Pharmaceuticals

ESMO 2024 Late-Breaking Data: Phase III ARANOTE Trial Shows NUBEQA® (darolutamide) Significantly Reduced Risk of Radiological Progression or Death in Metastatic Hormone-Sensitive Prostate Cancer

In the Phase III ARANOTE trial, NUBEQA® (darolutamide) plus androgen deprivation therapy (ADT) demonstrated an improvement in radiological progression-free survival (rPFS) with a 46% statistically significant reduction in the risk of progression or death (HR 0.54; 95% CI 0.41-0.71; P<0.0001) compared to placebo plus ADT
With these results, NUBEQA plus ADT now has demonstrated efficacy data in metastatic hormone-sensitive prostate cancer (mHSPC) both with and without docetaxel in the pivotal Phase III ARANOTE and ARASENS trials
Results were consistent with the established safety profile of NUBEQA with no new safety signals observed
ARANOTE results have been published simultaneously in The Journal of Clinical Oncology

Abstract: LBA68

WHIPPANY, N.J., September 16, 2024 – Results from the investigational pivotal Phase III ARANOTE trial demonstrated that NUBEQA® (darolutamide) plus androgen deprivation therapy (ADT) showed a statistically significant and clinically meaningful improvement in radiological progression-free survival (rPFS) compared to placebo plus ADT in patients with metastatic hormone-sensitive prostate cancer (mHSPC).¹ The results were presented today as a late-breaking oral presentation at the 2024 European Society for Medical Oncology (ESMO) Congress in Barcelona, Spain and published simultaneously in The Journal of Clinical Oncology.

The results were consistent with the established safety profile of NUBEQA, with no new safety signals observed. Rates of serious adverse events were similar between the treatment arms (23.6% for NUBEQA plus ADT compared to 23.5% for placebo plus ADT), while discontinuation due to treatment-emergent adverse events (TEAEs) was 6.1% in patients treated with NUBEQA plus ADT compared to 9% in patients receiving placebo plus ADT.¹

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).²

The randomized, double-blind, placebo-controlled Phase III ARANOTE trial was designed to assess the efficacy and safety of NUBEQA plus 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.¹

Each diagnosis of metastatic hormone-sensitive prostate cancer is unique, shaped by factors such as age, comorbidities and patient preferences. Each patient therefore requires a tailored treatment approach that thoughtfully addresses these key considerations. With the positive results from ARANOTE, in addition to the ARASENS data, darolutamide has now demonstrated efficacy and safety data both with and without chemotherapy in mHSPC.

Fred Saad

Professor and Chairman of Surgery and Director of Genitourinary Oncology at the University of Montreal Hospital Center (CHUM), and Principal Investigator of the ARANOTE trial

“The positive outcomes from the ARANOTE trial provide physicians with additional data that could broaden the use of NUBEQA as a treatment option for more patients with metastatic hormone-sensitive prostate cancer, which accounts for approximately 10% of prostate cancer diagnoses in the United States,” said Neal Shore, M.D., FACS, Medical Director, Carolina Urologic Research Center. “These data demonstrate the potential of this therapy to provide significant benefits to patients with mHSPC, regardless of chemotherapy use.”

“The ARANOTE trial was designed to investigate NUBEQA plus ADT compared to placebo plus ADT to provide an additional treatment option for patients with metastatic hormone-sensitive prostate cancer,” said Christian Rommel, Ph.D., Head of Research and Development at Bayer’s Pharmaceuticals Division. “Supported by our robust clinical development program, our goal is to expand the option of NUBEQA to as many patients as possible.”

Bayer plans to submit the data from the ARANOTE trial to the U.S. Food and Drug Administration (FDA) to support the expanded use of NUBEQA in patients with mHSPC.

Detailed Results from ARANOTE1
Results of the rPFS analysis were consistent across prespecified subgroups, including 40% risk reduction (HR 0.60, 95% CI: 0.44-0.80) in patients with high-volume mHSPC and 70% risk reduction (HR 0.30, 95% CI: 0.15-0.60) in patients with low-volume disease. An analysis of immature overall survival data (OS), which measures the time from treatment until death from any cause, showed an HR of 0.81 (95% CI 0.59-1.12) versus placebo plus ADT. The ARANOTE data also suggested clinical benefits across all other secondary endpoints, including delaying the time to castration-resistant prostate cancer (CRPC) (HR 0.40; 95% CI, 0.32-0.51), time to PSA progression (HR 0.31; 95% CI 0.23-0.41), time to pain progression (HR 0.72; 95% CI 0.54-0.96), and time to initiation of subsequent systemic therapy (HR 0.40; 95% CI 0.29-0.56), compared to placebo plus ADT, though not assessed for statistical significance.

Incidence rates for adverse events Grade 3 or higher were similar between the two groups (35.5% and 35.7%, respectively). The incidence of fatigue was lower with NUBEQA plus ADT than with placebo plus ADT (5.6% and 8.1%, respectively).

About the ARANOTE Trial¹
The primary endpoint of the ARANOTE trial is 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 (time to death from any cause), time to first castration-resistant event, time to initiation of subsequent anti-cancer therapy, time to prostate-specific antigen (PSA) progression, PSA undetectable rates, time to pain progression, and safety assessments.

About the ARASENS Trial³
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 overall survival (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 adverse events (AEs) as a measure of safety and tolerability.

About NUBEQA® (darolutamide)²
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.

In addition to the ARANOTE trial, darolutamide is being evaluated in a robust clinical development program, which includes studies across various stages of prostate cancer, including in the ARASTEP Phase III trial evaluating darolutamide plus ADT versus ADT alone in HSPC patients with high-risk biochemical recurrence (BCR), no evidence of metastatic disease by conventional imaging, and a positive PSMA PET/CT at baseline, as well as in the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP) led international Phase III co-operative group DASL-HiCaP (ANZUP1801) trial evaluating NUBEQA as an adjuvant treatment for localized prostate cancer with very high risk of recurrence. Information about these trials can be found at www.clinicaltrials.gov.

NUBEQA is developed jointly by Bayer and Orion Corporation, a globally operating Finnish pharmaceutical company.

INDICATIONS
NUBEQA® (darolutamide) 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 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.4 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.^5,6

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.7,8,9 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 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.

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^{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
^{1.    [Placeholder for ARANOTE reference]}
^{2.    NUBEQA (darolutamide) [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc.; October 2023.}
^{3.    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. September 2024}
^{4.    Hyuna S, et al. Ca Cancer J Clin. 2021;71:209-249.}
^{5.    Prostate Cancer: Statistic. Cancer.Net. https://www.cancer.net/cancer-types/prostate-cancer/statistics. September 2024.}
^{6.    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.}
^{7.    Piombino C, et al. Cancers (Basel). 2023;15(20):4945.}
^{8.    Helgstrand, JT et al. Cancer. 2018;124(14):2931-2938.}
^{9.    Buzzoni, C et al. Eur. Urol. 2015;68:885-890.}
^{PP-PF-ONC-US-0108-1 9/24}