Ad Hoc Analysis of ARAMIS Showed a High Percentage (97.2%) of Men with Non-Metastatic Castration-Resistant Prostate Cancer Received Full, Planned Dosing of NUBEQA® (darolutamide)

A new ad hoc analysis from the Phase III ARAMIS trial showed 97.2% of men with non-metastatic castration-resistant prostate cancer (nmCRPC) taking NUBEQA^® (darolutamide) plus androgen deprivation therapy (ADT) received the full, planned dose of 600 mg twice daily compared to 98.4% who received ADT alone.¹ The percent of planned dose was calculated as the actual dose received (sum of dose received over total time span) over the planned dose per protocol (sum of planned dose over total time span).¹ The study also evaluated dose modifications (interruptions or delays and reductions) and incidence of permanent discontinuation due to adverse events (AEs) in both treatment arms.¹ These data were presented at the ESMO Virtual Congress 2020, held from September 19-21, 2020.

"In clinical practice, ability to maintain planned dose and schedule are important considerations," said Matthew Smith, M.D., Ph.D., Director of the Genitourinary Malignancies Program, Massachusetts General Hospital Cancer Center. "These data support darolutamide's value as a treatment option in men with nmCRPC."

Data from the Phase III ARAMIS trial of men receiving NUBEQA plus ADT were analyzed ad hoc to determine tolerability and association of prostate-specific antigen (PSA) decline in response to treatment with NUBEQA plus ADT and metastasis-free survival (MFS).¹ ARAMIS was unblinded following positive results from the primary analysis for MFS.¹ The ad hoc analyses reported here were performed on data from both the primary and final analyses of the double-blind period.¹ The median time on treatment at primary analysis was 14.8 months for NUBEQA plus ADT and 11.0 months for ADT alone; at final analysis, the median time on treatment was 18.5 months for NUBEQA plus ADT and 11.6 months for ADT alone.¹

The association between PSA decline from baseline in response to NUBEQA plus ADT treatment and MFS was evaluated using the Cox proportional hazards model.¹ 97.2% of patients received the full, planned treatment dose of NUBEQA plus ADT after a median follow-up of 14.8 months.¹ At baseline, the median [range] PSA for NUBEQA plus ADT was 9.0 [0.3?858.3] ng/mL and 9.7 [1.5?885.2] ng/mL for ADT alone.¹ Additionally, 83.6% of patients on NUBEQA plus ADT had a PSA response (?50% decrease from baseline) versus 7.6% of patients on ADT alone.¹ The median PSA decrease from baseline for NUBEQA plus ADT was 91.7% compared to 31.9% for ADT alone.¹ Most patients (approximately 95%) with a maximum PSA decrease from baseline of >90% remained metastasis-free after one year.¹

Dose modifications (interruptions or delays and reductions) were experienced by 15.2% (145/954) of patients receiving NUBEQA plus ADT compared to 9.7% (54/554) who received ADT alone.¹ Notably, most patients in both treatment arms were able to re-escalate to the full, planned dose (91.7% [133/145] versus 88.9% [48/54], respectively).¹ Permanent discontinuation due to disease progression was higher in the ADT group than in the NUBEQA plus ADT group at the primary analysis (23.3% [129/554] versus 11.7% [112/954]) and the final analysis (25.8% [143/554] versus 12.6% [120/954]).¹ Disease progression was defined as the presence of centrally confirmed metastasis, with the exception of one patient receiving NUBEQA plus ADT and three patients receiving ADT alone, in the final analysis for whom metastasis was confirmed locally at the unblinding visit.¹ The safety population excluded one patient in the NUBEQA plus ADT group who did not receive any dose of NUBEQA.¹

Data from Primary Analysis of Phase III ARAMIS Trial

At the primary analysis, 1,509 patients from the Phase III ARAMIS trial demonstrated a highly significant improvement in the primary efficacy endpoint of MFS, with a median of 40.4 months (n=955) with NUBEQA plus ADT, compared to 18.4 months (n=554) for ADT alone (p<0.001); however, overall survival (OS) data were not yet mature at the time of the MFS analysis (57% of the required number of events). MFS is defined as the time from randomization to the time of first evidence of blinded independent central review (BICR)-confirmed distant metastasis or death from any cause within 33 weeks after the last evaluable scan, whichever occurred first. Adverse reactions occurring more frequently in the NUBEQA plus ADT arm (?2% over ADT alone) were fatigue (16% versus 11%), pain in extremity (6% versus 3%) and rash (3% versus 1%). NUBEQA plus ADT was not studied in women and there is a warning and precaution for embryo-fetal toxicity.

Permanent discontinuation due to adverse reactions occurred in 9% of patients in both arms of the study. The most frequent adverse reactions requiring discontinuation in patients who received NUBEQA plus ADT included cardiac failure (0.4%) and death (0.4%). Dose interruptions due to an adverse reaction occurred in 13% of patients treated with NUBEQA plus ADT. The most frequent adverse reactions requiring dosage interruption in patients who received NUBEQA plus ADT included hypertension (0.6%), diarrhea (0.5%) and pneumonia (0.5%). Dose reductions due to an adverse reaction occurred in 6% of patients treated with NUBEQA plus ADT. The most frequent adverse reactions requiring dosage reduction in patients treated with NUBEQA plus ADT included fatigue (0.7%), hypertension (0.3%) and nausea (0.3%).

About NUBEQA^® (darolutamide)²

NUBEQA is an androgen receptor inhibitor (ARi) with a distinct chemical structure that competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription.² A Phase III study in metastatic hormone-sensitive prostate cancer (ARASENS) is ongoing. Information about this trial can be found at www.clinicaltrials.gov.

On July 30th, 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 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 or ADT alone. The primary efficacy endpoint was MFS.

Developed jointly by Bayer and Orion Corporation, a globally operating Finnish pharmaceutical company, NUBEQA is indicated for the treatment of men with nmCRPC.² The approvals of NUBEQA 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.² Filings in other regions are underway or planned.

INDICATION

NUBEQA is approved for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC).²

IMPORTANT SAFETY INFORMATION

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 ?Concomitant use of NUBEQA with a combined P-gp and strong or moderate CYP3A4 inducer decreases darolutamide exposure, which may decrease NUBEQA activity. Avoid concomitant use of NUBEQA with combined P-gp and strong or moderate CYP3A4 inducers.

Concomitant use of NUBEQA with a combined P-gp and strong CYP3A4 inhibitor increases darolutamide exposure, which may increase the risk of NUBEQA adverse reactions. Monitor patients more frequently for NUBEQA adverse reactions and modify NUBEQA dosage as needed.

Effects of NUBEQA on Other Drugs ?NUBEQA is an inhibitor of breast cancer resistance protein (BCRP) transporter. Concomitant use of NUBEQA increases the exposure (AUC) and maximal concentration of BCRP substrates, which may increase the risk of BCRP substrate-related toxicities. Avoid concomitant use with drugs that are BCRP substrates where possible. If used together, monitor patients more frequently for adverse reactions, and consider dose reduction of the BCRP substrate drug. Consult the approved product labeling of the BCRP substrate when used concomitantly with NUBEQA.

For important risk and use information about NUBEQA, please see the accompanying full Prescribing Information.

About Prostate Cancer

Prostate cancer is the second most commonly diagnosed malignancy in men worldwide.³ In 2020, about 192,000 men in the U.S. will be diagnosed with prostate cancer and an estimated 33,000 will die from the disease.⁴ Prostate cancer is the fifth leading cause of death from cancer in men.³ Prostate cancer results from the abnormal proliferation of cells within the prostate gland, which is part of a man's reproductive system.⁵ It mainly affects men over the age of 50, and the risk increases with age.⁶

Treatment options range from surgery to radiation treatment to therapy using hormone-receptor antagonists, i.e., substances that stop the formation of testosterone or prevent its effect at the target location.⁷ However, in nearly all cases, the cancer eventually becomes resistant to conventional hormone therapy.⁸

Castration-resistant prostate cancer (CRPC) is an advanced form of the disease where the cancer keeps progressing even when the amount of testosterone is reduced to very low levels in the body. The field of treatment options for castration-resistant patients is evolving rapidly for CRPC patients who have prostate cancer that has not spread to other parts of the body with rising prostate-specific antigen (PSA) levels despite a castrate testosterone level, which is called non-metastatic castration-resistant prostate cancer, or nmCRPC.^9,10 About one-third of men with nmCRPC go on to develop metastases within two years.¹¹ In men with progressive nmCRPC, a short PSA doubling time is correlated with shortened time to first metastasis and death.¹⁰

About Prostate Cancer at Bayer

Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The company has the passion and determination to develop new medicines that help extend the lives of people living with cancer. Prostate cancer is the second most commonly diagnosed cancer in men and a key area of focus for Bayer.³ The company's franchise includes two products on the market and several compounds in development, including a unique approach of advancing targeted alpha therapies. Bayer is focused on addressing the unique needs of prostate cancer patients.

About Oncology at Bayer

Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. We have the passion and determination to develop innovative medicines to help extend the lives of people living with cancer. The oncology franchise at Bayer includes six marketed products across various indications and several compounds in different stages of clinical development. A key area of focus is prostate cancer, where we have several treatments on the market or in development. Another key focus at Bayer is on shifting oncology treatment, with an approved TRK inhibitor exclusively designed to treat solid tumors that have an NTRK gene fusion, a key oncogenic driver, and another TRK inhibitor advancing through the pipeline. The company's approach to research 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 benefit people by supporting efforts to overcome the major challenges presented by a growing and aging global population. At the same time, the Group aims to increase its earning power and create value through innovation and growth. Bayer is committed to the principles of sustainable development, and the Bayer brand stands for trust, reliability and quality throughout the world. In fiscal 2019, the Group employed around 104,000 people and had sales of 43.5 billion euros. Capital expenditures amounted to 2.9 billion euros, R&D expenses to 5.3 billion euros. For more information, go to www.bayer.us.

^© 2020 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.

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References

1. Fizazi, Karim; Shore, Neal; Smith, Matthew, et al. Tolerability and treatment response to darolutamide (DARO) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) in the phase 3 ARAMIS trial. European Society of Oncology (ESMO) Congress; September 2020. Poster: 633P.
2. NUBEQA^® (darolutamide) tablets [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, July 2019.
3. GLOBOCAN 2018: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2018. Prostate Cancer. https://onlinelibrary.wiley.com/doi/epdf/10.3322/caac.21492. Accessed September 2020.
4. American Cancer Society. Cancer Facts & Figures 2020. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf. Accessed September 2020.
5. American Cancer Society. What is Prostate Cancer? https://www.cancer.org/content/dam/CRC/PDF/Public/8793.00.pdf. Accessed September 2020.
6. American Cancer Society. Prostate Cancer Risk Factors. https://www.cancer.org/content/dam/CRC/PDF/Public/8794.00.pdf. Accessed September 2020.
7. National Cancer Institute. Hormone Therapy for Prostate Cancer. https://www.cancer.gov/types/prostate/prostate-hormone-therapy-fact-sheet. Accessed September 2020.
8. Nakazawa, Mary; Paller, Channing; Kyprianou, Natasha. Mechanisms of Therapeutic Resistance in Prostate Cancer. Curr Oncol Rep (2017) 19:13.
9. Mayo Clinic. Prostate cancer screening: Should you get a PSA test? https://www.mayoclinic.org/tests-procedures/psa-test/in-depth/prostate-cancer/art-20048087. Accessed September 2020.
10. Howard, Lauren; Moreira, Daniel M; DeHoedt, Amanda; Aronson, William J., et al. Thresholds for PSA doubling time in men with non-metastatic castration-resistant prostate cancer. BJU Int 2017;120: E80-E86.
11. Kirby, Mike, Hirst, Ceri, Crawford. E. David. Characterising the castration-resistant prostate cancer population: a systematic review. Int J Clin Pract.2011;65(11):1180-1192. doi:10.1111/j.1742-1241.2011.02799

PP-NUB-US-0617-1 09/20