CDK4/6i for ≥12 months†

ORSERDU is NOT indicated to target PIK3CA mutations.

Unlike PI3K pathway alterations that may pre-exist metastatic disease, ESR1 mutations are often acquired during endocrine therapy and are particularly relevant at progression^9-14

AI, aromatase inhibitor; CDK4/6i, cyclin-dependent kinase 4/6 inhibitor; CI, confidence interval; ESR1, estrogen receptor 1; ESR1m, estrogen receptor 1 mutation; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; IHC, immunohistochemistry; ISH, in situ hybridization; mPFS, median progression-free survival; PI3K, phosphoinositide 3-kinase; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PIK3CAm, PIK3CA mutation.

*54% of patients had liver and other sites of metastases (10% of these patients had no lung or bone involvement); 25% of patients had lung and other sites of metastases (2% of these patients had no liver or bone involvement).^3,7 †Includes E545K, H1047R, E542K, and others.⁷ ^‡85% of patients had bone and other sites of metastases (30% of these patients had no liver or lung involvement).⁷ ^§Locally assessed HER2 IHC score of 1+ and 2+ with no ISH amplification. Data not available for all patients.⁷ ^||Includes lung, liver, brain, pleural, and peritoneal involvement.²^¶Patients could have both liver and lung involvement; other visceral sites were also present.³

In an exploratory post hoc analysisORSERDU showed 5.3 months mPFS in patients who did not receive prior chemotherapy^15*

EXPLORATORY POST HOC ANALYSIS: mPFS IN PATIENTS WITHOUT PRIOR CHEMOTHERAPY¹⁵

Exploratory post hoc analysis: mPFS in patients with prior chemotherapy

AI, aromatase inhibitor; CI, confidence interval; HR, hazard ratio; mPFS, median progression-free survival; PFS, progression-free survival.

*No prior chemotherapy for advanced or metastatic disease.

In ESR1-mutated, ER+/HER2- mBC following progression on ET ORSERDU has real-world evidence in more than 1,000 patients across 2 published analyses^16,17

Please revisit the primary analysis of efficacy in EMERALD here.

LIMITATIONS OF REAL-WORLD EVIDENCE: Real-world evidence refers to the clinical evidence of a product's usage and potential benefits or risks derived from its data in the real world. These observational, retrospective analyses are designed to evaluate associations among variables and cannot establish causality between treatments and outcomes. Analyses can be associated with methodological challenges, and a high frequency of censoring has the potential to limit the validity of results. There is potential for missing, inaccurate, or incomplete data. Bias related to treatment selection and unobserved variables may not be fully addressed. Results are not intended for direct comparison with clinical trials and should be interpreted with caution.

About TTNT

TTNT is commonly used as a proxy endpoint for PFS. TTNT is the interval from starting one therapy to starting the next or death. This real-world endpoint reflects disease control, tolerability, and adherence, and systematic reviews in advanced solid tumors show strong correlation between TTNT and PFS.

LIMITATIONS OF TTNT: TTNT differs in clinical interpretation, does not account for progression in the same way as PFS, may be influenced by nondisease-related factors, is not a validated surrogate endpoint, and should be interpreted with caution.

RUGO HS, KAKLAMANI V, McARTHUR H, ET AL. CLIN CANCER RES. 2026. Real-world evidence examined the use of ORSERDU in 306 patients with ESR1-mutated, ER+/HER2- mBC¹⁷

Real-world analyses are designed to evaluate associations among variables, not causality. Results are descriptive and not intended for direct comparison with clinical trials.

Rugo et al real-world study

Objective: This analysis aimed to describe the real-world TTNT among patients treated with ORSERDU in a general population and clinically relevant subgroups.

Study design: Retrospective, observational study using US healthcare insurance claims data from the Komodo Research Dataset to identify patients for analysis.* Patients included adults with diagnosed ESR1-mutated, ER+/HER2- mBC who initiated ORSERDU in a real-world setting and received ORSERDU between January 2023 and February 2025. Outcomes measured were TTNT and TTD.†

Statistical analysis: The primary clinical outcome was TTNT. Real-world TTNT was defined as the time from index date^‡ until initiation of a new line of treatment. Outcomes were estimated using the Kaplan-Meier method. Nonadjusted survival curves were generated with 95% confidence intervals.

Limitations: Claims records can impose limitations related to missing or incomplete data.^16,17^§ Real-world differences versus prospective trials may be due to multiple factors, including: treatment heterogeneity, tumor burden, genomic profile, and follow-up duration from the time of first ORSERDU treatment. TTNT differs in clinical interpretation, does not account for progression in the same way as PFS, may be influenced by nondisease-related factors, is not a validated surrogate endpoint, and should be interpreted with caution. Safety was not evaluated.

*A Komodo Health data schema designed for real-world evidence and health economic outcomes research studies, linked with Foundation Medicine Inc. clinical-genomic (FMICG) data.¹⁷ †The follow-up time of patients without an event was censored at death, end of clinical activity, end of data availability, or at ORSERDU discontinuation, which was defined as a ≥90-day gap from the end of ORSERDU days of supply, whichever occurred first.¹⁷ ^‡Index date was defined as the time of first ORSERDU fill.¹⁷ ^§For example, therapy may be stopped due to toxicity or cost versus disease progression, prior drug exposures may be incomplete, or patients could lose insurance or be lost to follow-up.¹⁶

mTTNT OF 2L AND 3L PATIENTS WITH PRIOR ET +/- CDK4/6i FOR ≥12 MONTHS¹⁷

The mTTNT in the overall patient population was 7.9 months (95% CI: 7.1-9.8; n=306)¹⁷
The mTTD in the overall patient population was 5.2 months (95% CI: 4.3-6.6; n=128)¹⁸
The mTTD in patients with 1-2 prior lines of ET +/- a CDK4/6i for ≥12 months was 5.7 months (95% CI: 4.7-7.2; n=116)¹⁸

Real-world evidence seen in this study suggests consistency with data observed in the EMERALD exploratory post hoc analysis of patients with prior ET + CDK4/6i for ≥12 months^7,17

LLOYD MR, WEIPERT CM, ALI A, ET AL. CLIN CANCER RES. 2026. Real-world ORSERDU outcomes in 756 patients with ESR1-mutated, ER+/HER2- mBC¹⁶

Real-world analyses are designed to evaluate associations among variables, not causality. Results are descriptive and not intended for direct comparison with clinical trials.

Lloyd et al real-world study

Objective: This analysis used a large clinical-genomic database to assess the real-world use of ORSERDU and examine impact of prior treatments, type and number of ESR1 mutations, co-occurring PI3K pathway alterations on clinical outcomes.

Study design: Retrospective, observational study using the GuardantINFORM database to identify patients for analysis.* Patients included had ER+/HER2- metastatic breast cancer, were treated with a line of ORSERDU after FDA approval in January 2023 and had an activating ESR1 mutation detected on ctDNA sequencing within 6 months prior to elacestrant initiation†; prior CDK4/6i duration data were not available. Outcomes measured were TTD, TTNT, and OS; mOS was not reached with 118 events observed.

Statistical analysis: Outcomes were estimated using the Kaplan-Meier method. Nonadjusted KM curves were generated with 95% confidence intervals and Cox-Regression hazard ratios adjusted for age, gender, comorbidity index, year of ctDNA result, and line of therapy used.

Limitations: Claims records can impose limitations related to missing or incomplete data.^‡ Real-world differences versus prospective trials may be due to multiple factors, including: treatment heterogeneity, tumor burden, genomic profile, and follow-up duration from the time of first ORSERDU treatment. TTNT differs in clinical interpretation, does not account for progression in the same way as PFS, may be influenced by nondisease-related factors, is not a validated surrogate endpoint, and should be interpreted with caution. Safety was not evaluated.

*Large, real-world, clinical-genomic dataset with genetic sequencing information from Guardant360 (G360) testing that is linked to administrative claims data.¹⁶ †Patients were identified by International Classification of Diseases 9/10 codes. Patients were required to have ≥28 days of follow-up after the first ORSERDU claim. Eligibility criteria were utilized to decrease the degree of missing data and minimize the risk of bias.¹⁶ ^‡For example, therapy may be stopped due to toxicity or cost versus disease progression, prior drug exposures may be incomplete, or patients could lose insurance or be lost to follow-up.¹⁶

mTTNT WITH ORSERDU BY NUMBER OF PRIOR LINES OF THERAPY¹⁶

*91% of patients included in the analysis had at least one prior line of metastatic therapy: aromatase inhibitor, 79%; fulvestrant, 52%; CDK4/6i, 76%.¹⁶

In this exploratory analysis, the authors reported no statistically significant difference in ORSERDU treatment duration when comparing number of prior lines of therapy.

The mTTNT for the overall patient population was 6.4 months (95% CI: 5.6-8.0; n=742)†
The mTTD for the overall population was 4.6 months (95% CI: 4.0-5.4; n=742)
In patients with one or fewer prior lines of metastatic therapy, mTTD^‡ was 5.0 months (95% CI: 4.1-7.1; n=203); mTTD in patients with 2 prior lines was 4.4 months (95% CI: 4.0-5.5; n=151); and mTTD in patients with 3 or more prior lines was 4.5 months (95% CI: 4.0-5.6; n=388)

2L, 2nd Line; 3L, 3rd Line; CDK4/6i, cyclin-dependent kinase 4/6 inhibitor; CI, confidence interval; ctDNA, circulating tumor DNA; ER+, estrogen receptor positive; ESR1, estrogen receptor 1; ET, endocrine therapy; HER2-, human epidermal growth factor receptor 2-negative; KM, Kaplan-Meier; mBC, metastatic breast cancer; mOS, median overall survival; mTTD, median time-to-treatment-discontinuation; mTTNT, median time-to-next-treatment; NR, not reached at time of data cut-off; OS, overall survival; PFS, progression-free survival; PI3K, phosphoinositide 3-kinase; TTD, time-to-treatment-discontinuation; TTNT, time-to-next-treatment.

†A total of 742 patients were eligible for outcomes analysis on ORSERDU, with 14 patients excluded due to conflicting data in claims reports.¹⁶ ^‡TTD was defined as the start of a line of therapy until treatment claim discontinuation or death.¹⁶

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Learn more about Safety

IMPORTANT SAFETY INFORMATION

Warnings and Precautions

Dyslipidemia: Hypercholesterolemia and hypertriglyceridemia occurred in patients taking ORSERDU at an incidence of 30% and 27%, respectively. The incidence of Grade 3 and 4 hypercholesterolemia and hypertriglyceridemia were 0.9% and 2.2%, respectively. Monitor lipid profile prior to starting and periodically while taking ORSERDU.
Embryo-Fetal Toxicity: Based on findings in animals and its mechanism of action, ORSERDU can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ORSERDU and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ORSERDU and for 1 week after the last dose.

Adverse Reactions

Serious adverse reactions occurred in 12% of patients who received ORSERDU. Serious adverse reactions in >1% of patients who received ORSERDU were musculoskeletal pain (1.7%) and nausea (1.3%). Fatal adverse reactions occurred in 1.7% of patients who received ORSERDU, including cardiac arrest, septic shock, diverticulitis, and unknown cause (one patient each).
The most common adverse reactions (≥10%), including laboratory abnormalities, of ORSERDU were musculoskeletal pain (41%), nausea (35%), increased cholesterol (30%), increased AST (29%), increased triglycerides (27%), fatigue (26%), decreased hemoglobin (26%), vomiting (19%), increased ALT (17%), decreased sodium (16%), increased creatinine (16%), decreased appetite (15%), diarrhea (13%), headache (12%), constipation (12%), abdominal pain (11%), hot flush (11%), and dyspepsia (10%).

Drug Interactions

Concomitant use with CYP3A4 inducers and/or inhibitors: Avoid concomitant use of strong or moderate CYP3A4 inhibitors with ORSERDU. Avoid concomitant use of strong or moderate CYP3A4 inducers with ORSERDU.

Use in Specific Populations

Lactation: Advise lactating women to not breastfeed during treatment with ORSERDU and for 1 week after the last dose.
Hepatic Impairment: Avoid use of ORSERDU in patients with severe hepatic impairment (Child-Pugh C). Reduce the dose of ORSERDU in patients with moderate hepatic impairment (Child-Pugh B).

The safety and effectiveness of ORSERDU in pediatric patients have not been established.

ORSERDU is available as 345 mg tablets and 86 mg tablets.

INDICATION

ORSERDU (elacestrant) is indicated for the treatment of postmenopausal women or adult men with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.

To report SUSPECTED ADVERSE REACTIONS, contact Stemline Therapeutics, Inc. at 1-877-332-7961 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see full Prescribing Information.

References: 1. ORSERDU [prescribing information]. New York, NY: Stemline Therapeutics, Inc., a Menarini Group Company, 2023. 2. Bidard FC, Kaklamani VG, Neven P, et al. Elacestrant (oral selective estrogen receptor degrader) versus standard endocrine therapy for estrogen receptor–positive, human epidermal growth factor receptor 2–negative advanced breast cancer: results from the randomized phase III EMERALD trial. J Clin Oncol. 2022;40(28):3246-3256. 3. Data on file. Stemline Therapeutics, Inc., a Menarini Group Company. 4. NCI Dictionary of Cancer Terms. PFS. Accessed March 25, 2026. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/pfs 5. NCI Dictionary of Cancer Terms. Median survival. Accessed March 25, 2026. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/median-survival 6. Kok PS, Cho D, Yoon WH, et al. Validation of progression-free survival rate at 6 months and objective response for estimating overall survival in immune checkpoint inhibitor trials: a systematic review and meta-analysis. JAMA Netw Open. 2020;3(9):e2011809. 7. Bardia A, Cortés J, Bidard FC, et al. Elacestrant in ER+, HER2- metastatic breast cancer with ESR1-mutated tumors: subgroup analyses from the phase III EMERALD trial by prior duration of endocrine therapy plus CDK4/6 inhibitor and in clinical subgroups. Clin Cancer Res. 2024;30(19):4299-4309. 8. Bardia A, Cortés J, Bidard FC, et al. Elacestrant in ER+, HER2- metastatic breast cancer with ESR1-mutated tumors: subgroup analyses from the phase III EMERALD trial by prior duration of endocrine therapy plus CDK4/6 inhibitor and in clinical subgroups. Clin Cancer Res. 2024;30(19):4299-4309 [supplementary appendix]. 9. Brett JO, Spring LM, Bardia A, Wander SA. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res. 2021;23(1):85. 10. Mankoo PK, Sukumar S, Karchin R. PIK3CA somatic mutations in breast cancer: mechanistic insights from Langevin dynamics simulations. Proteins. 2009;75(2):499-508. 11. Casaubon JT, Kashyap S, Regan JP. BRCA1 and BRCA2 Mutations. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2023. 12. Arthur LM, Turnbull AK, Renshaw L, et al. Changes in PIK3CA mutation status are not associated with recurrence, metastatic disease or progression in endocrine-treated breast cancer. Breast Cancer Res Treat. 2014;147(1):211-219. 13. Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in hormone receptor–positive advanced breast cancer. N Engl J Med. 2023;388(22):2058-2070. 14. Clatot F, Perdrix A, Beaussire L, et al. Risk of early progression according to circulating ESR1 mutation, CA-15.3 and cfDNA increases under first-line anti-aromatase treatment in metastatic breast cancer. Breast Cancer Res. 2020;22(1):56. 15. Kaklamani V, Bardia A, Aftimos P, et al. Subgroup analysis of patients with no prior chemotherapy in EMERALD: a phase 3 trial evaluating elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC). Presented at: American Society of Clinical Oncology; June 3-7, 2022; Chicago, IL. 16. Lloyd MR, Weipert CM, Ali A, et al. Clinical and genomic factors associated with elacestrant outcomes in ESR1-mutant metastatic breast cancer. Clin Cancer Res. 2026;32(1):169-178. 17. Rugo HS, Kaklamani V, McArthur H, et al. Real-world outcomes of elacestrant in ER+, HER2-, ESR1-mutant metastatic breast cancer. Clin Cancer Res. 2026;32(1):179-187. 18. Rugo HS, Kaklamani V, McArthur H, et al. Real-world outcomes of elacestrant in ER+, HER2-, ESR1-mutant metastatic breast cancer. Clin Cancer Res. 2026;32(1):179-187 [supplementary appendix].

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