U.S. FDA Accepts Supplemental New Drug Application (sNDA) and Grants Priority Review for NUBEQA® (darolutamide) in Combination with Docetaxel for Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)

• Application is being reviewed concurrently among participating international health authorities under the FDA Oncology Center of Excellence's (OCE) Project Orbis initiative

Bayer today announced the U.S. Food and Drug Administration (FDA) has accepted a supplemental New Drug Application (sNDA) and granted Priority Review for the oral androgen receptor inhibitor (ARi) NUBEQA^® (darolutamide) in combination with docetaxel for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC).

The sNDA is based on positive results from the investigational Phase III ARASENS trial demonstrating a statistically significant improvement in overall survival (OS) for NUBEQA plus androgen deprivation therapy (ADT) and docetaxel in men with mHSPC compared to ADT plus docetaxel, which were published in The New England Journal of Medicine.¹ NUBEQA is currently indicated for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC).

“Bayer remains dedicated to addressing unmet needs in prostate cancer treatment for various stages of the disease,” said Christine Roth, Member of the Executive Committee of Bayer’s Pharmaceutical Division and Head of the Oncology SBU at Bayer. “Today’s sNDA acceptance, confirmation of Priority Review and participation in Project Orbis, bring us closer to adding a new indication for NUBEQA in combination with docetaxel to benefit men with mHSPC.”

The application is being conducted under the FDA Oncology Center of Excellence's (OCE) Project Orbis initiative, which provides a framework for concurrent submission and review of cancer treatments among participating international health authorities.

Bayer recently submitted applications to the European Medicine Agency (EMA), the Ministry of Health, Labor and Welfare (MHLW) in Japan, and China’s Center of Drug Evaluation (CDE). Additional submissions in mHSPC are planned globally.

About the ARASENS Trial²

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 (a guideline recommended standard-of-care) 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 this 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), 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)³

NUBEQA is an androgen receptor inhibitor (ARi) with a distinct chemical structure that competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription.³

On July 30, 2019, the FDA approved NUBEQA^® (darolutamide) based on the ARAMIS trial, a randomized, double-blind, placebo-controlled, multi-center Phase III study, which evaluated the safety and efficacy of oral NUBEQA in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) who were receiving a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy. In the clinical study, 1,509 patients were randomized in a 2:1 ratio to receive 600 mg of NUBEQA orally twice daily in combination with androgen deprivation therapy (ADT) or ADT alone. The primary efficacy endpoint was metastasis-free survival (MFS). NUBEQA is also being investigated in further studies across various stages of prostate cancer, including in the ARANOTE Phase III trial evaluating NUBEQA plus ADT versus ADT alone for metastatic hormone-sensitive prostate cancer (mHSPC), 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.

Developed jointly by Bayer and Orion Corporation, a globally operating Finnish pharmaceutical company, NUBEQA is indicated for the treatment of men with nmCRPC.³ The approvals of NUBEQA for nmCRPC in the U.S., European Union (EU), and other global markets have been based on the pivotal Phase III ARAMIS trial data evaluating the efficacy and safety of NUBEQA plus ADT compared to ADT alone.³ Filings in other regions are underway or planned.

INDICATION FOR NUBEQA^® (darolutamide)

NUBEQA^® (darolutamide) is an androgen receptor inhibitor indicated for the treatment of patients with non-metastatic castration-resistant prostate cancer.

IMPORTANT SAFETY INFORMATION FOR NUBEQA^® (darolutamide)

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

Serious adverse reactions occurred in 25% of patients receiving NUBEQA and in 20% of patients receiving placebo. Serious adverse reactions in ≥1% of patients who received NUBEQA were urinary retention, pneumonia, and hematuria. Overall, 3.9% of patients receiving NUBEQA and 3.2% of patients receiving placebo died from adverse reactions, which included death (0.4%), cardiac failure (0.3%), cardiac arrest (0.2%), general physical health deterioration (0.2%), and pulmonary embolism (0.2%) for NUBEQA.

Adverse reactions occurring more frequently in the NUBEQA arm (≥2% over placebo) were fatigue (16% vs 11%), pain in extremity (6% vs 3%) and rash (3% vs 1%).

Clinically significant adverse reactions occurring in ≥2% of patients treated with NUBEQA included ischemic heart disease (4.0% vs 3.4% on placebo) and heart failure (2.1% vs 0.9% on placebo).

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 commonly diagnosed malignancy in men worldwide. In 2020, an estimated 1.4 million men were diagnosed with prostate cancer, and about 375,000 died from the disease worldwide.⁴

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.^5,6 Upon relapse, when the disease will metastasize or spread, the disease is hormone-sensitive and androgen deprivation therapy (ADT) is the cornerstone of treatment. Current treatment options for men with metastatic hormone-sensitive prostate cancer (mHSPC) include hormone therapy, such as ADT, androgen receptor pathway inhibitors plus ADT or a combination of docetaxel chemotherapy and ADT. Despite these treatments, a large proportion of men with mHSPC will eventually experience progression to metastatic castration-resistant prostate cancer (mCRPC), a condition with high morbidity and limited survival.^7,8

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. Its products and services are designed to help people and planet thrive by supporting efforts to master the major challenges presented by a growing and aging global population. Bayer is committed to drive sustainable development and generate 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 2021, the Group employed around 100,000 people and had sales of 44.1 billion euros. R&D expenses before special items amounted to 5.3 billion euros. For more information, go to www.bayer.com.

^© 2022 Bayer

BAYER, the Bayer Cross and NUBEQA are registered trademarks of Bayer.

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. Smith M., Hussain M., Saad F. et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med. 2022.

2. 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.

3. NUBEQA^® (darolutamide) tablets [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, January 2021.

4. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians. https://acsjournals.onlinelibrary.wiley.com/doi/epdf/10.3322/caac.21660. Accessed May 2022.

5. Cancer.Net 2020: Prostate Cancer Statistics. https://www.cancer.net/cancer-types/prostate-cancer/statistics. Accessed May 2022.

6. American Cancer Society: Hormone Therapy for Prostate Cancer. https://www.cancer.org/cancer/prostate-cancer/treating/hormone-therapy.html. Accessed May 2022.

7. Siegel DA, O’Neil ME, Richards TB, Dowling NF, Weir HK. Prostate Cancer Incidence and Survival, by Stage and Race/Ethnicity — United States, 2001–2017. MMWR Morb Mortal Wkly Rep 2020;69:1473–1480. http://dx.doi.org/10.15585/mmwr.mm6941a1.

8. Ng, K., Smith, S., Shamash, J. Metastatic Hormone-Sensitive Prostate Cancer (mHSPC): Advances and Treatment Strategies in the First-Line Setting. Oncol Ther 8, 209–230 (2020). https://doi.org/10.1007/s40487-020-00119-z.

PP-NUB-US-1668-1 5/22

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