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NUBEQA® (darolutamide) Plus Androgen Deprivation Therapy Showed a Statistically Significant Improvement in Overall Survival with Proven Efficacy and Tolerability in Men with Non-Metastatic Castration-Resistant Prostate Cancer

May 13, 2020 Off By BusinessWire

NUBEQA reduced the risk of death by 31 percent (HR=0.69, 95% CI 0.53-0.88; p=0.003) compared to placebo in its secondary endpoint of overall survival in men with non-metastatic castration-resistant prostate cancer (nmCRPC)¹
Updated results on secondary endpoints also show that NUBEQA delayed the time to pain progression, time to first initiation of treatment with cytotoxic chemotherapy, and time to first symptomatic skeletal event (SSE)¹
Any grade treatment-emergent adverse events at final analysis were generally consistent with the primary analysis of the Phase III ARAMIS trial^1,2
These data will be presented at the American Society of Clinical Oncology (ASCO) 2020 Virtual Scientific Program on Friday, May 29, and will be available on the ASCO website

Abstract: 5514

WHIPPANY, N.J.–(BUSINESS WIRE)–NUBEQA^® (darolutamide) plus androgen deprivation therapy (ADT) is shown to significantly improve overall survival (OS) compared to ADT alone, in men with non-metastatic castration-resistant prostate cancer (nmCRPC).¹ These data from the pre-specified final OS analysis of the Phase III ARAMIS trial will be presented at the American Society of Clinical Oncology (ASCO) 2020 Virtual Scientific Program, which takes place from May 29-31, 2020.

Previously published results in 1,509 patients from the Phase III ARAMIS trial demonstrated a highly significant improvement in the primary efficacy endpoint of metastasis-free survival (MFS), with a median of 40.4 months (n=955) with NUBEQA plus ADT, compared to 18.4 months (n=554) for placebo plus ADT (p<0.001); however OS data were not yet mature at the time of the MFS analysis.²MFS 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 arm (≥2 percent over placebo) were fatigue (16 percent versus 11 percent), pain in extremity (6 percent versus 3 percent) and rash (3 percent versus 1 percent).² NUBEQA was not studied in women and there is a warning and precaution for embryo-fetal toxicity.²

“Men with nmCRPC typically do not have cancer symptoms. In selecting a treatment for these patients, my goal as a clinician is to improve their overall survival while limiting side effects and drug interactions,” said Karim Fizazi, M.D., Ph.D., Professor of Medicine at the Institut Gustave Roussy, Villejuif, France. “These data add to the growing evidence for darolutamide as an effective treatment option with proven tolerability that extends patients’ lives and delays cancer symptoms.”

Final OS Analysis Presented at ASCO Virtual Scientific Program

Men receiving NUBEQA plus ADT showed a statistically significant improvement in the secondary endpoint of OS compared to ADT alone, with a 31 percent reduction in risk of death (HR=0.69, 95% CI 0.53-0.88; p=0.003).¹

With extended follow-up, any grade treatment-emergent adverse events (AEs) at final analysis were generally consistent with the primary analysis of the Phase III ARAMIS trial.^1,2 Previously, in the primary analysis, any grade AEs occurred in 83.2 percent who received NUBEQA plus ADT and 76.9 percent who received ADT alone.²Grade 3 or 4 AEs occurred in 24.7 percent who received NUBEQA plus ADT and 19.5 percent who received ADT alone.² Grade 5 AEs occurred in 3.9 percent who received NUBEQA plus ADT and 3.2 percent who received ADT alone.² Serious AEs occurred in 24.8 percent receiving NUBEQA plus ADT and in 20.0 percent receiving ADT alone.² The percentage who discontinued the trial regimen because of AEs was 8.9 percent in the NUBEQA plus ADT group and 8.7 percent in the ADT group.²

Previously, OS data were not mature at the time of MFS analysis (57 percent of the required number of events).² Secondary endpoints were evaluated in a hierarchical order, with a significance level of 0.05 split between the primary analysis and final analysis (planned to occur after 240 deaths from any cause) of secondary endpoints.^1,2 The endpoint OS was used to determine the alpha spend and significance threshold for each of the secondary endpoints.² Given the OS analysis did not meet the threshold for statistical significance, this prevented all of the secondary endpoints from meeting the criteria for statistical significance at the interim analysis.²

In the follow-up analysis of the same secondary endpoints, all were statistically significant.¹ NUBEQA plus ADT showed statistical significance in delaying time to pain progression (HR=0.65, 95% CI 0.53-0.79; p<0.001), time to first initiation of treatment with cytotoxic chemotherapy (HR=0.58, 95% CI 0.44-0.76; p<0.001) and time to first symptomatic skeletal event (SSE) (HR=0.48, 95% CI 0.29-0.82; p=0.005) versus ADT alone.¹

Time to pain progression was defined as at least a 2-point worsening from baseline of the pain score on Brief Pain Inventory-Short Form or initiation of opioids, in patients treated with NUBEQA as compared to ADT alone. Pain progression was reported in 28 percent of all patients at the interim analysis.

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 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.

Adverse reactions occurring more frequently in the NUBEQA arm (≥2 % over placebo) were fatigue (16% versus 11%), pain in extremity (6% versus 3%) and rash (3% versus 1%). NUBEQA was not studied in women and there is a warning and precaution for embryo-fetal toxicity.

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 in the U.S., European Union (EU), Australia, Brazil, Canada, and Japan 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

NUBEQA is approved for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC).³

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.⁴In 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.⁵ Prostate cancer is the fifth leading cause of death from cancer in men.⁴ Prostate cancer results from the abnormal proliferation of cells within the prostate gland, which is part of a man’s reproductive system.⁶ It mainly affects men over the age of 50, and the risk increases with age.⁷

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.⁸ However, in nearly all cases, the cancer eventually becomes resistant to conventional hormone therapy.⁹

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.^10,11About one-third of men with nmCRPC go on to develop metastases within two years.¹² In men with progressive nmCRPC, a short PSA doubling time is correlated with shortened time to first metastasis and death.¹¹

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 now expands to 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 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.

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

Fizazi, Karim; Shore, Neal; Tammela, Teuvo, et al. Overall survival (OS) results of phase III ARAMIS study of darolutamide (DARO) added to androgen deprivation therapy (ADT) for nonmetastatic castration-resistant prostate cancer (nmCRPC). American Society of Clinical Oncology (ASCO) 2020 Virtual Scientific Program; May 2020. Abstract 5514
Fizazi, Karim; Shore, Neal; Tammela, Teuvo, et al. Darolutamide in Nonmetastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2019.
NUBEQA^® (darolutamide) tablets [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, July 2019.
GLOBOCAN 2018: Estimated Cancer Incidence, Mortality and Prevalence Worldwide in 2018. Prostate Cancer. https://onlinelibrary.wiley.com/doi/epdf/10.3322/caac.21492. Accessed April 2020.
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 April 2020.
American Cancer Society. What is Prostate Cancer? https://www.cancer.org/content/dam/CRC/PDF/Public/8793.00.pdf. Accessed April 2020.
American Cancer Society. Prostate Cancer Risk Factors. https://www.cancer.org/content/dam/CRC/PDF/Public/8794.00.pdf. Accessed April 2020.
National Cancer Institute. Hormone Therapy for Prostate Cancer. https://www.cancer.gov/types/prostate/prostate-hormone-therapy-fact-sheet. Accessed April 2020.
Nakazawa, Mary; Paller, Channing; Kyprianou, Natasha. Mechanisms of Therapeutic Resistance in Prostate Cancer. Curr Oncol Rep (2017) 19:13.
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 April 2020.
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.
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