OATP1B1

WHIPPANY, N.J.--( BUSINESS WIRE )--New subgroup data from the investigational Phase III ARANOTE trial show NUBEQA ® (darolutamide) plus androgen-deprivation therapy (ADT) improved radiological progression-free survival (rPFS) in patients with high and low-volume metastatic hormone sensitive (mHSPC) by 40% (hazard ratio [HR] 0.60; 95% confidence interval [CI] 0.44-0.80) and 70% (HR 0.30; 95% CI 0.15-0.60) respectively, compared to placebo plus ADT. The overall incidence of adverse events was low, with incidence similar in the high and low-volume subgroups and consistent with the overall population. The full results were presented during the American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) 2025 Congress. NUBEQA is indicated in the U.S. for the treatment of adult patients with mHSPC in combination with docetaxel and for the treatment of adult patients with non-metastatic castration-resistant prostate cancer (nmCRPC). 1 Full results from the Phase III ARANOTE trial were first presented at the European Society for Medical Oncology (ESMO) Congress in September 2024 and showed that NUBEQA plus ADT significantly reduced the risk of radiological progression or death by 46% compared to placebo plus ADT (HR 0.54; 95% CI 0.41-0.71; P<0.0001), in patients with mHSPC. Prostate cancer is the second most common cancer in men. 2 Only 30% of those diagnosed with mHSPC will survive five years or more after diagnosis. 3 Most people with mHSPC eventually progress to metastatic castration-resistant prostate cancer (mCRPC), a condition with limited long-term survival. 4,5 “ At Bayer, our mission in prostate cancer care is centered on improving patient outcomes across all disease stages. The expanding body of evidence for NUBEQA highlights Bayer’s commitment to supporting the diverse needs of prostate cancer patients,” said Christine Roth, Global Head of Product Strategy and Commercialization at Bayer’s Pharmaceuticals Division. “ The data shared at ASCO GU continue to build on the established clinical profile of NUBEQA and providing additional evidence to support the safety and efficacy benefits for patients living with prostate cancer.” In the ARANOTE trial, patients with mHSPC were randomized 2:1 to receive NUBEQA plus ADT versus placebo plus ADT. High-volume disease was defined by the presence of visceral metastases and/or ≥4 bone metastases with ≥1 beyond the vertebral column/pelvis, as delineated in the CHAARTED criteria. Of 669 patients included in the full analysis set, 472 (71%) had high-volume disease and 197 (29%) had low-volume disease. The subgroup analysis showed that, in the low-volume (LV) subgroup, NUBEQA plus ADT reduced the risk of radiological progression or death by 70% (HR 0.30; 95% CI: 0.15-0.60) with median rPFS not reached, compared to placebo plus ADT. In the high-volume (HV) subgroup, NUBEQA plus ADT reduced the risk of radiological progression or death by 40% (HR 0.60; 95% CI: 0.44-0.80) with median rPFS of 30.2 months with NUBEQA versus 19.2 months with placebo. Secondary endpoints presented included that NUBEQA delayed time to mCRPC (HV: HR 0.46; 95% CI: 0.36-0.60; LV: HR 0.21; 95% CI: 0.12-0.37) and time to prostate-specific antigen (PSA) progression (HV: HR 0.34; 95% CI: 0.25-0.46; LV: HR 0.19; 95% CI: 0.10-0.37) and a higher proportion achieved PSA <0.2 ng/mL with NUBEQA vs placebo (HV: 54.6% vs 15.5%; LV: 82.6% vs 25.4%) in high and low-volume subgroups. Treatment-emergent adverse events were low and similar across both high- and low-volume subgroups, and consistent with the overall population. Other data presented at ASCO GU 2025 included an age-related subgroup analysis of the Phase III ARASENS trial and additional real-world data analysis, both in mHSPC patients showing positive responses with NUBEQA in combination with ADT and docetaxel across key clinically relevant endpoints. Data from the ARASENS subgroup analysis of 1,305 patients with ages ranging from 41-89 years showed that patients with mHSPC benefited from NUBEQA in combination with ADT and docetaxel, irrespective of age (<75 y and ≥75 y). Consistent improvements were seen in overall survival (OS; <75 y HR 0.70; 95% CI 0.58-0.84; ≥75 y HR 0.61; 95% CI 0.41-0.91), time to mCRPC (<75 y HR 0.35; 95% CI 0.30-0.43; ≥75 y HR 0.42; 95% CI 0.28-0.64), and time to initiation of subsequent therapy (<75 y HR 0.40; 95% CI 0.34-0.48; ≥75 y HR 0.35; 95% CI 0.22-0.54). The results were consistent with the established safety profile of NUBEQA in both age subgroups, with similar incidences of treatment-emergent adverse events versus placebo. Additionally, a retrospective cohort analysis of adult patients in the U.S. who initiated treatment with androgen receptor pathway inhibitor triplet therapy (either NUBEQA + ADT + DOC [DAR] or abiraterone + ADT + DOC [ABI] found that therapy with NUBEQA in combination with ADT and docetaxel led to lower probability of treatment discontinuation (DAR; 25% [95% CI 0.177-0.334] vs ABI; 38%; 95% CI 0.286-0.484 at 18 months), lower probability of progression to mCRPC (DAR; 24% 95% CI 0.175-0.335 vs ABI; 46% 95% CI 0.358-0.574 at 18 months), and a higher number of patients achieving PSA responses (undetectable level PSA at 12 months; DAR; 61.2% (n=94/141) vs ABI; 46.6% (n=43/102)). About the ARANOTE Trial 6 The ARANOTE trial (NCT04736199) is a Phase III, randomized, double-blind, placebo-controlled trial designed to assess the efficacy and safety of NUBEQA in combination with standard ADT in patients with mHSPC. A total of 669 patients were randomized 2:1 to receive either 600 mg of NUBEQA (n=446) or placebo (n=223) twice daily in addition to ADT. The primary endpoint of the ARANOTE trial was rPFS, measured as time from randomization to date of first documented radiological disease progression or death due to any cause, whichever occurs first. Secondary endpoints include overall survival (OS; time to death from any cause), time to first castration-resistant event, time to initiation of subsequent anti-cancer therapy, time to PSA progression, PSA undetectable rates, time to pain progression, and safety assessments. About the ARASENS Trial 7 The ARASENS trial (NCT02799602) is the only randomized Phase III, multi-center, double-blind, placebo-controlled trial prospectively designed to compare the use of a second-generation androgen receptor inhibitor (ARi) (NUBEQA) plus androgen deprivation therapy (ADT) and the chemotherapy docetaxel to ADT plus docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC). A total of 1,306 newly diagnosed patients were randomized in a 1:1 ratio to receive 600 mg of NUBEQA twice a day or matching placebo plus ADT and docetaxel. The primary endpoint of the trial was OS. Secondary endpoints included time to castration-resistant prostate cancer (CRPC), time to pain progression, time to first symptomatic skeletal event (SSE), and time to initiation of subsequent anticancer therapy, all measured at 12-week intervals, as well as AEs as a measure of safety and tolerability. About NUBEQA ® (darolutamide) 1 NUBEQA ® (darolutamide) is an androgen receptor inhibitor (ARi) with a distinct chemical structure that competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription. NUBEQA is developed jointly by Bayer and Orion Corporation, a globally operating Finnish pharmaceutical company. NUBEQA is an androgen receptor inhibitor indicated for the treatment of adult patients with: Non-metastatic castration-resistant prostate cancer (nmCRPC) Metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel IMPORTANT SAFETY INFORMATION Warnings & Precautions Ischemic Heart Disease – In a study of patients with nmCRPC (ARAMIS), ischemic heart disease occurred in 3.2% of patients receiving NUBEQA versus 2.5% receiving placebo, including Grade 3-4 events in 1.7% vs. 0.4%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA vs. 0.2% receiving placebo. In a study of patients with mHSPC (ARASENS), ischemic heart disease occurred in 3.2% of patients receiving NUBEQA with docetaxel vs. 2% receiving placebo with docetaxel, including Grade 3-4 events in 1.3% vs. 1.1%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA with docetaxel vs. 0% receiving placebo with docetaxel. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue NUBEQA for Grade 3-4 ischemic heart disease. Seizure – In ARAMIS, Grade 1-2 seizure occurred in 0.2% of patients receiving NUBEQA vs. 0.2% receiving placebo. Seizure occurred 261 and 456 days after initiation of NUBEQA. In ARASENS, seizure occurred in 0.6% of patients receiving NUBEQA with docetaxel, including one Grade 3 event, vs. 0.2% receiving placebo with docetaxel. Seizure occurred 38 to 340 days after initiation of NUBEQA. It is unknown whether antiepileptic medications will prevent seizures with NUBEQA. Advise patients of the risk of developing a seizure while receiving NUBEQA and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others. Consider discontinuation of NUBEQA in patients who develop a seizure during treatment. Embryo-Fetal Toxicity – Safety and efficacy of NUBEQA have not been established in females. NUBEQA can cause fetal harm and loss of pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment with NUBEQA and for 1 week after the last dose. Adverse Reactions In ARAMIS, serious adverse reactions occurred in 25% of patients receiving NUBEQA vs. 20% of patients receiving placebo. Serious adverse reactions in ≥1% of patients who received NUBEQA included urinary retention, pneumonia, and hematuria. Fatal adverse reactions occurred in 3.9% of patients receiving NUBEQA vs. 3.2% of patients receiving placebo. Fatal adverse reactions in patients who received NUBEQA included death (0.4%), cardiac failure (0.3%), cardiac arrest (0.2%), general physical health deterioration (0.2%), and pulmonary embolism (0.2%). The most common adverse reactions (>2% with a ≥2% increase over placebo), including laboratory test abnormalities, were increased AST, decreased neutrophil count, fatigue, increased bilirubin, pain in extremity and rash. Clinically relevant adverse reactions occurring in ≥2% of patients treated with NUBEQA included ischemic heart disease and heart failure. In ARASENS, serious adverse reactions occurred in 45% of patients receiving NUBEQA with docetaxel vs. 42% of patients receiving placebo with docetaxel. Serious adverse reactions in ≥2% of patients who received NUBEQA with docetaxel included febrile neutropenia (6%), decreased neutrophil count (2.8%), musculoskeletal pain (2.6%), and pneumonia (2.6%). Fatal adverse reactions occurred in 4% of patients receiving NUBEQA with docetaxel vs. 4% of patients receiving placebo with docetaxel. Fatal adverse reactions in patients who received NUBEQA included COVID-19/COVID-19 pneumonia (0.8%), myocardial infarction (0.3%), and sudden death (0.3%). The most common adverse reactions (≥10% with a ≥2% increase over placebo with docetaxel) were constipation, rash, decreased appetite, hemorrhage, increased weight, and hypertension. The most common laboratory test abnormalities (≥30%) were anemia, hyperglycemia, decreased lymphocyte count, decreased neutrophil count, increased AST, increased ALT, and hypocalcemia. Clinically relevant adverse reactions in <10% of patients who received NUBEQA with docetaxel included fractures, ischemic heart disease, seizures, and drug-induced liver injury. Drug Interactions Effect of Other Drugs on NUBEQA – Combined P-gp and strong or moderate CYP3A4 inducers decrease NUBEQA exposure, which may decrease NUBEQA activity. Avoid concomitant use. Combined P-gp and strong CYP3A4 inhibitors increase NUBEQA exposure, which may increase the risk of NUBEQA adverse reactions. Monitor more frequently and modify NUBEQA dose as needed. Effects of NUBEQA on Other Drugs – NUBEQA inhibits breast cancer resistance protein (BCRP) transporter. Concomitant use increases exposure (AUC) and maximal concentration of BCRP substrates, which may increase the risk of BCRP substrate-related toxicities. Avoid concomitant use where possible. If used together, monitor more frequently for adverse reactions, and consider dose reduction of the BCRP substrate. NUBEQA inhibits OATP1B1 and OATP1B3 transporters. Concomitant use may increase plasma concentrations of OATP1B1 or OATP1B3 substrates. Monitor more frequently for adverse reactions and consider dose reduction of these substrates. Review the Prescribing Information of drugs that are BCRP, OATP1B1, and OATP1B3 substrates when used concomitantly with NUBEQA. For important risk and use information about NUBEQA, please see the accompanying full Prescribing Information . About Metastatic Hormone-Sensitive Prostate Cancer Prostate cancer is the second most common cancer in men and the fifth most common cause of cancer death in men worldwide. 2,8 In 2020, an estimated 1.4 million men were diagnosed with prostate cancer, including almost 300,000 cases in the U.S., and about 375,000 died from the disease worldwide. 9,10 At the time of diagnosis, most men have localized prostate cancer, meaning their cancer is confined to the prostate gland and can be treated with curative surgery or radiotherapy. Upon relapse when the disease will metastasize or spread, androgen deprivation therapy (ADT) is the cornerstone of treatment for this hormone-sensitive disease. Approximately 10% of men will already present with mHSPC when first diagnosed. 11,12,13 Men with metastatic hormone-sensitive prostate cancer (mHSPC) will start their treatment with hormone therapy, such as ADT, androgen receptor inhibitor (ARi) plus ADT or a combination of the chemotherapy docetaxel and ADT. Despite this treatment, most men with mHSPC will eventually progress to metastatic castration-resistant prostate cancer (CRPC), a condition with limited survival. 4,5 About Oncology at Bayer Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The oncology franchise at Bayer includes six marketed products and several other assets in various stages of clinical development. Together, these products reflect the company’s approach to research, which prioritizes targets and pathways with the potential to impact the way that cancer is treated. About Bayer Bayer is a global enterprise with core competencies in the life science fields of health care and nutrition. In line with its mission, “Health for all, Hunger for none,” the company’s products and services are designed to help people and the planet thrive by supporting efforts to master the major challenges presented by a growing and aging global population. Bayer is committed to driving sustainable development and generating a positive impact with its businesses. At the same time, the Group aims to increase its earning power and create value through innovation and growth. The Bayer brand stands for trust, reliability and quality throughout the world. In fiscal 2023, the Group employed around 100,000 people and had sales of 47.6 billion euros. R&D expenses before special items amounted to 5.8 billion euros. For more information, go to www.bayer.com . © 2025 Bayer BAYER, the Bayer Cross and NUBEQA are registered trademarks of Bayer. Find more information at www.pharma.bayer.com Our online press service is just a click away: www.bayer.us/en/newsroom Follow us on Facebook: http://www.facebook.com/pharma.bayer Follow us on X: https://X.com/BayerUS Forward-Looking Statements This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer’s public reports which are available on the Bayer website at www.bayer.com . The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments. References NUBEQA ® (darolutamide) [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc.; October 2023. Bray F et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. https://acsjournals.onlinelibrary.wiley.com/doi/10.3322/caac.21834 . Accessed: January 2025. Ng, K et al. Oncol Ther . 2020;8:209–230. Siegel DA et al. MMWR Morb Mortal Wkly Rep . 2020;69:1473–1480. Hahn AW et al. Am Soc Clin Oncol Educ Book . 2018 May 23;38:363-371. ClinicalTrials.gov NCT04736199. Darolutamide in Addition to ADT Versus ADT in Metastatic Hormone-sensitive Prostate Cancer (ARANOTE). https://www.clinicaltrials.gov/study/NCT04736199 . Accessed: January 2025. ClinicalTrials.gov NCT02799602. ODM-201 in Addition to Standard ADT and Docetaxel in Metastatic Castration Sensitive Prostate Cancer (ARASENS). https://clinicaltrials.gov/ct2/show/NCT02799602 . Accessed: January 2025. Hyuna S et al. Ca Cancer J Clin 2021 ; 71:209–249. Prostate Cancer: Statistic. Cancer.Net. https://www.cancer.net/cancer-types/prostate-cancer/statistics . September 2024. American Cancer Society. Cancer Facts & Figures 2024. https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/2024-cancer-facts-figures.html . September 2024 Piombino C et al. Cancers (Basel). 2023 Oct 11;15(20):4945. Helgstrand JT et al. Cancer. 2018;124(14):2931-2938. Buzzoni C et al. Eur. Urol. 2015;68:885–890.

WHIPPANY, N.J.--( BUSINESS WIRE )--Bayer will present new data from its prostate cancer portfolio at the upcoming American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, taking place in San Francisco, California, from February 13-15, 2025. These presentations reinforce Bayer´s commitment to advancing treatments across different stages of prostate cancer. Data will include a subgroup analysis from the investigational Phase III ARANOTE trial, evaluating the efficacy and safety of NUBEQA ® (darolutamide) and androgen-deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) by disease volume. Subgroup analyses from the investigational Phase III ARASENS trial will be presented, including evaluating age-related efficacy and safety of NUBEQA plus ADT and docetaxel in patients with mHSPC and an analysis of concomitant granulocyte colony-stimulating factor (G-CSF) use in maintaining an efficacious dose and safe delivery of docetaxel in combination with NUBEQA in patients with mHSPC. Lead-in phase results will be presented from the investigational Phase II ARAMON trial, investigating NUBEQA monotherapy in patients with castration-sensitive prostate cancer (CSPC) after biochemical recurrence (BCR) and other data to be presented will focus on clinical use and outcomes of androgen-receptor pathway inhibitors triplet therapy for mHSPC. A trial-in-progress update will also be presented for the ongoing investigational Phase III ARASTEP trial investigating NUBEQA plus ADT in patients with high-risk BCR of prostate cancer. NUBEQA is indicated in the U.S. for the treatment of adult patients with mHSPC in combination with docetaxel and for the treatment of adult patients with non-metastatic castration-resistant prostate cancer (nmCRPC). 1 In radiopharmaceuticals, investigator-initiated research will be presented on XOFIGO ® (radium-223 dichloride) without ADT in patients with BCR and positron emission tomography (PET) findings in the bones. Investigator-initiated research will be presented evaluating the safety and efficacy of retreatment of metastatic castration-resistant prostate cancer (mCRPC) patients with XOFIGO therapy in daily practice. Data from three Real World Evidence studies, reviewing data from over 30 observational studies, will be presented. XOFIGO is indicated in the U.S. for the treatment of patients with castration-resistant prostate cancer (CRPC), symptomatic bone metastases and no known visceral metastatic disease. 2 Details on selected abstracts from Bayer at the 2025 ASCO GU Cancers Symposium are listed below: NUBEQA (darolutamide) Darolutamide plus ADT in patients with metastatic hormone-sensitive prostate cancer (mHSPC) by disease volume: Subgroup analysis of the phase 3 ARANOTE trial Abstract: 151; February 13. 11:25 AM – 12:45 PM PST Age-related efficacy and safety of darolutamide plus androgen-deprivation therapy (ADT) and docetaxel in patients with metastatic hormone-sensitive prostate cancer (mHSPC): a subgroup analysis of ARASENS Abstract: 143; February 13. 11:25 AM – 12:45 PM PST Concomitant G-CSF use in maintaining an efficacious dose and safe delivery of docetaxel in combination with darolutamide in patients with metastatic hormone sensitive prostate cancer (mHSPC): ARASENS, a phase 3 study Abstract: 152; February 13. 11:25 AM – 12:45 PM PST Darolutamide monotherapy in patients with castration-sensitive prostate cancer (CSPC) after biochemical recurrence (BCR): ARAMON lead-in phase results Abstract: 150; February 13. 11:25 AM – 12:45 PM PST Clinical use and outcomes of Androgen-Receptor pAthwAy inhibitors Triplet therapy for metastatic hormone-sensitive prostate cancer (ARAAT) – Real World Evidence (RWE) Abstract: 66; February 13. 11:25 AM – 12:45 PM PST Darolutamide plus androgen-deprivation therapy (ADT) in patients with high-risk biochemical recurrence (BCR) of prostate cancer: A phase 3, randomized, double-blind, placebo-controlled study (ARASTEP) - Trial in Progress (TiP) Abstract: TPS432; February 13. 11:25 AM – 12:45 PM PST XOFIGO (radium-223 dichloride) Re-treatment of metastatic castration-resistant prostate cancer patients with radium-223 therapy in daily practice - Investigator-Initiated Research (IIR) Abstract: 183; February 13. 11:25 AM – 12:45 PM PST Radium 223 without Androgen Deprivation Therapy (ADT) in Patients (Pts) with Biochemically Recurrent Prostate Cancer (BCR) and PET Findings in the Bones - Investigator-Initiated Research (IIR) Abstract: 180; February 13. 11:25 AM -12:45 PM PST Effectiveness and safety of radium-223 in men with metastatic castration-resistant prostate cancer (mCRPC): A systematic literature review of 48 real-world studies – Real World Evidence (RWE) Abstract: 81; February 13. 11:25 AM – 12:45 PM PST Real-world treatment patterns and survival in men with metastatic castration-resistant prostate cancer (mCRPC) who previously progressed from metastatic hormone-sensitive prostate cancer (mHSPC) between 2020 to 2023 in the United States – Real World Evidence (RWE) Abstract: 99; February 13. 11:25 AM -12:45 PM PST Treatment patterns and survival in men with metastatic castration-resistant prostate cancer (mCRPC): A systematic literature review of 35 real-world observational studies – Real World Evidence (RWE) Abstract: 101; February 13. 11:25 AM -12:45 PM PST About NUBEQA ® (darolutamide) 1 NUBEQA ® (darolutamide) is an androgen receptor inhibitor (ARi) with a distinct chemical structure that competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription. NUBEQA is developed jointly by Bayer and Orion Corporation, a globally operating Finnish pharmaceutical company. NUBEQA is an androgen receptor inhibitor indicated for the treatment of adult patients with: Non-metastatic castration-resistant prostate cancer (nmCRPC) Metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel IMPORTANT SAFETY INFORMATION Warnings & Precautions Ischemic Heart Disease – In a study of patients with nmCRPC (ARAMIS), ischemic heart disease occurred in 3.2% of patients receiving NUBEQA versus 2.5% receiving placebo, including Grade 3-4 events in 1.7% vs. 0.4%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA vs. 0.2% receiving placebo. In a study of patients with mHSPC (ARASENS), ischemic heart disease occurred in 3.2% of patients receiving NUBEQA with docetaxel vs. 2% receiving placebo with docetaxel, including Grade 3-4 events in 1.3% vs. 1.1%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA with docetaxel vs. 0% receiving placebo with docetaxel. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue NUBEQA for Grade 3-4 ischemic heart disease. Seizure – In ARAMIS, Grade 1-2 seizure occurred in 0.2% of patients receiving NUBEQA vs. 0.2% receiving placebo. Seizure occurred 261 and 456 days after initiation of NUBEQA. In ARASENS, seizure occurred in 0.6% of patients receiving NUBEQA with docetaxel, including one Grade 3 event, vs. 0.2% receiving placebo with docetaxel. Seizure occurred 38 to 340 days after initiation of NUBEQA. It is unknown whether antiepileptic medications will prevent seizures with NUBEQA. Advise patients of the risk of developing a seizure while receiving NUBEQA and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others. Consider discontinuation of NUBEQA in patients who develop a seizure during treatment. Embryo-Fetal Toxicity – Safety and efficacy of NUBEQA have not been established in females. NUBEQA can cause fetal harm and loss of pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment with NUBEQA and for 1 week after the last dose. Adverse Reactions In ARAMIS, serious adverse reactions occurred in 25% of patients receiving NUBEQA vs. 20% of patients receiving placebo. Serious adverse reactions in ≥1% of patients who received NUBEQA included urinary retention, pneumonia, and hematuria. Fatal adverse reactions occurred in 3.9% of patients receiving NUBEQA vs. 3.2% of patients receiving placebo. Fatal adverse reactions in patients who received NUBEQA included death (0.4%), cardiac failure (0.3%), cardiac arrest (0.2%), general physical health deterioration (0.2%), and pulmonary embolism (0.2%). The most common adverse reactions (>2% with a ≥2% increase over placebo), including laboratory test abnormalities, were increased AST, decreased neutrophil count, fatigue, increased bilirubin, pain in extremity and rash. Clinically relevant adverse reactions occurring in ≥2% of patients treated with NUBEQA included ischemic heart disease and heart failure. In ARASENS, serious adverse reactions occurred in 45% of patients receiving NUBEQA with docetaxel vs. 42% of patients receiving placebo with docetaxel. Serious adverse reactions in ≥2% of patients who received NUBEQA with docetaxel included febrile neutropenia (6%), decreased neutrophil count (2.8%), musculoskeletal pain (2.6%), and pneumonia (2.6%). Fatal adverse reactions occurred in 4% of patients receiving NUBEQA with docetaxel vs. 4% of patients receiving placebo with docetaxel. Fatal adverse reactions in patients who received NUBEQA included COVID-19/COVID-19 pneumonia (0.8%), myocardial infarction (0.3%), and sudden death (0.3%). The most common adverse reactions (≥10% with a ≥2% increase over placebo with docetaxel) were constipation, rash, decreased appetite, hemorrhage, increased weight, and hypertension. The most common laboratory test abnormalities (≥30%) were anemia, hyperglycemia, decreased lymphocyte count, decreased neutrophil count, increased AST, increased ALT, and hypocalcemia. Clinically relevant adverse reactions in <10% of patients who received NUBEQA with docetaxel included fractures, ischemic heart disease, seizures, and drug-induced liver injury. Drug Interactions Effect of Other Drugs on NUBEQA – Combined P-gp and strong or moderate CYP3A4 inducers decrease NUBEQA exposure, which may decrease NUBEQA activity. Avoid concomitant use. Combined P-gp and strong CYP3A4 inhibitors increase NUBEQA exposure, which may increase the risk of NUBEQA adverse reactions. Monitor more frequently and modify NUBEQA dose as needed. Effects of NUBEQA on Other Drugs – NUBEQA inhibits breast cancer resistance protein (BCRP) transporter. Concomitant use increases exposure (AUC) and maximal concentration of BCRP substrates, which may increase the risk of BCRP substrate-related toxicities. Avoid concomitant use where possible. If used together, monitor more frequently for adverse reactions, and consider dose reduction of the BCRP substrate. NUBEQA inhibits OATP1B1 and OATP1B3 transporters. Concomitant use may increase plasma concentrations of OATP1B1 or OATP1B3 substrates. Monitor more frequently for adverse reactions and consider dose reduction of these substrates. Review the Prescribing Information of drugs that are BCRP, OATP1B1, and OATP1B3 substrates when used concomitantly with NUBEQA. For important risk and use information about NUBEQA, please see the accompanying full Prescribing Information . About Metastatic Hormone-Sensitive Prostate Cancer Prostate cancer is the second most common cancer in men and the fifth most common cause of cancer death in men worldwide. 3 In 2020, an estimated 1.4 million men were diagnosed with prostate cancer, including almost 300,000 cases in the U.S., and about 375,000 died from the disease worldwide. 4,5 At the time of diagnosis, most men have localized prostate cancer, meaning their cancer is confined to the prostate gland and can be treated with curative surgery or radiotherapy. Upon relapse when the disease will metastasize or spread, androgen deprivation therapy (ADT) is the cornerstone of treatment for this hormone-sensitive disease. Approximately 10% of men will already present with mHSPC when first diagnosed. 6,7,8 Men with metastatic hormone-sensitive prostate cancer (mHSPC) will start their treatment with hormone therapy, such as ADT, androgen receptor inhibitor (ARi) plus ADT or a combination of the chemotherapy docetaxel and ADT. Despite this treatment, most men with mHSPC will eventually progress to castration-resistant prostate cancer (CRPC), a condition with limited survival. About XOFIGO (radium Ra 223 dichloride) Injection 2 Xofigo is indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease. IMPORTANT SAFETY INFORMATION Warnings and Precautions: Bone Marrow Suppression: In the phase 3 ALSYMPCA trial, 2% of patients in the Xofigo arm experienced bone marrow failure or ongoing pancytopenia, compared to no patients treated with placebo. There were two deaths due to bone marrow failure. For 7 of 13 patients treated with Xofigo bone marrow failure was ongoing at the time of death. Among the 13 patients who experienced bone marrow failure, 54% required blood transfusions. Four percent (4%) of patients in the Xofigo arm and 2% in the placebo arm permanently discontinued therapy due to bone marrow suppression. In the randomized trial, deaths related to vascular hemorrhage in association with myelosuppression were observed in 1% of Xofigo-treated patients compared to 0.3% of patients treated with placebo. The incidence of infection-related deaths (2%), serious infections (10%), and febrile neutropenia (<1%) was similar for patients treated with Xofigo and placebo. Myelosuppression–notably thrombocytopenia, neutropenia, pancytopenia, and leukopenia–has been reported in patients treated with Xofigo. Monitor patients with evidence of compromised bone marrow reserve closely and provide supportive care measures when clinically indicated. Discontinue Xofigo in patients who experience life-threatening complications despite supportive care for bone marrow failure Hematological Evaluation: Monitor blood counts at baseline and prior to every dose of Xofigo. Prior to first administering Xofigo, the absolute neutrophil count (ANC) should be ≥1.5 × 109/L, the platelet count ≥100 × 109/L, and hemoglobin ≥10 g/dL. Prior to subsequent administrations, the ANC should be ≥1 × 109/L and the platelet count ≥50 × 109/L. Discontinue Xofigo if hematologic values do not recover within 6 to 8 weeks after the last administration despite receiving supportive care Concomitant Use With Chemotherapy: Safety and efficacy of concomitant chemotherapy with Xofigo have not been established. Outside of a clinical trial, concomitant use of Xofigo in patients on chemotherapy is not recommended due to the potential for additive myelosuppression. If chemotherapy, other systemic radioisotopes, or hemibody external radiotherapy are administered during the treatment period, Xofigo should be discontinued Increased Fractures and Mortality in Combination With Abiraterone Plus Prednisone/Prednisolone: Xofigo is not recommended for use in combination with abiraterone acetate plus prednisone/prednisolone outside of clinical trials. At the primary analysis of the Phase 3 ERA-223 study that evaluated concurrent initiation of Xofigo in combination with abiraterone acetate plus prednisone/prednisolone in 806 asymptomatic or mildly symptomatic mCRPC patients, an increased incidence of fractures (28.6% vs 11.4%) and deaths (38.5% vs 35.5%) have been observed in patients who received Xofigo in combination with abiraterone acetate plus prednisone/prednisolone compared to patients who received placebo in combination with abiraterone acetate plus prednisone/prednisolone. Safety and efficacy with the combination of Xofigo and agents other than gonadotropin-releasing hormone analogues have not been established Embryo-Fetal Toxicity: The safety and efficacy of Xofigo have not been established in females. Xofigo can cause fetal harm when administered to a pregnant female. Advise pregnant females and females of reproductive potential of the potential risk to a fetus. Advise male patients to use condoms and their female partners of reproductive potential to use effective contraception during and for 6 months after completing treatment with Xofigo Administration and Radiation Protection: Xofigo should be received, used, and administered only by authorized persons in designated clinical settings. The administration of Xofigo is associated with potential risks to other persons from radiation or contamination from spills of bodily fluids such as urine, feces, or vomit. Therefore, radiation protection precautions must be taken in accordance with national and local regulations Fluid Status: Dehydration occurred in 3% of patients on Xofigo and 1% of patients on placebo. Xofigo increases adverse reactions such as diarrhea, nausea, and vomiting, which may result in dehydration. Monitor patients’ oral intake and fluid status carefully and promptly treat patients who display signs or symptoms of dehydration or hypovolemia Injection Site Reactions: Erythema, pain, and edema at the injection site were reported in 1% of patients on Xofigo Secondary Malignant Neoplasms: Xofigo contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure may be associated with an increased risk of cancer and hereditary defects. Due to its mechanism of action and neoplastic changes, including osteosarcomas, in rats following administration of radium-223 dichloride, Xofigo may increase the risk of osteosarcoma or other secondary malignant neoplasms. However, the overall incidence of new malignancies in the randomized trial was lower on the Xofigo arm compared to placebo (<1% vs 2%; respectively), but the expected latency period for the development of secondary malignancies exceeds the duration of follow-up for patients on the trial Subsequent Treatment With Cytotoxic Chemotherapy: In the randomized clinical trial, 16% of patients in the Xofigo group and 18% of patients in the placebo group received cytotoxic chemotherapy after completion of study treatments. Adequate safety monitoring and laboratory testing was not performed to assess how patients treated with Xofigo will tolerate subsequent cytotoxic chemotherapy Adverse Reactions: The most common adverse reactions (≥10%) in the Xofigo arm vs the placebo arm, respectively, were nausea (36% vs 35%), diarrhea (25% vs 15%), vomiting (19% vs 14%), and peripheral edema (13% vs 10%). Grade 3 and 4 adverse events were reported in 57% of Xofigo-treated patients and 63% of placebo-treated patients. The most common hematologic laboratory abnormalities in the Xofigo arm (≥10%) vs the placebo arm, respectively, were anemia (93% vs 88%), lymphocytopenia (72% vs 53%), leukopenia (35% vs 10%), thrombocytopenia (31% vs 22%), and neutropenia (18% vs 5%) Please see the full Prescribing Information for Xofigo (radium Ra 223 dichloride). About Oncology at Bayer Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The oncology franchise at Bayer includes six marketed products and several other assets in various stages of clinical development. Together, these products reflect the company’s approach to research, which prioritizes targets and pathways with the potential to impact the way that cancer is treated. About Bayer Bayer is a global enterprise with core competencies in the life science fields of health care and nutrition. In line with its mission, “Health for all, Hunger for none,” the company’s products and services are designed to help people and the planet thrive by supporting efforts to master the major challenges presented by a growing and aging global population. Bayer is committed to driving sustainable development and generating a positive impact with its businesses. At the same time, the Group aims to increase its earning power and create value through innovation and growth. The Bayer brand stands for trust, reliability and quality throughout the world. In fiscal 2023, the Group employed around 100,000 people and had sales of 47.6 billion euros. R&D expenses before special items amounted to 5.8 billion euros. For more information, go to www.bayer.com . © 2025 Bayer BAYER, the Bayer Cross, NUBEQA and XOFIGO are registered trademarks of Bayer. Find more information at www.pharma.bayer.com Our online press service is just a click away: www.bayer.us/en/newsroom Follow us on Facebook: http://www.facebook.com/pharma.bayer Follow us on X: https://X.com/BayerUS Forward-Looking Statements This release may contain forward-looking statements based on current assumptions and forecasts made by Bayer management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer’s public reports which are available on the Bayer website at www.bayer.com . The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments. References NUBEQA ® (darolutamide) [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc.; October 2023. XOFIGO ® (radium Ra 223 dichloride) Injection [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc.; October 2024. Hyuna S et al. Ca Cancer J Clin 2021 ; 71:209–249. Prostate Cancer: Statistic. Cancer.Net. https://www.cancer.net/cancer-types/prostate-cancer/statistics . September 2024. American Cancer Society. Cancer Facts & Figures 2024. https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/2024-cancer-facts-figures.html . September 2024. Piombino C et al. Cancers (Basel). 2023 Oct 11;15(20):4945. Helgstrand JT et al. Cancer. 2018;124(14):2931-2938. Buzzoni C et al. Eur. Urol. 2015;68:885–890.

NEW YORK--( BUSINESS WIRE )-- Pfizer Inc. (NYSE: PFE) today announced positive results from the Phase 3 BREAKWATER trial evaluating BRAFTOVI ® (encorafenib) in combination with cetuximab (marketed as ERBITUX ® ) and mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) in patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation. At the time of this analysis, the BRAFTOVI combination regimen demonstrated a clinically meaningful and statistically significant improvement in confirmed objective response rate (ORR) assessed by blinded independent central review (BICR) compared to patients receiving chemotherapy with or without bevacizumab (60.9% vs 40.0%, odds ratio =2.443, p=0.0008). These results will be presented today in an oral presentation (Abstract 16) at the 2025 American Society of Clinical Oncology Gastrointestinal Cancer Symposium (ASCO GI) and were simultaneously published in Nature Medicine . “ Despite the high unmet need in this patient population, prior to the recent encorafenib combination regimen approval, there were no approved biomarker-driven therapies indicated for people with previously untreated BRAF V600E -mutant metastatic colorectal cancer,” said Scott Kopetz, M.D., Ph.D., FACP, Professor and Deputy Chair of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center and co-principal investigator of the BREAKWATER trial. “ These data from the BREAKWATER study show the potential for this targeted treatment regimen to become the new standard of care for people with BRAF V600E -mutant metastatic colorectal cancer, for whom long-term disease control is critical.” The estimated median duration of response as assessed by BICR was 13.9 months (95% Confidence Interval [CI]: 8.5-not estimable [NE]) with BRAFTOVI plus cetuximab and mFOLFOX6 and 11.1 months (95% CI: 6.7-12.7) with chemotherapy with or without bevacizumab. Of patients on BRAFTOVI plus cetuximab and mFOLFOX6, 22.4% (n=15) had a response lasting 12 months or longer, compared to 11.4% (n=5) with chemotherapy with or without bevacizumab. The median time to response as assessed by BICR was 7.1 weeks (range 5.7-53.7) with BRAFTOVI plus cetuximab and mFOLFOX6 and 7.3 weeks (range 5.4-48.0) with chemotherapy with or without bevacizumab. Overall survival (OS) data were immature at the time of this analysis but demonstrated a promising trend in favor of BRAFTOVI plus cetuximab and mFOLFOX6 compared to patients receiving chemotherapy with or without bevacizumab. Median OS with BRAFTOVI plus cetuximab with chemotherapy was not estimable (95% CI: 19.8-NE) and 14.6 months (95% CI: 13.4-NE) with chemotherapy with or without bevacizumab (Hazard Ratio [HR]: 0.47, 95% CI: 0.318-0.691). The BREAKWATER trial is ongoing for OS and progression-free survival (PFS), with PFS results expected in 2025. “ These results of this first analysis were the basis for the first approval of a targeted therapy regimen for use in the first-line setting for patients with metastatic colorectal cancer with a BRAF V600E mutation,” said Roger Dansey, M.D., Chief Oncology Officer, Pfizer. “ We are highly encouraged by these response results, which are indicative of the clinically meaningful benefit of BRAFTOVI in reducing tumor size or having no detectable cancer, along with the promising interim analysis of overall survival. We look forward to additional read-outs from the BREAKWATER trial this year.” The safety profile of BRAFTOVI in combination with cetuximab and mFOLFOX6 in the BREAKWATER trial was consistent with the known safety profile of each respective agent. No new safety signals were identified. Serious treatment-emergent adverse events occurred in 37.7% of patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6 compared to 34.6% of patients receiving chemotherapy with or without bevacizumab. BRAFTOVI in combination with cetuximab and mFOLFOX6 was granted accelerated approval by the U.S. Food and Drug Administration (FDA) for the treatment of patients with BRAF V600E -mutant mCRC in December 2024. The approval was among the first in the industry to be conducted under the FDA’s Project FrontRunner, which seeks to support the development and approval of new cancer drugs for advanced or metastatic disease. The BREAKWATER data are also being discussed with other regulatory authorities around the world to support potential future additional license applications for the BRAFTOVI combination regimen in this indication. Pfizer is continuing its commitment to help non-scientists understand the latest findings with the development of abstract plain language summaries (APLS) for company-sponsored research being presented, which are written in non-technical language. Those interested in learning more can visit www.Pfizer.com/apls to access the summaries. About BREAKWATER BREAKWATER is a Phase 3, randomized, active-controlled, open-label, multicenter trial of BRAFTOVI with cetuximab, alone or in combination with mFOLFOX6 in participants with previously untreated BRAF V600E-mutant mCRC. Patients were randomized to receive BRAFTOVI 300 mg orally once daily in combination with cetuximab (discontinued after randomization of 158 patients), BRAFTOVI 300 mg orally once daily in combination with cetuximab and mFOLFOX6 (n=236) or mFOLFOX6, FOLFOXIRI, or CAPOX each with or without bevacizumab (control-arm) (n=243). The dual primary endpoints are ORR, which was met at the time of analysis, and PFS as assessed by BICR. OS is a key secondary endpoint. About Colorectal Cancer (CRC) CRC is the third most common type of cancer in the world, with approximately 1.8 million new diagnoses in 2022. 1 It is the second leading cause of cancer-related deaths. 2 Overall, the lifetime risk of developing CRC is about 1 in 24 for men and 1 in 26 for women. 2 In the U.S. alone, an estimated 154,270 people will be diagnosed with cancer of the colon or rectum in 2025, and approximately 53,000 are estimated to die from the disease each year. 3 For 20% of those diagnosed with CRC, the disease has metastasized, or spread, making it harder to treat, and up to 50% of patients with localized disease eventually develop metastases. 4 BRAF mutations are estimated to occur in 8-12% of people with mCRC and represent a poor prognosis for these patients. 5 The BRAF V600E mutation is the most common BRAF mutation and the risk of mortality in CRC patients with the BRAF V600E mutation is more than double that of patients with no known mutation present. 5,6 Despite the high unmet need in BRAF V600E -mutant mCRC, prior to December 20, 2024, there were no approved biomarker-driven therapies specifically indicated for people with previously untreated BRAF V600E -mutant mCRC. 7,8 About BRAFTOVI ® (encorafenib) BRAFTOVI is an oral small molecule kinase inhibitor that targets BRAF V600E . Inappropriate activation of proteins in the MAPK signaling pathway (RAS-RAF-MEK-ERK) has been shown to occur in certain cancers, including CRC. Pfizer has exclusive rights to BRAFTOVI in the U.S., Canada, Latin America, Middle East, and Africa. Ono Pharmaceutical Co., Ltd. has exclusive rights to commercialize the product in Japan and South Korea, Medison has exclusive rights to commercialize the product in Israel and Pierre Fabre Laboratories has exclusive rights to commercialize the product in all other countries, including Europe and Asia (excluding Japan and South Korea). INDICATION AND USAGE BRAFTOVI ® (encorafenib) is indicated, in combination with cetuximab and mFOLFOX6, for the treatment of patients with metastatic colorectal cancer (mCRC) with a BRAF V600E mutation, as detected by an FDA-approved test. This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). BRAFTOVI is also indicated, in combination with cetuximab, for the treatment of adult patients with mCRC with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy. Limitations of Use : BRAFTOVI is not indicated for treatment of patients with wild-type BRAF CRC. IMPORTANT SAFETY INFORMATION Refer to the prescribing information for cetuximab and individual product components of mFOLFOX6 for recommended dosing and additional safety information. WARNINGS AND PRECAUTIONS New Primary Malignancies: New primary malignancies, cutaneous and non-cutaneous, can occur. In BEACON CRC (previously treated BRAF V600E mutation-positive mCRC), cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in 1.4% of patients with CRC, and a new primary melanoma occurred in 1.4% of patients who received BRAFTOVI in combination with cetuximab. In BREAKWATER (previously untreated BRAF V600E mutation-positive mCRC) skin papilloma was reported in 2.6%, basal cell carcinoma in 1.3%, squamous cell carcinoma of skin in 0.9%, keratoacanthoma in 0.4% and malignant melanoma in situ in 0.4% of patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6. Perform dermatologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Dose modification is not recommended for new primary cutaneous malignancies. Based on its mechanism of action, BRAFTOVI may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving BRAFTOVI for signs and symptoms of non-cutaneous malignancies. Discontinue BRAFTOVI for RAS mutation-positive non-cutaneous malignancies. Monitor patients for new malignancies prior to initiation of treatment, while on treatment, and after discontinuation of treatment. Tumor Promotion in BRAF Wild-Type Tumors: In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation using an FDA-approved test prior to initiating BRAFTOVI. Cardiomyopathy: Cardiomyopathy manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients. Assess left ventricular ejection fraction (LVEF) by echocardiogram or multi-gated acquisition (MUGA) scan prior to initiating treatment, 1 month after initiating treatment, and then every 2 to 3 months during treatment. The safety has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN). Patients with cardiovascular risk factors should be monitored closely. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. Hepatotoxicity: Hepatotoxicity can occur. In BREAKWATER (previously untreated BRAF V600E mutation-positive mCRC), the incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6 was 2.2% for alkaline phosphatase, 1.3% for ALT, and 0.9% for AST. Monitor liver laboratory tests before initiation of BRAFTOVI, monthly during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. Hemorrhage: In BEACON CRC (previously treated BRAF V600E mutation-positive mCRC), hemorrhage occurred in 19% of patients receiving BRAFTOVI in combination with cetuximab; Grade 3 or higher hemorrhage occurred in 1.9% of patients, including fatal gastrointestinal hemorrhage in 0.5% of patients. The most frequent hemorrhagic events were epistaxis (6.9%), hematochezia (2.3%), and rectal hemorrhage (2.3%). In BREAKWATER (previously untreated BRAF V600E mutation-positive mCRC), hemorrhage occurred in 30% of patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6; Grade 3 or 4 hemorrhage occurred in 3% of patients. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. Uveitis: Uveitis, including iritis and iridocyclitis, has been reported in patients treated with BRAFTOVI. Assess for visual symptoms at each visit. Perform an ophthalmological evaluation at regular intervals and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. QT Prolongation: BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients. In BREAKWATER (previously untreated BRAF V600E mutation-positive mCRC), an increase of QTcF >500 ms was measured in 3.6% (8/222) of patients receiving BRAFTOVI in combination with cetuximab and mFOLFOX6. Monitor patients who already have or who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. Correct hypokalemia and hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently discontinue for QTc >500 ms. Embryo-Fetal Toxicity: BRAFTOVI can cause fetal harm when administered to pregnant women. BRAFTOVI can render hormonal contraceptives ineffective. Advise females of reproductive potential to use effective nonhormonal contraception during treatment with BRAFTOVI and for 2 weeks after the final dose. Risks Associated with Combination Treatment: BRAFTOVI is indicated for use as part of a regimen in combination with cetuximab, or in combination with cetuximab and mFOLFOX6. Refer to the prescribing information for cetuximab and individual product components of mFOLFOX6 for additional risk information. Lactation: Advise women not to breastfeed during treatment with BRAFTOVI and for 2 weeks after the final dose. Infertility: Advise males of reproductive potential that BRAFTOVI may impair fertility. ADVERSE REACTIONS BREAKWATER Trial (previously untreated BRAF V600E mutation-positive mCRC) Serious adverse reactions occurred in 38% of patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6. Serious adverse reactions in >3% of patients included intestinal obstruction (3.5%) and pyrexia (3.5%). Fatal gastrointestinal perforation occurred in 0.9% of patients who received BRAFTOVI in combination with cetuximab and mFOLFOX6. Most common adverse reactions (≥25%, all grades) in the BRAFTOVI with cetuximab and mFOLFOX6 arm compared to the control arm (mFOLFOX6 ± bevacizumab or FOLFOXIRI ± bevacizumab or CAPOX ± bevacizumab) were peripheral neuropathy (62% vs 53%), nausea (51% vs 48%), fatigue (49% vs 38%), rash (31% vs 4%), diarrhea (34% vs 47%), decreased appetite (33% vs 25%), vomiting (33% vs 21%), hemorrhage (30% vs 18%), abdominal pain (26% vs 27%), and pyrexia (26% vs 14%). Most common laboratory abnormalities (≥10%, grade 3 or 4) in the BRAFTOVI with cetuximab and mFOLFOX6 arm compared to the control arm (mFOLFOX6 ± bevacizumab or FOLFOXIRI ± bevacizumab or CAPOX ± bevacizumab) were: increased lipase (51% vs 25%), decreased neutrophil count (36% vs 34%), decreased hemoglobin (13% vs 5%), decreased white blood cell count (12% vs 7%), and increased glucose (11% vs 2%). BEACON CRC Trial (previously treated BRAF V600E mutation-positive mCRC) Most common adverse reactions (≥25%, all grades) in the BRAFTOVI with cetuximab arm compared to irinotecan with cetuximab or FOLFIRI with cetuximab (control) were: fatigue (51% vs 50%), nausea (34% vs 41%), diarrhea (33% vs 48%), dermatitis acneiform (32% vs 43%), abdominal pain (30% vs 32%), decreased appetite (27% vs 27%), arthralgia (27% vs 3%), and rash (26% vs 26%). Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI in combination with cetuximab was pancreatitis. Most common laboratory abnormalities (all grades) (≥20%) in the BRAFTOVI with cetuximab arm compared to irinotecan with cetuximab or FOLFIRI with cetuximab (control) were: anemia (34% vs 48%) and lymphopenia (24% vs 35%). DRUG INTERACTIONS Strong or moderate CYP3A4 inhibitors: Avoid coadministration of BRAFTOVI with strong or moderate CYP3A4 inhibitors, including grapefruit juice. If coadministration is unavoidable, reduce the BRAFTOVI dose. Strong CYP3A4 inducers: Avoid coadministration of BRAFTOVI with strong CYP3A4 inducers. Sensitive CYP3A4 substrates: Avoid the coadministration of BRAFTOVI with CYP3A4 substrates (including hormonal contraceptives) for which a decrease in plasma concentration may lead to reduced efficacy of the substrate. If the coadministration cannot be avoided, see the CYP3A4 substrate product labeling for recommendations. Dose reductions of drugs that are substrates of OATP1B1, OATP1B3, or BCRP may be required when used concomitantly with BRAFTOVI. Avoid coadministration of BRAFTOVI with drugs known to prolong QT/QTc interval. View the full Prescribing Information . About Pfizer Oncology At Pfizer Oncology, we are at the forefront of a new era in cancer care. Our industry-leading portfolio and extensive pipeline includes three core mechanisms of action to attack cancer from multiple angles, including small molecules, antibody-drug conjugates (ADCs), and bispecific antibodies, including other immune-oncology biologics. We are focused on delivering transformative therapies in some of the world’s most common cancers, including breast cancer, genitourinary cancer, hematology-oncology, and thoracic cancers, which includes lung cancer. Driven by science, we are committed to accelerating breakthroughs to help people with cancer live better and longer lives. About Pfizer: Breakthroughs That Change Patients’ Lives At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products, including innovative medicines and vaccines. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world’s premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For 175 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at www.Pfizer.com . In addition, to learn more, please visit us on www.Pfizer.com and follow us on X at @Pfizer and @Pfizer News , LinkedIn , YouTube and like us on Facebook at Facebook.com/Pfizer . Disclosure Notice The information contained in this release is as of January 25, 2025. Pfizer assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments. This release contains forward-looking information about the BRAFTOVI ® (encorafenib) plus cetuximab and mFOLFOX6 combination and an indication in the U.S. for the treatment of metastatic colorectal cancer (mCRC) with a BRAF V600E mutation, as detected by an FDA-approved test, including their potential benefits and discussions with other regulatory authorities to support potential future additional license applications for the BRAFTOVI combination regimen in this indication, that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risks and uncertainties include, among other things, uncertainties regarding the commercial success of BRAFTOVI plus cetuximab and mFOLFOX6; the uncertainties inherent in research and development, including the ability to meet anticipated clinical endpoints, commencement and/or completion dates for our clinical trials, regulatory submission dates, regulatory approval dates and/or launch dates, as well as the possibility of unfavorable new clinical data and further analyses of existing clinical data; whether the BREAKWATER trial will meet the primary endpoint of PFS or the secondary endpoint of OS; the risk that clinical trial data are subject to differing interpretations and assessments by regulatory authorities; whether regulatory authorities will be satisfied with the design of and results from our clinical studies; whether and when any drug applications may be filed in any additional jurisdictions for BRAFTOVI plus cetuximab and mFOLFOX6 for the treatment of patients with metastatic CRC with a BRAFV600E mutation or in any jurisdictions for any other potential indications for BRAFTOVI; whether and when any such other applications may be approved by regulatory authorities, which will depend on a myriad factors, including making a determination as to whether the product's benefits outweigh its known risks and determination of the product's efficacy and, if approved, whether BRAFTOVI plus cetuximab and mFOLFOX6 will be commercially successful; decisions by regulatory authorities impacting labeling, manufacturing processes, safety and/or other matters that could affect the availability or commercial potential of BRAFTOVI or BRAFTOVI plus cetuximab and mFOLFOX6; uncertainties regarding the impact of COVID-19 on Pfizer’s business, operations and financial results; and competitive developments. A further description of risks and uncertainties can be found in Pfizer’s Annual Report on Form 10-K for the fiscal year ended December 31, 2023, and in its subsequent reports on Form 10-Q, including in the sections thereof captioned “Risk Factors” and “ Forward-Looking Information and Factors That May Affect Future Results”, as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available at www.sec.gov and www.pfizer.com . Erbitux ® is a registered trademark of Eli Lilly and Company and Merck KGaA, Darmstadt, Germany. References American Cancer Society. Global Cancer Facts & Figures 5th Edition. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/global-cancer-facts-and-figures/global-cancer-facts-and-figures-2024.pdf . Last accessed: January 2025. American Cancer Society. Key Statistics for Colorectal Cancer. Available at: https://www.cancer.org/cancer/types/colon-rectal-cancer/about/key-statistics.html . Last accessed: January 2025. American Cancer Society. Cancer Facts & Figures 2025. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2025/2025-cancer-facts-and-figures-acs.pdf . Last accessed: January 2025. Ciardiello F, Ciardiello D, Martini G, et al . Clinical management of metastatic colorectal cancer in the era of precision medicine. CA Cancer J Clin . 2022;72:372–40. Josep Tabernero et al., The Evolving Treatment Landscape in BRAF-V600E–Mutated Metastatic Colorectal Cancer. Am Soc Clin Oncol Educ Book 42, 254-263(2022). DOI:10.1200/EDBK_349561 Safaee Ardekani G, Jafarnejad SM, Tan L, et al . The prognostic value of BRAF mutation in colorectal cancer and melanoma: a systematic review and meta-analysis. PloS ONE . 2012;7(10):e47054. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ) for Colon Cancer. V.5.2024 © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed December 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. Cervantes A, Adam R, Roselló S, et al . Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol . 2023;34(1):10–32.