The Menarini Group and Stemline Therapeutics Inc. announced that the European Commission has approved ORSERDU® (elacestrant) as a monotherapy for the treatment of postmenopausal women, and men, with estrogen receptor (ER)-positive, HER2-negative, locally advanced or metastatic breast cancer (mBC) with an activating ESR1 mutation who have disease progression following at least one line of endocrine therapy including a CDK 4/6 inhibitor. The European Commission?s approval follows the positive opinion of the Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA), which was issued in July 2023. With this approval, ORSERDU is the first and only therapy specifically indicated for the treatment of ER+, HER2- tumors that harbor ESR1 mutations.

ESR1 mutations are acquired mutations that develop as a result of exposure to endocrine therapy, and they are found in up to 40% of patients with ER+, HER2- mBC. ESR1 mutations are a known driver of resistance to standard endocrine therapy, and until now, the tumors that harbor these mutations have been more difficult to treat. The approval of ORSERDU is supported by data from the Phase 3 EMERALD trial, which demonstrated statistically significant progression-free survival (PFS) with elacestrant versus standard-of-care (SOC), defined as investigator?s choice of an approved endocrine monotherapy.

The primary endpoints of the study were PFS in the overall patient population and in patients with ESR1 mutations. In the group of patients whose tumors had ESR1 mutations, elacestrant achieved a median PFS of 3.8 months vs 1.9 months on the SOC, and reduced the risk of progression or death by 45% (PFS HR=0.55, 95% CI: 0.39, 0.77) vs SOC. A post hoc subgroup analysis of the EMERALD PFS results, which was presented at the San Antonio Breast Cancer Symposium (SABCS) 2022, demonstrated that the duration of prior CDK4/6i treatment was positively associated with longer PFS on elacestrant but not with SOC.

For patients with ESR1 mutations who were treated with CDK4/6i for =12 months prior to randomization on EMERALD, elacestrant achieved a median PFS of 8.6 months versus 1.9 months on SOC, with a 59% reduction in the risk of progression or death (HR=0.41 95% CI: 0.26-0.63). Safety data were consistent with previously reported results. The most common (= 10%) adverse reactions with ORSERDU were nausea, triglycerides increased, cholesterol increased, vomiting, fatigue, dyspepsia, diarrhoea, calcium decreased, back pain, creatinine increased, arthralgia, sodium decreased, constipation, headache, hot flush, abdominal pain, anaemia, potassium decreased, and alanine aminotransferase increased.

Important Safety Information for ORSERDU is provided below. Stemline and its affiliates will commercialize the product within Europe. The EMERALD Phase 3 trial is a randomized, open label, active-controlled study evaluating elacestrant as second- or third-line monotherapy in ER+, HER2- advanced/metastatic breast cancer patients.

The study enrolled 478 patients who had received prior treatment with one or two lines of endocrine therapy, including a CDK4/6 inhibitor. Patients in the study were randomized to receive either elacestrant or the investigator's choice of an approved hormonal agent. The primary endpoints of the study were progression-free survival (PFS) in the overall patient population and in patients with estrogen receptor 1 gene (ESR1) mutations.

In the group of patients whose tumors had ESR1 mutations, elacestrant achieved a median PFS of 3.8 months vs 1.9 months on the SOC, and reduced the risk of progression or death by 45% (PFS HR=0.55, 95% CI: 0.39, 0.77) vs SOC. Indication: ORSERDU (elacestrant) monotherapy is indicated for the treatment of postmenopausal women, and men, with estrogen receptor (ER)-positive, HER2-negative, locally advanced or metastatic breast cancer with an activating ESR1 mutation who have disease progression following at least one line of endocrine therapy including a CDK 4/6 inhibitor. Hepatic Impairment:Administration of ORSERDU should be undertaken with caution at a dose of 258 mg once daily in patients with moderate hepatic impairment (Child-Pugh B).

In the absence of clinical data, ORSERDU is not recommended in patients with severe hepatic impairment (Child-Pugh C). Concomitant use of strong or moderate CYP3A4 inhibitors with ORSERDU should be avoided. Concomitant use of strong or moderate CYP3A4 inducers with ORSERDU should be avoided.

Thromboembolic events: Thromboembolic events are commonly observed in patients with advanced breast cancer and have been observed in clinical studies with ORSERDU. This should be taken into consideration when prescribing ORSERDU to patients at risk. Adverse Reactions: Serious adverse reactions reported in = 1% of patients included nausea, dyspnoea, and thromboembolism (venous).

The most common (= 10%) adverse reactions with ORSERDU were nausea, triglycerides increased, cholesterol increased, vomiting, fatigue, dyspepsia, diarrhoea, calcium decreased, back pain, creatinine increased, arthralgia, sodium decreased, constipation, headache, hot flush, abdominal pain, anaemia, potassium decreased, and alanine aminotransferase increased. The most common Grade =3 (=2%) adverse reactions of elacestrant were nausea (2.7%), AST increased (2.7%), ALT increased (2.3%), anaemia (2%), back pain (2%), and bone pain (2%). Nausea: Nausea was reported in 35% of patients.

Grade 3-4 nausea events were reported in 2.5% of patients. Nausea occurred more frequently in the first cycle and from Cycle 2 onward, the incidence of nausea was generally lower in subsequent cycles (i.e., over time). Elderly: Gastrointestinal disorders were reported more frequently in patients aged = 75 years.

Fertility, pregnancy, and lactation: ORSERDU should not be used during pregnancy or in women of childbearing potential not using contraception. Based on the mechanism of action of elacestrant and findings from reproductive toxicity studies in animals, ORSERDU can cause foetal harm when administered to pregnant women. Females of reproductive potential should be advised to use effective contraception during treatment with ORSERDU and for one week after the last dose.

It is recommended that lactating women should not breast-feed during treatment with ORSERDU and one week after the last dose of ORSERDU. Based on findings from animal studies and its mechanism of action, ORSERDU may impair fertility in females and males of reproductive potential. Effects on ability to drive and use machines: Fatigue, asthenia, and insomnia have been reported in some patients taking ORSERDU.

Caution should be observed by patients who experience those adverse reactions when driving or operating machinery. The safety and efficacy of ORSERDU in children from birth to 18 years of age has not been established.