Feb 14, 2019   SOURCE: PR NewsWire

Bayer's investigational drug darolutamide plus androgen deprivation therapy (ADT) significantly extends metastasis-free survival compared to placebo plus ADT in non-metastatic castration-resistant prostate cancer

WHIPPANY, N.J., Feb. 14, 2019 /PRNewswire/ -- Results from the pivotal Phase III ARAMIS trial in patients with non-metastatic castration-resistant prostate cancer (nmCRPC) showed a statistically significant improvement in metastasis-free survival (MFS) with the investigational drug darolutamide plus androgen deprivation therapy (ADT) compared to placebo plus ADT (HR=0.41, 95% CI 0.34-0.50; P<0.001).(2) This translates to a 59 percent reduction in the risk of metastasis or death.(1) The median MFS was 40.4 months in the darolutamide arm compared with 18.4 months for the placebo arm - an overall difference in median MFS of 22 months.(1 )

The incidence of adverse events (AEs) was generally similar in the darolutamide and placebo arms; only fatigue occurred in more than 10 percent of patients (15.8 percent with darolutamide plus ADT versus 11.4 percent with placebo plus ADT).(2) The most common grade 3-4 AEs for darolutamide and placebo were 24.7 percent and 19.5 percent, respectively.(2 )Grade 3-4 AEs occurring in greater than or equal to 2 percent of patients were hypertension (3.1 percent versus 2.2 percent) and urinary retention (1.6 percent versus 2.0 percent) for darolutamide and placebo, respectively.(2)

These data were presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) in San Francisco and published simultaneously in The New England Journal of Medicine.

"These data are exciting for the prostate cancer community, as they show darolutamide's potential to treat asymptomatic nmCRPC patients and delay spread of the disease," said Karim Fizazi, M.D., Ph.D., Professor of Medicine at the Institut Gustave Roussy, University of Paris Sud, France.

"These data demonstrate that darolutamide may be an option for men with nmCRPC and can potentially fulfill an unmet need for these patients," said Matthew Smith, M.D., Ph.D., Director of the Genitourinary Malignancies Program, Massachusetts General Hospital Cancer Center.

"Bayer is working diligently to bring treatments to patients in need," said Scott Z. Fields, M.D., senior vice president and head of Oncology Development at Bayer's Pharmaceutical Division. "With the positive results of the ARAMIS trial, we are one step closer to our goal of bringing darolutamide to patients and physicians."

Bayer plans to discuss the data from the ARAMIS trial with health authorities regarding the submission of new drug applications. Bayer has been granted Fast Track designation by the U.S. Food and Drug Administration (FDA) for darolutamide in men with nmCRPC. Darolutamide is being developed jointly by Bayer and Orion Corporation, a globally operating Finnish pharmaceutical company.

Detailed study results
The ARAMIS trial also included several key secondary endpoints.(2) At the time of the first interim analysis, median OS had not yet been reached in either treatment arm.(1) However, these interim results demonstrated a trend in favor of darolutamide plus ADT (HR=0.71, 95% CI 0.50-0.99; P=0.045).(1) Median time to pain progression was 40.3 months in the darolutamide arm compared to 25.4 months in the placebo arm (HR=0.65, 95% CI 0.53-0.79; P<0.001).(1) Median time to cytotoxic chemotherapy was not reached yet in the darolutamide arm compared to 38.2 months in the placebo arm (HR=0.43, 95% CI 0.31-0.60; P<0.001).(1) Median time to first symptomatic skeletal event (SSE) was also not reached yet in either treatment arm; however, these interim results demonstrated a trend in favor of darolutamide plus ADT (HR=0.43, 95% CI 0.22-0.84; P<0.001).(1) SSE was defined as external beam radiation therapy (EBRT) to relieve skeletal symptoms, new symptomatic pathologic bone fracture, or occurrence of spinal cord compression or tumor-related orthopedic surgical intervention, whichever occurs first.(2)

Time-to-event exploratory endpoints included progression-free survival (PFS) and time to prostate-specific antigen (PSA) progression.(2) Median PFS was 36.8 months in the darolutamide arm compared to 14.8 months in the placebo arm (HR=0.38, 95% CI 0.32-0.45; P<0.001).(1) Time to PSA progression was 33.2 months in the darolutamide arm versus 7.3 months in the placebo arm (HR=0.13, 95% CI 0.11-0.16; P<0.001).(2)

Exploratory PRO-based endpoints (based on the Functional Assessment of Cancer Therapy-Prostate; FACT-P, European Organisation for Research and Treatment of Cancer quality of life; EORTC-QLQ-PR25, and EQ-5D-3L questionnaires) were also evaluated in the ARAMIS trial.(1)

About the ARAMIS trial design
The ARAMIS trial is a randomized, Phase III, multi-center, double-blind, placebo-controlled trial evaluating the safety and efficacy of oral darolutamide in patients with nmCRPC who are currently being treated with ADT as standard of care and are at high risk for developing metastatic disease. 1,509 patients were randomized in a 2:1 ratio to receive 600 mg of darolutamide twice a day or placebo along with ADT.

The primary endpoint of this trial is MFS defined as time between randomization and evidence of metastasis or death. The secondary endpoints of this trial are OS, time to pain progression, time to initiation of first cytotoxic chemotherapy, time to first SSE, and characterization of the safety and tolerability of darolutamide.

About castration-resistant prostate cancer (CRPC)
Prostate cancer is the second most commonly diagnosed malignancy in men worldwide.(3) In 2018, an estimated 1.2 million men were diagnosed with prostate cancer, and about 358,000 died from the disease worldwide.(3) 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.(4) It mainly affects men over the age of 50, and the risk increases with age.(5 )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.(6) However, in nearly all cases, the cancer eventually becomes resistant to conventional hormone therapy.(7)

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, but until recently, there have been no effective treatment options for CRPC patients who have rising PSA levels while on ADT and no detectable metastases. In men with progressive nmCRPC, a short PSA doubling time has been consistently associated with reduced time to first metastasis and death.(8)

About darolutamide
Darolutamide is an investigational, non-steroidal androgen receptor antagonist with a chemical structure that binds to the receptor and exhibits antagonistic activity, thereby inhibiting the receptor function and the growth of prostate cancer cells. In addition to the Phase III trial ARAMIS in men with nmCRPC, darolutamide is also being investigated in a Phase III study in metastatic hormone-sensitive prostate cancer (ARASENS). Information about these trials can be found at www.clinicaltrials.gov.

Darolutamide is not approved by the U.S. FDA, the European Medicines Agency or any other health authority.

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 five 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 agriculture. Its products and services are designed to benefit people and improve their quality of life. At the same time, the Group aims to create value through innovation, growth and high earning power. Bayer is committed to the principles of sustainable development and to its social and ethical responsibilities as a corporate citizen. In fiscal 2017, the Group employed around 99,800 people and had sales of EUR 35.0 billion. Capital expenditures amounted to EUR 2.4 billion, R&D expenses to EUR 4.5 billion. For more information, go to www.bayer.us.

© 2019 Bayer
BAYER and the Bayer Cross are registered trademarks of Bayer.

Media Contact:
Rose Talarico, Tel. +1 862.404.5302
E-Mail: rose.talarico@bayer.com

Forward-Looking Statement
This news release may contain forward-looking statements based on current assumptions and forecasts made by Bayer Group or subgroup 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. Fizazi, Karim; Shore, Neal; Tammela, Teuvo, et al. ARAMIS: Efficacy and
       safety of darolutamide in non-metastatic castration-resistant prostate
       cancer (nmCRPC). American Society of Clinical Oncology Genitourinary
       Cancers Symposium 2019; February 14, 2019; San Francisco, CA. Abstract
       140.
    2. Fizazi, Karim; Shore, Neal; Tammela, Teuvo, et al. Darolutamide in
       Nonmetastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2019.
    3. GLOBOCAN 2018: Estimated Cancer Incidence, Mortality and Prevalence
       Worldwide in 2018. Prostate Cancer.
       http://gco.iarc.fr/today/data/pdf/fact-sheets/cancers/cancer-fact-sheets-
       19.pdf. Accessed February 2019.
    4. American Cancer Society. What is Prostate Cancer?
       https://www.cancer.org/content/dam/CRC/PDF/Public/8793.00.pdf. Accessed
       February 2019.
    5. American Cancer Society. Prostate Cancer Risk Factors.
       https://www.cancer.org/content/dam/CRC/PDF/Public/8794.00.pdf. Accessed
       February 2019.
    6. National Cancer Institute. Hormone Therapy for Prostate Cancer.
       https://www.cancer.gov/types/prostate/prostate-hormone-therapy-fact-sheet
       . Accessed February 2019.
    7. Nakazawa, Mary; Paller, Channing; Kyprianou, Natasha.  Mechanisms of
       Therapeutic Resistance in Prostate Cancer. Curr Oncol Rep (2017) 19:13.
    8. 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.



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