Tamoxifen

As monotherapy, imlunestrant significantly reduced the risk of progression or death by 38% compared to standard endocrine therapy (ET) in patients with ESR1 mutations As combination therapy, imlunestrant plus Verzenio significantly reduced the risk of progression or death by 43%, compared to imlunestrant alone, in all patients, regardless of ESR1 mutation status These data were published simultaneously in the New England Journal of Medicine and will be presented today at the 2024 San Antonio Breast Cancer Symposium INDIANAPOLIS, Dec. 11, 2024 /PRNewswire/ -- Eli Lilly and Company (NYSE: LLY) today announced results from the Phase 3 EMBER-3 study of imlunestrant, an investigational, oral selective estrogen receptor degrader (SERD), in patients with estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (ABC), whose disease progressed on a prior aromatase inhibitor (AI), with or without a CDK4/6 inhibitor. Imlunestrant demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) as monotherapy in patients with an ESR1 mutation versus standard of care endocrine therapy (SOC ET), reducing the risk of disease progression or death by 38%. Imlunestrant in combination with Verzenio (abemaciclib; CDK4/6 inhibitor) reduced the risk of progression or death by 43% versus imlunestrant alone, in all patients. These results were published in The New England Journal of Medicine and will be shared in a late-breaking oral presentation at the San Antonio Breast Cancer Symposium (SABCS) today, Wednesday, December 11 at 9:15 AM CT/10:15 AM ET. These data are being submitted to regulatory health authorities globally. "The median progression free survival observed in EMBER-3 is among the most compelling we've seen in CDK4/6 pre-treated ER+, HER2- advanced breast cancer patients and indicates a potential shift in the therapy options we provide for these patients, which are currently very limited," said Komal Jhaveri, M.D., section head, endocrine therapy research and clinical director, early drug development at Memorial Sloan Kettering Cancer Center, and one of the study's principal investigators. "The benefit and safety profile of the imlunestrant and abemaciclib combination signal a potential new all-oral option for patients." In the EMBER-3 study, patients were randomized 1:1:1 to receive imlunestrant alone, SOC ET, or the imlunestrant-abemaciclib combination. Randomization was stratified by prior CDK4/6 inhibitor use, the presence of visceral metastases and geographic region. Patients enrolled as first line (1L) treatment for ABC (32%), following disease recurrence on or within 12 months of completing adjuvant AI, with or without CDK4/6 inhibitor for early breast cancer (EBC), or as second line (2L) treatment for ABC (64%), following progression on AI, with or without CDK4/6 inhibitor as initial therapy for ABC. Primary endpoints were investigator-assessed PFS of imlunestrant versus SOC ET therapy in patients with ESR1 mutations, imlunestrant versus SOC ET in all patients, and imlunestrant-abemaciclib versus imlunestrant in all patients. Imlunestrant versus standard of care endocrine therapy Imlunestrant significantly improved PFS versus SOC ET in patients with an ESR1 mutation. In patients with an ESR1 mutation, median PFS was 5.5 months with imlunestrant versus 3.8 months with SOC ET [HR=0.62 (95% CI 0.46-0.82); p-value<0.001]. The overall response rate (ORR) with imlunestrant was 14% compared to 8% with SOC ET in patients with an ESR1 mutation. In all patients, the median PFS was 5.6 months with imlunestrant versus 5.5 months with SOC ET [HR=0.87 (95% CI 0.72-1.04); p-value 0.12] and did not reach statistical significance. Consistent with preclinical data demonstrating central nervous system (CNS) penetrance and CNS-activity of imlunestrant, CNS progression rates from a post-hoc analysis were lower with imlunestrant in all patients (HR=0.47; 95% CI, 0.16-1.38), as well as patients with an ESR1 mutation (HR=0.18; 95% CI, 0.04-0.90), however, these analyses are limited by low event numbers and lack of mandated serial asymptomatic CNS imaging in all patients. Imlunestrant in combination with abemaciclib versus imlunestrant alone Imlunestrant-abemaciclib significantly improved PFS compared to imlunestrant in all patients, regardless of ESR1 mutation status, with median PFS of 9.4 months for imlunestrant-abemaciclib versus 5.5 months for imlunestrant alone [HR=0.57 (95% CI 0.44-0.73); p-value <0.001]. The PFS benefit of the combination was consistent across subgroups, regardless of ESR1 mutation, or PI3K pathway mutation status, and including in patients who had previously received CDK4/6 inhibitor treatment. In all patients, the ORR with imlunestrant-abemaciclib was 27% compared to 12% with imlunestrant alone. Safety in the imlunestrant-abemaciclib arm was consistent with the known safety profile of fulvestrant in combination with abemaciclib, with mostly low-grade adverse events including diarrhea (86%), nausea (49%), neutropenia (48%) and anemia (44%), and had a low discontinuation rate (6.3%).1,2 Overall survival (OS) results for EMBER-3 were immature at the time of analysis. The trial will continue to assess OS as a secondary endpoint. "EMBER-3 is the first Phase 3 trial to show benefit of combining an oral SERD with a CDK4/6 inhibitor for a patient population where an all-oral regimen would represent a meaningful advance," said David Hyman, M.D., Chief Medical Officer, Lilly. "We're highly encouraged by these data for both imlunestrant as monotherapy and in combination with Verzenio, as well as the safety and tolerability profile, which demonstrate the potential for imlunestrant to be a meaningful new oral endocrine therapy option for patients. We look forward to sharing these results with the oncology community and completing regulatory submissions to global health authorities." An estimated 70 to 80% of hormone receptor positive breast cancers are ER+ and after progression on initial endocrine therapy, are predominantly treated with fulvestrant, which is administered by intramuscular injection in a doctor's office.3,4 According to patient-reported outcomes data from EMBER-3, 72% of patients receiving fulvestrant in the standard ET group reported injection site pain, swelling, or redness. Imlunestrant is an orally administered, brain penetrant, pure ER antagonist that delivers continuous ER target inhibition. Imlunestrant is also being investigated in the adjuvant setting in people with ER+, HER2- early breast cancer (EBC) with an increased risk of recurrence. This Phase 3 trial, EMBER-4, is expected to enroll 6,000 EBC patients worldwide. About EMBER-3 EMBER-3 is a Phase 3, randomized, open-label study of imlunestrant, investigator's choice of endocrine therapy, and imlunestrant in combination with abemaciclib in patients with estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) locally advanced or metastatic breast cancer whose disease has recurred or progressed during or following an aromatase inhibitor (AI) therapy with or without a CDK 4/6 inhibitor. The trial enrolled 874 adult patients, 32% of which enrolled from the adjuvant setting into first-line treatment of ABC and 64% as second line treatment following progression on initial therapy for ABC. Enrolled trial participants were randomized between imlunestrant, investigator's choice of fulvestrant or exemestane, or imlunestrant plus abemaciclib. More information on the EMBER-3 study can be found on clinicaltrials.gov. About Metastatic/Advanced Breast Cancer Metastatic/advanced breast cancer (ABC) is a cancer that has spread from the breast tissue to other parts of the body. Locally advanced breast cancer means the cancer has grown outside the organ where it started but has not yet spread to other parts of the body.1 Of all high risk early-stage breast cancer cases diagnosed in the U.S., approximately 30% will become metastatic5 and an estimated 6-10% of all new breast cancer cases are initially diagnosed as being metastatic.6 Survival is lower among women with a more advanced stage of disease at diagnosis: five-year relative survival is 99% for localized disease, 86% for regional/locally advanced disease, and 30% for metastatic/advanced disease.7 Other factors, such as tumor size, also impact five-year survival estimates.7 About Breast Cancer Breast cancer is the second most commonly diagnosed cancer worldwide (following lung cancer), according to GLOBOCAN. The estimated 2.3 million new cases indicate that close to 1 in every 4 cancers diagnosed in 2022 is breast cancer. With approximately 666,000 deaths in 2022, breast cancer is the fourth-leading cause of cancer death worldwide.8 In the U.S., it is estimated that there will be more than 310,000 new cases of breast cancer diagnosed in 2024. Breast cancer is the second leading cause of cancer death in women in the U.S.9 About Imlunestrant Imlunestrant is a brain-penetrant, oral selective estrogen receptor degrader (SERD), that delivers continuous ER inhibition, including in ESR1-mutant cancers. The estrogen receptor (ER) is the key therapeutic target for patients with estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Novel degraders of ER may overcome endocrine therapy resistance while providing consistent oral pharmacology and convenience of administration. Imlunestrant is currently being studied as a treatment for advanced breast cancer and as an adjuvant treatment in early breast cancer, including: NCT04975308, NCT05514054 , NCT04188548, NCT05307705. About Verzenio® (abemaciclib) Verzenio® (abemaciclib) is approved to treat people with certain HR+, HER2- breast cancers in the adjuvant and advanced or metastatic setting. Verzenio is the first CDK4/6 inhibitor approved to treat node-positive, high risk early breast cancer (EBC) patients.10 For HR+, HER2- breast cancer, The National Comprehensive Cancer Network® (NCCN®) recommends consideration of two years of abemaciclib (Verzenio) added to endocrine therapy as a Category 1 treatment option in the adjuvant setting.11 NCCN® also includes Verzenio plus endocrine therapy as a preferred treatment option for HR+, HER2- metastatic breast cancer.11 The collective results of Lilly's clinical development program continue to differentiate Verzenio as a CDK4/6 inhibitor. In high risk EBC, Verzenio has shown a persistent and deepening benefit beyond the two-year treatment period in the monarchE trial, an adjuvant study designed specifically to investigate a CDK4/6 inhibitor in a node-positive, high risk EBC population.12 In metastatic breast cancer, Verzenio has demonstrated statistically significant OS in the Phase 3 MONARCH 2 study.13 Verzenio has shown a consistent and generally manageable safety profile across clinical trials. Verzenio is an oral tablet taken twice daily and available in strengths of 50 mg, 100 mg, 150 mg, and 200 mg. Discovered and developed by Lilly researchers, Verzenio was first approved in 2017 and is currently authorized for use in more than 90 counties around the world. For full details on indicated uses of Verzenio in HR+, HER2- breast cancer, please see full Prescribing Information, available at . INDICATIONS FOR VERZENIO® VERZENIO® is a kinase inhibitor indicated: in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive, early breast cancer at high risk of recurrence. in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. in combination with fulvestrant for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. IMPORTANT SAFETY INFORMATION FOR VERZENIO (abemaciclib) Severe diarrhea associated with dehydration and infection occurred in patients treated with Verzenio. Across four clinical trials in 3691 patients, diarrhea occurred in 81 to 90% of patients who received Verzenio. Grade 3 diarrhea occurred in 8 to 20% of patients receiving Verzenio. Most patients experienced diarrhea during the first month of Verzenio treatment. The median time to onset of the first diarrhea event ranged from 6 to 8 days; and the median duration of Grade 2 and Grade 3 diarrhea ranged from 6 to 11 days and 5 to 8 days, respectively. Across trials, 19 to 26% of patients with diarrhea required a Verzenio dose interruption and 13 to 23% required a dose reduction. Instruct patients to start antidiarrheal therapy, such as loperamide, at the first sign of loose stools, increase oral fluids, and notify their healthcare provider for further instructions and appropriate follow-up. For Grade 3 or 4 diarrhea, or diarrhea that requires hospitalization, discontinue Verzenio until toxicity resolves to ≤Grade 1, and then resume Verzenio at the next lower dose. Neutropenia, including febrile neutropenia and fatal neutropenic sepsis, occurred in patients treated with Verzenio. Across four clinical trials in 3691 patients, neutropenia occurred in 37 to 46% of patients receiving Verzenio. A Grade ≥3 decrease in neutrophil count (based on laboratory findings) occurred in 19 to 32% of patients receiving Verzenio. Across trials, the median time to first episode of Grade ≥3 neutropenia ranged from 29 to 33 days, and the median duration of Grade ≥3 neutropenia ranged from 11 to 16 days. Febrile neutropenia has been reported in <1% of patients exposed to Verzenio across trials. Two deaths due to neutropenic sepsis were observed in MONARCH 2. Inform patients to promptly report any episodes of fever to their healthcare provider. Monitor complete blood counts prior to the start of Verzenio therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia. Severe, life-threatening, or fatal interstitial lung disease (ILD) or pneumonitis can occur in patients treated with Verzenio and other CDK4/6 inhibitors. In Verzenio-treated patients in EBC (monarchE), 3% of patients experienced ILD or pneumonitis of any grade: 0.4% were Grade 3 or 4 and there was one fatality (0.1%). In Verzenio-treated patients in MBC (MONARCH 1, MONARCH 2, MONARCH 3), 3.3% of Verzenio-treated patients had ILD or pneumonitis of any grade: 0.6% had Grade 3 or 4, and 0.4% had fatal outcomes. Additional cases of ILD or pneumonitis have been observed in the postmarketing setting, with fatalities reported. Monitor patients for pulmonary symptoms indicative of ILD or pneumonitis. Symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded by means of appropriate investigations. Dose interruption or dose reduction is recommended in patients who develop persistent or recurrent Grade 2 ILD or pneumonitis. Permanently discontinue Verzenio in all patients with Grade 3 or 4 ILD or pneumonitis. Grade ≥ 3 increases in alanine aminotransferase (ALT) (2 to 6%) and aspartate aminotransferase (AST) (2 to 3%) were reported in patients receiving Verzenio. Across three clinical trials in 3559 patients (monarchE, MONARCH 2, MONARCH 3), the median time to onset of Grade ≥3 ALT increases ranged from 57 to 87 days and the median time to resolution to Grade <3 was 13 to 14 days. The median time to onset of Grade ≥3 AST increases ranged from 71 to 185 days and the median time to resolution to Grade <3 ranged from 11 to 15 days. Monitor liver function tests (LFTs) prior to the start of Verzenio therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, dose discontinuation, or delay in starting treatment cycles is recommended for patients who develop persistent or recurrent Grade 2, or any Grade 3 or 4 hepatic transaminase elevation. Venous thromboembolic events (VTE) were reported in 2 to 5% of patients across three clinical trials in 3559 patients treated with Verzenio (monarchE, MONARCH 2, MONARCH 3). VTE included deep vein thrombosis, pulmonary embolism, pelvic venous thrombosis, cerebral venous sinus thrombosis, subclavian and axillary vein thrombosis, and inferior vena cava thrombosis. In clinical trials, deaths due to VTE have been reported in patients treated with Verzenio. Verzenio has not been studied in patients with early breast cancer who had a history of VTE. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate. Dose interruption is recommended for EBC patients with any grade VTE and for MBC patients with a Grade 3 or 4 VTE. Verzenio can cause fetal harm when administered to a pregnant woman, based on findings from animal studies and the mechanism of action. In animal reproduction studies, administration of abemaciclib to pregnant rats during the period of organogenesis caused teratogenicity and decreased fetal weight at maternal exposures that were similar to the human clinical exposure based on area under the curve (AUC) at the maximum recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Verzenio and for 3 weeks after the last dose. Based on findings in animals, Verzenio may impair fertility in males of reproductive potential. There are no data on the presence of Verzenio in human milk or its effects on the breastfed child or on milk production. Advise lactating women not to breastfeed during Verzenio treatment and for at least 3 weeks after the last dose because of the potential for serious adverse reactions in breastfed infants. The most common adverse reactions (all grades, ≥ 10%) observed in monarchE for Verzenio plus tamoxifen or an aromatase inhibitor vs tamoxifen or an aromatase inhibitor, with a difference between arms of ≥ 2%, were diarrhea (84% vs 9%), infections (51% vs 39%), neutropenia (46% vs 6%), fatigue (41% vs 18%), leukopenia (38% vs 7%), nausea (30% vs 9%), anemia (24% vs 4%), headache (20% vs 15%), vomiting (18% vs 4.6%), stomatitis (14% vs 5%), lymphopenia (14% vs 3%), thrombocytopenia (13% vs 2%), decreased appetite (12% vs 2.4%), ALT increased (12% vs 6%), AST increased (12% vs 5%), dizziness (11% vs 7%), rash (11% vs 4.5%), and alopecia (11% vs 2.7 %). The most frequently reported ≥ 5% Grade 3 or 4 adverse reaction that occurred in the Verzenio arm vs the tamoxifen or an aromatase inhibitor arm of monarchE were neutropenia (19.6% vs 1%), leukopenia (11% vs <1%), diarrhea (8% vs 0.2%), and lymphopenia (5% vs <1%). Lab abnormalities (all grades; Grade 3 or 4) for monarchE in ≥ 10% for Verzenio plus tamoxifen or an aromatase inhibitor with a difference between arms of ≥ 2% were increased serum creatinine (99% vs 91%; .5% vs <.1%), decreased white blood cells (89% vs 28%; 19.1% vs 1.1%), decreased neutrophil count (84% vs 23%; 18.7% vs 1.9%), anemia (68% vs 17%; 1% vs .1%), decreased lymphocyte count (59% vs 24%; 13.2 % vs 2.5%), decreased platelet count (37% vs 10%; .9% vs .2%), increased ALT (37% vs 24%; 2.6% vs 1.2%), increased AST (31% vs 18%; 1.6% vs .9%), and hypokalemia (11% vs 3.8%; 1.3% vs 0.2%). The most common adverse reactions (all grades, ≥ 10%) observed in MONARCH 3 for Verzenio plus anastrozole or letrozole vs anastrozole or letrozole, with a difference between arms of ≥ 2%, were diarrhea (81% vs 30%), fatigue (40% vs 32%), neutropenia (41% vs 2%), infections (39% vs 29%), nausea (39% vs 20%), abdominal pain (29% vs 12%), vomiting (28% vs 12%), anemia (28% vs 5%), alopecia (27% vs 11%), decreased appetite (24% vs 9%), leukopenia (21% vs 2%), creatinine increased (19% vs 4%), constipation (16% vs 12%), ALT increased (16% vs 7%), AST increased (15% vs 7%), rash (14% vs 5%), pruritus (13% vs 9%), cough (13% vs 9%), dyspnea (12% vs 6%), dizziness (11% vs 9%), weight decreased (10% vs 3.1%), influenza-like illness (10% vs 8%), and thrombocytopenia (10% vs 2%). The most frequently reported ≥ 5% Grade 3 or 4 adverse reactions that occurred in the Verzenio arm vs the placebo arm of MONARCH 3 were neutropenia (22% vs 1%), diarrhea (9% vs 1.2%), leukopenia (7% vs <1%)), increased ALT (6% vs 2%), and anemia (6% vs 1%). Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 3 in ≥ 10% for Verzenio plus anastrozole or letrozole with a difference between arms of ≥ 2% were increased serum creatinine (98% vs 84%; 2.2% vs 0%), decreased white blood cells (82% vs 27%; 13% vs 0.6%), anemia (82% vs 28%; 1.6% vs 0%), decreased neutrophil count (80% vs 21%; 21.9% vs 2.6%), decreased lymphocyte count (53% vs 26%; 7.6% vs 1.9%), decreased platelet count (36% vs 12%; 1.9% vs 0.6%), increased ALT (48% vs 25%; 6.6% vs 1.9%), and increased AST (37% vs 23%; 3.8% vs 0.6%). The most common adverse reactions (all grades, ≥ 10%) observed in MONARCH 2 for Verzenio plus fulvestrant vs fulvestrant, with a difference between arms of ≥ 2%, were diarrhea (86% vs 25%), neutropenia (46% vs 4%), fatigue (46% vs 32%), nausea (45% vs 23%), infections (43% vs 25%), abdominal pain (35% vs 16%), anemia (29% vs 4%), leukopenia (28% vs 2%), decreased appetite (27% vs 12%), vomiting (26% vs 10%), headache (20% vs 15%), dysgeusia (18% vs 2.7%), thrombocytopenia (16% vs 3%), alopecia (16% vs 1.8%), stomatitis (15% vs 10%), ALT increased (13% vs 5%), pruritus (13% vs 6%), cough (13% vs 11%), dizziness (12% vs 6%), AST increased (12% vs 7%), peripheral edema (12% vs 7%), creatinine increased (12% vs <1%), rash (11% vs 4.5%), pyrexia (11% vs 6%), and weight decreased (10% vs 2.2%). The most frequently reported ≥ 5% Grade 3 or 4 adverse reactions that occurred in the Verzenio arm vs the placebo arm of MONARCH 2 were neutropenia (25% vs 1%), diarrhea (13% vs 0.4%), leukopenia (9% vs 0%), anemia (7% vs 1%), and infections (5.7% vs 3.5%). Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 2 in ≥ 10% for Verzenio plus fulvestrant with a difference between arms of ≥ 2% were increased serum creatinine (98% vs 74%; 1.2% vs 0%), decreased white blood cells (90% vs 33%; 23.7% vs .9%), decreased neutrophil count (87% vs 30%; 32.5% vs 4.2%), anemia (84% vs 34%; 2.6% vs .5%), decreased lymphocyte count (63% vs 32%; 12.2% vs 1.8%), decreased platelet count (53% vs 15%; 2.1% vs 0%), increased ALT (41% vs 32%; 4.6% vs 1.4%), and increased AST (37% vs 25%; 3.9% vs 4.2%). The most common adverse reactions (all grades, ≥ 10%) observed in MONARCH 1 with Verzenio were diarrhea (90%), fatigue (65%), nausea (64%), decreased appetite (45%), abdominal pain (39%), neutropenia (37%), vomiting (35%), infections (31%), anemia (25%), thrombocytopenia (20%), headache (20%), cough (19%), constipation (17%), leukopenia (17%), arthralgia (15%), dry mouth (14%), weight decreased (14%), stomatitis (14%), creatinine increased (13%), alopecia (12%), dysgeusia (12%), pyrexia (11%), dizziness (11%), and dehydration (10%). The most frequently reported ≥ 5% Grade 3 or 4 adverse reactions from MONARCH 1 with Verzenio were diarrhea (20%), neutropenia (24%), fatigue (13%), and leukopenia (5%). Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 1 with Verzenio were increased serum creatinine (99%; .8%), decreased white blood cells (91%; 28%), decreased neutrophil count (88%; 26.6%), anemia (69%; 0%), decreased lymphocyte count (42%; 13.8%), decreased platelet count (41%; 2.3%), increased ALT (31%; 3.1%), and increased AST (30%; 3.8%). Strong and moderate CYP3A inhibitors increased the exposure of abemaciclib plus its active metabolites to a clinically meaningful extent and may lead to increased toxicity. Avoid concomitant use of ketoconazole. Ketoconazole is predicted to increase the AUC of abemaciclib by up to 16-fold. In patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the Verzenio dose to 100 mg twice daily with concomitant use of strong CYP3A inhibitors other than ketoconazole. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the Verzenio dose to 50 mg twice daily with concomitant use of strong CYP3A inhibitors. If a patient taking Verzenio discontinues a strong CYP3A inhibitor, increase the Verzenio dose (after 3 to 5 half-lives of the inhibitor) to the dose that was used before starting the inhibitor. With concomitant use of moderate CYP3A inhibitors, monitor for adverse reactions and consider reducing the Verzenio dose in 50 mg decrements. Patients should avoid grapefruit products. Avoid concomitant use of strong or moderate CYP3A inducers and consider alternative agents. Coadministration of strong or moderate CYP3A inducers decreased the plasma concentrations of abemaciclib plus its active metabolites and may lead to reduced activity. With severe hepatic impairment (Child-Pugh C), reduce the Verzenio dosing frequency to once daily. The pharmacokinetics of Verzenio in patients with severe renal impairment (CLcr <30 mL/min), end stage renal disease, or in patients on dialysis is unknown. No dosage adjustments are necessary in patients with mild or moderate hepatic (Child-Pugh A or B) and/or renal impairment (CLcr ≥30-89 mL/min). Please see full Prescribing Information and Patient Information for Verzenio. AL HCP ISI 12OCT2021 About Lilly Lilly is a medicine company turning science into healing to make life better for people around the world. We've been pioneering life-changing discoveries for nearly 150 years, and today our medicines help tens of millions of people across the globe. Harnessing the power of biotechnology, chemistry and genetic medicine, our scientists are urgently advancing new discoveries to solve some of the world's most significant health challenges: redefining diabetes care; treating obesity and curtailing its most devastating long-term effects; advancing the fight against Alzheimer's disease; providing solutions to some of the most debilitating immune system disorders; and transforming the most difficult-to-treat cancers into manageable diseases. With each step toward a healthier world, we're motivated by one thing: making life better for millions more people. That includes delivering innovative clinical trials that reflect the diversity of our world and working to ensure our medicines are accessible and affordable. To learn more, visit Lilly.com and Lilly.com/news, or follow us on Facebook, Instagram, and LinkedIn. P-LLY © Lilly USA, LLC 2024. ALL RIGHTS RESERVED. MSK Disclosure: Dr. Jhaveri has financial interests related to Eli Lilly and Company. Cautionary Statement Regarding Forward-Looking Statements This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about Verzenio as a treatment for people with certain types of breast cancer and imlunestrant as a potential treatment for people with certain types of breast cancer and reflects Lilly's current beliefs and expectations. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of drug research, development, and commercialization. Among other things, there is no guarantee that planned or ongoing studies will be completed as planned, that future study results will be consistent with study results to date, that Verzenio will receive additional regulatory approvals, or that imlunestrant will prove to be a safe and effective treatment for certain types of breast cancer or receive regulatory approval. For further discussion of these and other risks and uncertainties that could cause actual results to differ from Lilly's expectations, see Lilly's Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release. References SOURCE Eli Lilly and Company WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Conference Call and Webcast Today at 4:30 p.m. ET Development Program Highlights and Anticipated Milestones Ovaprene® hormone-free monthly intravaginal contraceptive candidate – pivotal Phase 3 contraceptive efficacy study recruiting across the United States; foundation grant announced yesterday will provide funding to allow Daré to expand the number of clinical sites to accelerate the development timeline Sildenafil Cream, 3.6% topical formulation of sildenafil being developed to treat female sexual arousal disorder - continued operational progress toward a planned Phase 3 study, including constructive discussions with FDA; Phase 3 design, development, and collaboration strategy updates DARE-HPV proprietary, fixed-dose formulation of lopinavir and ritonavir in a soft gel vaginal insert for the treatment of human papillomavirus (HPV)-related cervical diseases – conducting activities necessary to enable submission of an IND application to the FDA for a Phase 2, randomized, placebo-controlled, double-blind clinical study of DARE-HPV for clearance of high-risk HPV infection in women, which will be supported with funding Daré receives as an ARPA-H Sprint for Women’s Health $10 million awardee DARE-VVA1 proprietary formulation of tamoxifen for intravaginal administration being developed as a hormone-free alternative to estrogen-based therapies for the treatment of moderate-to-severe dyspareunia, or pain during sexual intercourse – conducting activities in preparation for a Phase 2 clinical study of DARE-VVA1 based on Daré's FDA-cleared IND DARE-PTB1 intravaginal ring designed to deliver bio-identical progesterone continuously for up to 14 days for the prevention of preterm birth – conducting activities necessary to enable submission of an IND application to the FDA for a Phase 1 clinical study, which will be supported by a $2 million grant from NICHD Foundation grant of up to approximately $10.7 million to fund activities related to the identification and development of a novel non-hormonal intravaginal contraceptive product candidate and to add additional clinical sites to accelerate the ongoing Ovaprene® pivotal study. SAN DIEGO, Nov. 14, 2024 (GLOBE NEWSWIRE) -- Daré Bioscience, Inc. (NASDAQ: DARE), a leader in innovation for the health and wellbeing of women, today reported financial results for the quarter ended September 30, 2024 and provided a company update. “We continue to be excited about the increased attention on the health and wellbeing of women, including by the Advanced Research Projects Agency for Health (ARPA-H) as evidenced by their recent announcement related to the awardees of the ARPA-H Sprint for Women’s Health and our announcement of the $10 million award we were selected to receive for DARE-HPV, an innovative investigational treatment for HPV-related cervical diseases. Essentially all cervical cancer cases worldwide are caused by HPV infection. We are also very pleased by the foundation’s continued commitment to invest in the development of non-hormonal contraceptive methods as evidenced by the grant we announced yesterday of up to approximately $10.7 million to fund activities related to our identification and development of a novel non-hormonal intravaginal contraceptive product candidate and to add additional clinical sites to accelerate the ongoing Ovaprene® pivotal study.” “We continue to execute on our mission to accelerate development of and bring to market innovative treatments that women want and need by advancing our late-stage candidates – all of which represent a first-in-category opportunity – as we seek to deliver value for all Daré stakeholders. In addition to the continued commercialization by our collaborator Organon of XACIATO™ (clindamycin phosphate) vaginal gel 2%, the first FDA-approved product to emerge from our portfolio and a treatment for bacterial vaginosis in females aged 12 and older* that is available by prescription nationwide, we continue to advance our first-in-category Phase 3 development candidates with ongoing enrollment in our Phase 3 study of Ovaprene at sites across the U.S., and continued constructive interactions with the FDA focused on aligning on the Phase 3 program for Sildenafil Cream 3.6% in female sexual arousal disorder. Despite its high prevalence, there are currently no FDA-approved treatments for female sexual arousal disorder and we look forward to advancing this program into Phase 3. Additionally, we are conducting activities in preparation for a Phase 2 clinical study of DARE-VVA1 and a Phase 1 study of DARE-PTB1, which is supported by a $2 million grant from NICHD,” said Sabrina Martucci Johnson, President and CEO of Daré Bioscience. “The progress across our portfolio, along with the $10.7 million grant agreement announced yesterday, the $10 million award from ARPA-H announced in October, the $15 million equity line arrangement we established with Lincoln Park Capital Fund, LLC in October, and the $22 million we secured in the non-dilutive strategic royalty financing in the second quarter, put Daré on track for meaningful milestones in 2025.” *Please see below for important safety and other information. Ovaprene® Phase 3 StudyOvaprene is a novel, investigational hormone-free monthly intravaginal contraceptive whose U.S. commercial rights are under a license agreement with Bayer HealthCare. Working with study collaborators at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health (NIH) and commercial collaborator Bayer, Daré commenced patient enrollment in the Ovaprene® pivotal Phase 3 clinical study in December 2023. Non-hormonal contraception represents a significant commercial market opportunity, and there are currently no monthly, hormone-free contraceptives approved by the U.S. Food and Drug Administration (FDA). Ovaprene® has potential to be a disruptive product in the contraceptive category and an important option for women who cannot use hormone-based birth control products or prefer not to do so. Recruitment is currently proceeding at 10 sites across the United States, supported by a central advertising campaign for the study that launched in March 2024. Based on the current average enrollment rate, Daré anticipates that approximately half of its target number of participants to complete the study, or 125 women, will complete approximately 6 months of product use by the end of the second quarter of 2025. The foundation grant announced yesterday will provide funding to allow Daré to expand the number of clinical sites recruiting in the study, which is intended to accelerate the overall development timeline. Sildenafil Cream, 3.6% Progress toward Phase 3 StudySildenafil Cream is a proprietary, investigational cream formulation of sildenafil, the active ingredient in Viagra®, for topical on-demand administration to treat female sexual arousal disorder (FSAD). Daré completed all study analyses of data from the exploratory Phase 2b RESPOND clinical study and held an end-of-Phase 2 meeting with the FDA in December 2023. In prior quantitative studies, Sildenafil Cream increased genital tissue blood flow, and the Phase 2b at-home study was specifically designed to identify the patient population that experienced the most meaningful improvement from Sildenafil Cream and the questions to ask them that best reflect that improvement. The patient population and the endpoints proposed to the FDA for Phase 3 clinical development were those where Daré's exploratory post-hoc analyses of the Phase 2b study data showed that Sildenafil Cream demonstrated statistically significant and meaningful patient improvement. Ongoing discussions with the FDA are focused on aligning on primary and secondary patient reported outcome endpoints for the Phase 3 studies as well as other data that might be required for a new drug application (NDA) submission. Based on FDA feedback Daré has received, two successful Phase 3 clinical studies of Sildenafil Cream will be required to support an NDA for Sildenafil Cream for the treatment of FSAD, and Daré anticipates that each Phase 3 study will be approximately $15.0 million in direct costs. Daré will take into account its capital resources before initiating a Phase 3 study. Daré’s planned initial Phase 3 study of Sildenafil Cream, 3.6% would be the first ever Phase 3 pivotal study of a therapeutic candidate for the treatment of arousal disorder in women. Daré intends to provide updates on the Phase 3 program, as well as relevant updates on the initial Phase 3 study timing and Daré’s collaboration strategy as they become available. Financial Highlights for the Quarter ended September 30, 2024 Cash and cash equivalents: $11.2 million at September 30, 2024. General and administrative expenses: $2.0 million in 3Q-2024 as compared to $2.7 million in 3Q-2023, with the current quarter’s decrease primarily attributable to reduced professional services expense and reduced commercial readiness expenses. Research and development expenses: $2.7 million in 3Q-2024 as compared to $6.7 million in 3Q-2023, a 60% decrease compared to Q3-2023, with the current quarter’s decrease primarily attributable to a decrease in costs related to development activities for Sildenafil Cream as a result of the Phase 2b RESPOND clinical study completion in June 2023, partially offset by increases in costs related to Ovaprene’s development, including the ongoing pivotal Phase 3 clinical trial. Conference Call Daré will host a conference call and live webcast today, November 14, 2024, at 4:30 p.m. Eastern Time to review financial results for the quarter ended September 30, 2024 and to provide a company update. To access the conference call via phone, dial (646) 307-1963 (U.S.) or (800) 715-9871 (toll free). The conference ID number for the call is 6400145. The live webcast can be accessed under “Presentations, Events & Webcasts” in the Investors section of the company's website at http://ir.darebioscience.com. Please log in approximately 5-10 minutes prior to the call to register and to download and install any necessary software. The webcast will be archived under “Presentations, Events & Webcasts” in the Investors section of the company's website at http://ir.darebioscience.com and available for replay until November 28, 2024. About XACIATO™ (clindamycin phosphate) vaginal gel 2% XACIATO is indicated for the treatment of bacterial vaginosis in females 12 years and older. A single-dose user-filled disposable applicator delivers 5g of vaginal gel containing 100mg of clindamycin. Selected Safety Information XACIATO is contraindicated in individuals with a history of hypersensitivity to clindamycin or lincomycin. Clostridioides difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including clindamycin, and may range in severity from mild diarrhea to fatal colitis. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Polyurethane condoms are not recommended during treatment with XACIATO or for 7 days following treatment. During this time period, polyurethane condoms may not be reliable for preventing pregnancy or for protecting against transmission of HIV and other sexually transmitted diseases. Latex or polyisoprene condoms should be used. XACIATO may result in the overgrowth of Candida spp. in the vagina resulting in vulvovaginal candidiasis, which may require antifungal treatment. The most common adverse reactions reported in >2% of patients and at a higher rate in the XACIATO group than in the placebo group were vulvovaginal candidiasis and vulvovaginal discomfort. XACIATO has not been studied in pregnant women. However, based on the low systemic absorption of XACIATO following the intravaginal route of administration in nonpregnant women, maternal use is not likely to result in significant fetal exposure to the drug. There are no data on the effect of clindamycin on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for clindamycin and any potential adverse effects on the breastfed child from clindamycin or from the underlying maternal condition. Please see the Prescribing Information, Patient Information, and Instructions for Use. About Daré Bioscience Daré Bioscience is a biopharmaceutical company committed to advancing innovative products for women’s health. The company’s mission is to identify, develop and bring to market a diverse portfolio of differentiated therapies that prioritize women's health and well-being, expand treatment options, and improve outcomes, primarily in the areas of contraception, sexual health, pelvic pain, fertility, infectious diseases, and menopause. The first FDA-approved product to emerge from Daré’s portfolio of women’s health product candidates is XACIATO™ (clindamycin phosphate) vaginal gel 2%, a lincosamide antibacterial indicated for the treatment of bacterial vaginosis in female patients 12 years of age and older, which is under a global license agreement with Organon. Visit www.xaciato.com for information about XACIATO. Daré’s portfolio also includes potential first-in-category candidates in clinical development: Ovaprene®, a novel, hormone-free monthly intravaginal contraceptive whose U.S. commercial rights are under a license agreement with Bayer; Sildenafil Cream, 3.6%, a novel cream formulation of sildenafil, the active ingredient in Viagra®, to treat female sexual arousal disorder (FSAD); and DARE-HRT1, a combination bio-identical estradiol and progesterone intravaginal ring for menopausal hormone therapy. To learn more about Daré’s full portfolio of women’s health product candidates and mission to deliver differentiated therapies for women, please visit www.darebioscience.com. Daré Bioscience leadership has been named on the Medicine Maker’s Power List and Endpoints News’ Women in Biopharma 2022. In 2023, Daré's CEO was honored as one of Fierce Pharma’s Most Influential People in Biopharma for Daré’s contributions to innovation and advocacy in the women’s health space. Daré Bioscience placed #1 in the Small Company category of the San Diego Business Journal’s 2023 Best Places to Work Awards. Daré may announce material information about its finances, product and product candidates, clinical trials and other matters using the Investors section of its website (http://ir.darebioscience.com), SEC filings, press releases, public conference calls and webcasts. Daré will use these channels to distribute material information about the company and may also use social media to communicate important information about the company, its finances, product and product candidates, clinical trials and other matters. The information Daré posts on its investor relations website or through social media channels may be deemed to be material information. Daré encourages investors, the media, and others interested in the company to review the information Daré posts in the Investors section of its website and to follow these X (formerly Twitter) accounts: @SabrinaDareCEO and @DareBioscience. Any updates to the list of social media channels the company may use to communicate information will be posted in the Investors section of Daré’s website. Forward-Looking Statements Daré cautions you that all statements, other than statements of historical facts, contained in this press release, are forward-looking statements. Forward-looking statements, in some cases, can be identified by terms such as “believe,” “may,” “will,” “estimate,” “continue,” “anticipate,” “design,” “intend,” “expect,” “could,” “plan,” “potential,” “predict,” “seek,” “should,” “would,” “project,” “target,” “objective,” “on track,” or the negative version of these words and similar expressions. In this press release, forward-looking statements include, but are not limited to, statements relating to plans and expectations with respect to Daré’s product candidates, including clinical development plans, trial design, timelines, costs, milestones, targeted indications, anticipated regulatory approval pathways, and potential alignment with the FDA on requirements for a successful NDA submission, the potential for FDA approval of Ovaprene based on a single pivotal clinical study, the expectation that a product candidate, if approved, could be a first-in-category product, the potential market size and opportunity for a product candidate, if approved, the amount and timing of Daré’s receipt of funds under the recently announced foundation grant agreement, Daré’s anticipated use of funds it receives and Daré’s expectations with respect to the impact of such grant funding on its Ovaprene development program, the expectation that Daré will receive $10 million in funding under ARPA-H’s Sprint for Women’s Health, Daré’s ability to access $15 million in additional capital under its equity line arrangement with Lincoln Park Capital Fund at times and in amounts it desires to help advance development of its investigational products, and the potential for Daré’s product candidates to demonstrate they are safe and effective for their respective target indications. As used in this press release, the description of a product candidate as “first-in-category” is a forward-looking statement relating to the potential of the candidate to represent a new category of product if it were to receive marketing approval for the indication for which Daré is developing it. Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause Daré’s actual results, performance or achievements to be materially different from future results, performance or achievements expressed or implied by the forward-looking statements in this press release, including, without limitation, risks and uncertainties related to: Daré’s ability to raise additional capital when and as needed to advance its product candidates, execute its business strategy and continue as a going concern; Daré’s ability to achieve the product development and other milestones required for it to receive payments under its ARPA-H funding award and grant agreements with the foundation; the limits on Daré’s ability to sell stock to Lincoln Park Capital Fund under the purchase agreement at times it may desire to raise additional capital; Daré’s ability to develop, obtain FDA or foreign regulatory approval for, and commercialize its product candidates and to do so on communicated timelines; failure or delay in starting, conducting and completing clinical trials of a product candidate; Daré’s ability to design and conduct successful clinical trials, to enroll a sufficient number of patients, to meet established clinical endpoints, to avoid undesirable side effects and other safety concerns, and to demonstrate sufficient safety and efficacy of its product candidates; Daré’s ability to add new clinical study sites to the Ovaprene pivotal study and the ability of such additional sites to enroll subjects in a manner that accelerates the study timeline; Daré’s dependence on third parties to conduct clinical trials and manufacture and supply clinical trial material and commercial product; the risk that positive findings in early clinical and/or nonclinical studies of a product candidate may not be predictive of success in subsequent clinical and/or nonclinical studies of that candidate; the risk that the FDA, other regulatory authorities, members of the scientific or medical communities or investors may not accept or agree with Daré’s interpretation of or conclusions regarding data from clinical studies of its product candidates; the risk that development of a product candidate requires more clinical or nonclinical studies than Daré anticipates; the loss of, or inability to attract, key personnel; the effects of macroeconomic conditions, geopolitical events, public health emergencies, and major disruptions in government operations on Daré’s operations, financial results and condition, and ability to achieve current plans and objectives; the risk that developments by competitors make Daré’s product or product candidates less competitive or obsolete; difficulties establishing and sustaining relationships with development and/or commercial collaborators; failure of Daré’s product or product candidates, if approved, to gain market acceptance or obtain adequate coverage or reimbursement from third-party payers; Daré’s ability to retain its licensed rights to develop and commercialize a product or product candidate; Daré’s ability to satisfy the monetary obligations and other requirements in connection with its exclusive, in-license agreements covering the critical patents and related intellectual property related to its product and product candidates; Daré’s ability to adequately protect or enforce its, or its licensor’s, intellectual property rights; the lack of patent protection for the active ingredients in certain of Daré’s product candidates which could expose its products to competition from other formulations using the same active ingredients; product liability claims; governmental investigations or actions relating to Daré’s product or product candidates or the business activities of Daré, its commercial collaborators or other third parties on which Daré relies; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; cybersecurity incidents or similar events that compromise Daré’s technology systems or those of third parties on which it relies and/or significantly disrupt Daré’s business; and disputes or other developments concerning Daré’s intellectual property rights. Daré’s forward-looking statements are based upon its current expectations and involve assumptions that may never materialize or may prove to be incorrect. All forward-looking statements are expressly qualified in their entirety by these cautionary statements. For a detailed description of Daré’s risks and uncertainties, you are encouraged to review its documents filed with the SEC including Daré’s recent filings on Form 8-K, Form 10-K and Form 10-Q. You are cautioned not to place undue reliance on forward-looking statements, which speak only as of the date on which they were made. Daré undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law. Contacts: Daré Bioscience Investor Relationsinnovations@darebioscience.com Source: Daré Bioscience, Inc. Daré Bioscience, Inc. and Subsidiaries Condensed Consolidated Statements of Operations and Comprehensive Loss (Unaudited) Three months ended September 30, 2024 2023 Revenue License fee revenue$- $1,000,000 Royalty revenue 41,691 - Total revenue 41,691 1,000,000 Operating expenses General and administrative 2,041,268 2,696,779 Research and development 2,656,772 6,674,636 License fee expense 25,000 25,000 Total operating expenses 4,723,040 9,396,415 Loss from operations (4,681,349) (8,396,415) Other income (expense) (21,152) 97,319 Net loss$(4,702,501) $(8,299,096) Foreign currency translation adjustments$22,935 $(15,030) Comprehensive loss$(4,679,566) $(8,314,126) Loss per common share: Basic$(0.55) $(1.09) Diluted$(0.55) $(1.09) Weighted average number of shares outstanding: Basic 8,534,433 7,587,637 Diluted 8,534,433 7,587,637 Daré Bioscience, Inc. and Subsidiaries Condensed Consolidated Balance Sheets Data September 30,2024 December 31,2023 (unaudited) Cash and cash equivalents$11,232,609 $10,476,056 Working capital (deficit)$1,790,546 $(2,936,897) Total assets$18,058,801 $21,282,215 Total stockholders' deficit$(1,484,483) $(5,047,640)