On September 9, 2020 Bayer reported that The New England Journal of Medicine today published the full overall survival (OS) results from the pre-specified final OS analysis of the Phase III ARAMIS trial for NUBEQA (darolutamide) in men with non-metastatic castration-resistant prostate cancer (nmCRPC) (Press release, Bayer, SEP 9, 2020, View Source [SID1234564859]).1 These data were also presented as part of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2020 Virtual Scientific Program, held in May 2020.

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"Through ongoing research, we have established the importance of focusing treatments on extending lives and limiting side effects for men living with nmCRPC. With these encouraging darolutamide results, physicians are further armed to treat based on the multiple needs of this patient population including efficacy, delaying morbidity and treatment tolerability," said Karim Fizazi, M.D., Ph.D., Professor of Medicine at the Institut Gustave Roussy, Villejuif, France, and lead ARAMIS study investigator.

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 androgen deprivation therapy (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 (57% of the required number of events).2 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 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.

Men receiving NUBEQA plus ADT showed a statistically significant improvement in OS compared to placebo plus ADT, with a 31% reduction in risk of death (HR=0.69, 95% CI 0.53-0.88; p=0.003).1 This OS improvement was achieved despite 56% of patients (309 of 554) taking placebo receiving subsequent NUBEQA or other life-prolonging therapy after the trial was unblinded at data cut-off for final analysis (November 15, 2019), including 170 patients from the ADT group who crossed over.1

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% of all patients at the interim analysis.

With an extended follow-up of median 29 months for the overall study population, 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 In the final analysis, any grade AEs occurred in 85.7% who received NUBEQA plus ADT (primary analysis: 83.2%) and 79.2% (primary analysis: 76.9%) who received ADT alone.1,2 Grade 3 or 4 AEs occurred in 26.3% (primary analysis: 24.7%) who received NUBEQA plus ADT and 21.7% (primary analysis: 19.5%) who received ADT alone.1,2 Grade 5 AEs occurred in 4.0% (primary analysis: 3.9%) who received NUBEQA plus ADT and 3.4% (primary analysis: 3.2%) who received ADT alone.1,2 Serious AEs occurred in 26.1% (primary analysis: 24.8%) receiving NUBEQA plus ADT and in 21.8% (primary analysis: 20.0%) receiving ADT alone.1,2 Permanent discontinuation of treatment due to adverse reactions was unchanged from the primary analysis, occurring in 9% of patients in both arms of the study.1,2

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.

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), 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

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.4 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.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.10,11 About 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.