Written By: Aarti Bhambre, BPharm
Reviewed By: Pharmacally Editorial Team
On September 25, 2025, the U.S. Food and Drug Administration (FDA) approved Inluriyo (imlunestrant) for the treatment of adult patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2–), estrogen receptor 1 (ESR1)-mutated advanced or metastatic breast cancer whose disease has progressed following at least one line of endocrine therapy. With Inluriyo, these patients now have access to the first FDA-approved oral selective estrogen receptor degrader (SERD) specifically designed to target both wild-type and ESR1-mutant receptors. The Marketing Authorization Holder for Inluriyo is Eli Lilly and Company. Lilly Oncology has led the clinical development of imlunestrant, including the pivotal Phase 3 EMBER-3 trial.
About Inluriyo
Inluriyo is an oral selective estrogen receptor degrader (SERD) developed by Eli Lilly and Company. Imlunestrant not only blocks estrogen receptor activity but also promotes receptor degradation. This dual action reduces estrogen receptor signaling, even in cancers with estrogen receptor 1 (ESR1) mutations, which commonly arise after aromatase inhibitor therapy and cause the receptor to become ligand-independent, remaining active even without estrogen binding. By binding to the receptor, antagonizing its activity, and inducing degradation, imlunestrant suppress tumor growth and overcome endocrine resistance. It is administered as a once-daily oral regimen 400 mg (two 200 mg tablets) taken on an empty stomach, either at least two hours before food or one hour after food and is also being studied in combination with the CDK4/6 inhibitor abemaciclib for broader ER+/HER2– breast cancer populations.
Clinical Evidence – EMBER-3 Trial
The FDA’s approval of Inluriyo was supported by findings from the Phase 3 EMBER-3 trial (NCT04975308), a large, randomized, multicenter study designed to evaluate the efficacy and safety of imlunestrant. The trial enrolled approximately 874 patients with ER-positive, HER2-negative advanced or metastatic breast cancer whose disease had progressed after aromatase inhibitor therapy, with many participants also having prior exposure to CDK 4/6 inhibitors. Within this population, about 256 patients carried ESR1 mutations, making them a critical subgroup for the approval decision. Patients were randomized to receive either imlunestrant monotherapy, standard endocrine therapy (commonly fulvestrant or exemestane) based on investigator’s choice or a combination of imlunestrant with the CDK4/6 inhibitor abemaciclib. The trial’s primary endpoint was progression-free survival (PFS), with secondary measures including overall response rate (ORR), overall survival (OS), safety, and quality-of-life outcomes.
In the ESR1-mutated subgroup, imlunestrant monotherapy demonstrated a clinically significant improvement in outcomes compared with standard endocrine therapy. Median progression-free survival was 5.5 months with imlunestrant versus 3.8 months with standard therapy with 38% reduction in the risk of disease progression or death. The objective response rate also favored imlunestrant at 14.3% compared with 7.7% for standard therapy. Beyond monotherapy, the combination of imlunestrant with abemaciclib showed further promise: across the overall study population, median PFS was 9.4 months with the combination compared to 5.5 months with imlunestrant alone with benefit observed regardless of ESR1 mutation status. These results highlight imlunestrant ability to address the challenge of endocrine resistance in ESR1-mutated disease while also laying the groundwork for its broader use in combination regimens for ER+/HER2– advanced breast cancer.
Safety and Precautions
The most common adverse reactions observed in patients receiving Inluriyo, occurring in at least 10% of participants, included both clinical symptoms and laboratory abnormalities. Reported events were decreased hemoglobin (30%), musculoskeletal pain (30%), reduced calcium levels (26%), neutropenia (26%), elevated AST (25%), fatigue (23%), diarrhea (22%), elevated ALT (21%), increased triglycerides (21%), nausea (17%), thrombocytopenia (16%), constipation (10%), elevated cholesterol (10%), and abdominal pain (10%).
The Inluriyo also come with some important safety warnings and precautions; based on animal studies and its mechanism of action, the drug can cause embryo-fetal harm and should not be used during pregnancy; patients of reproductive potential should be advised to use effective contraception during treatment and for at least one week after the final dose. Because imlunestrant is metabolized by the CYP3A enzyme system, concomitant use with strong CYP3A inhibitors or inducers should be avoided, with dosage adjustments considered if such combinations cannot be prevented. In addition, the drug inhibits both P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters, which means caution is required when administering it alongside substrates of these pathways where even small changes in concentration could result in significant adverse reactions. For lactating women, breastfeeding is not recommended during therapy and for one week after the last dose due to the potential for serious adverse effects in the breastfeeding infant
About Breast Cancer
Metastatic breast cancer (MBC) develops when cancer spreads beyond the breast to distant organs. In the United States, about 30% of high-risk early-stage breast cancers eventually progress to metastatic disease, while 6–10% of cases are metastatic at diagnosis. Prognosis declines sharply with disease stage the five-year survival rate is about 99% for localized disease, 86% for regional disease, and only 30% for metastatic disease. These figures underscore the urgent need for therapies that can extend survival and improve quality of life in patients with advanced disease.
Globally, breast cancer remains a major health challenge. According to GLOBOCAN 2022, there were approximately 2.3 million new cases worldwide, making breast cancer the second most commonly diagnosed cancer after lung cancer and the fourth leading cause of cancer death, accounting for around 666,000 deaths. In the United States alone, more than 310,000 new cases are expected in 2024, and breast cancer continues to rank as the second leading cause of cancer-related death among women. These statistics highlight both the scale of the disease and the importance of new therapeutic options like Inluriyo in the ongoing effort to improve patient outcomes.
Key Opinions
Leaders from the oncology community and patient advocacy groups welcomed the approval of Inluriyo as a significant advancement for patients with ESR1-mutated metastatic breast cancer. Jean Sachs, CEO of Living Beyond Breast Cancer, emphasized that the approval broadens the treatment landscape for individuals who test positive for the ESR1 mutation. Jacob Van Naarden, executive vice president and president of Lilly Oncology, highlighted the therapy as part of Lilly’s commitment to improving outcomes through innovative, all-oral treatment approaches that can make the patient journey more manageable. From a clinical perspective, Dr. Komal Jhaveri of Memorial Sloan Kettering Cancer Center and a principal investigator of the EMBER-3 trial, noted that ESR1 mutations present in nearly half of patients previously treated with hormone therapy often drive resistance, and that Inluriyo represents an important advancement in overcoming this challenge. The FDA confirmed these views in its announcement, underscoring that the availability of a targeted oral SERD specifically addressing ESR1 mutations fulfills a significant unmet need in advanced hormone receptor–positive breast cancer care.
References
U.S. FDA approves Inluriyo (imlunestrant) for adults with ER+, HER2-, ESR1-mutated advanced or metastatic breast cancer, Elli Lilly, 25 September 2025, https://investor.lilly.com/news-releases/news-release-details/us-fda-approves-inluriyo-imlunestrant-adults-er-her2-esr1
FDA approves imlunestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer, USFDA, 25 September 2025, https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-imlunestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast
A Study of Imlunestrant, Investigator’s Choice of Endocrine Therapy, and Imlunestrant Plus Abemaciclib in Participants With ER+, HER2- Advanced Breast Cancer (EMBER-3), ClinicalTrials.gov ID NCT04975308, https://www.clinicaltrials.gov/study/NCT04975308
American Cancer Society, Breast Cancer Facts & Figures 2022–2024
Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185countries. CA Cancer J Clin. 2024;74(3):229‐263. doi:10.3322/caac.21834BRAY ET AL. – 263