U.S. FDA Approves Additional Indication of NUBEQA® (darolutamide) in Combination with Docetaxel for the Treatment of Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)

August 5, 2022

WHIPPANY, N.J.–(BUSINESS WIRE)– Bayer announced today the U.S. Food and Drug Administration (FDA) has approved a supplemental New Drug Application (sNDA) for the oral androgen receptor inhibitor (ARi) NUBEQA® (darolutamide) with docetaxel for the treatment of adult patients with metastatic hormone-sensitive prostate cancer (mHSPC).1

The approval is based on results of the Phase III ARASENS trial that demonstrated a statistically significant increase in overall survival (OS), the trial’s primary endpoint, with a reduction in the risk of death by 32% for those treated with NUBEQA plus androgen deprivation therapy (ADT) and docetaxel compared to ADT and docetaxel (HR=0.68, 95% CI 0.57-0.80; P<0.0001). Treatment with NUBEQA plus ADT and docetaxel also resulted in a statistically significant delay in time to pain progression (HR=0.79, 95% CI 0.66-0.95; P=0.006).1

The ARASENS results were presented earlier this year at the 2022 ASCO GU Cancers Symposium and simultaneously published in The New England Journal of Medicine.2 NUBEQA is also indicated for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC). NUBEQA is being investigated in further studies across various stages of prostate cancer.

Incidence of adverse reactions was similar between both study arms.Adverse
reactions reported for NUBEQA with docetaxel above 10% with a ≥2%
increase over placebo with docetaxel were constipation (23% versus 20%),
decreased appetite (19% versus 13%), rash (19% versus 15%), hemorrhage
(18% versus 13%), increased weight (18% versus 16%), and hypertension
(14% versus 9%). Serious adverse reactions occurred in 45% of patients
receiving NUBEQA with docetaxel and in 42% of patients receiving placebo
with docetaxel. Fatal adverse reactions occurred in 4% of patients
receiving NUBEQA with docetaxel and in 4% of patients receiving placebo
with docetaxel.1

“NUBEQA plus ADT and docetaxel has shown significant benefit in overall
survival and a favorable safety profile for patients with metastatic
hormone-sensitive prostate cancer,” said Matthew Smith, M.D., Ph.D.,
Director of the Genitourinary Malignancies Program, Massachusetts
General Hospital Cancer Center. “This new indication for NUBEQA is
particularly meaningful, as it highlights its proven tolerability and
provides a new option for patients.”

Prostate cancer remains the second leading cancer-related cause of death
among men in the U.S., with up to one-third of patients developing
metastatic disease.3,4 The incidence of mHSPC has increased by 72% in the U.S. over the past 10 years.5
Approximately one in three patients who are diagnosed with mHSPC
survive the disease five years or longer, with most eventually
experiencing progression to castration-resistant prostate cancer (CRPC).4,5

“With compelling data from the Phase III ARASENS and ARAMIS trials,
NUBEQA has demonstrated significant efficacy in mHSPC and nmCRPC,” said
Christine Roth, Member of the Executive Committee of Bayer’s
Pharmaceutical Division and Head of the Oncology SBU at Bayer. “The
expansion of NUBEQA’s indication to reach a broader population in the
U.S. reaffirms Bayer’s commitment to provide proven and tolerable
treatment options to eligible patients across different stages of
prostate cancer.”

“Prostate cancer is the most common cancer among men in the U.S., with
chances of survival decreasing dramatically for those diagnosed with
mHSPC compared to localized prostate cancer,” said Charles J. Ryan,
M.D., President and Chief Executive Officer, Prostate Cancer Foundation
(PCF). “This approval adds a different treatment approach for mHSPC
patients and their physicians to choose from.”

The application received Priority Review designation granted by the FDA
and was submitted under the FDA’s Real-Time Oncology Review (RTOR) pilot
program, which aims to provide a more efficient review process of
applications to ensure that safe and effective cancer treatments are
available to patients as early as possible. Ongoing reviews are also
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.

About the ARASENS Trial6

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 and docetaxel (a guideline recommended
treatment) 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 75 mg/m2 of docetaxel, for 6 cycles. Treatment
with NUBEQA plus ADT or ADT continued until symptomatic progressive
disease, change of antineoplastic therapy, unacceptable toxicity, death,
or withdrawal.

The primary endpoint of this trial was overall survival (OS). Time to pain progression was a secondary endpoint.

Permanent discontinuation of NUBEQA due to adverse reactions occurred in
14% of patients treated in the NUBEQA with docetaxel arm. The most
common adverse reactions which resulted in permanent discontinuation of
NUBEQA were rash (1.1%), musculoskeletal pain (0.9%), and increased
aspartate aminotransferase (AST) (0.9%). Dosage interruptions of NUBEQA
due to adverse reactions occurred in 23% of patients treated in the
NUBEQA with docetaxel arm. The most common adverse reactions (>2%)
requiring dosage interruption of NUBEQA were increased alanine
aminotransferase (ALT) (3.2%), increased AST (3.1%) and febrile
neutropenia (2.1%). Dosage reductions of NUBEQA due to adverse reactions
occurred in 9% of patients treated in the NUBEQA with docetaxel arm.
The most common adverse reactions (>2%) requiring dosage reduction of
NUBEQA were increased ALT (2.8%) and increased AST (2.5%). The most
common adverse reactions (≥10% with a ≥2% increase over placebo with
docetaxel) were constipation, decreased appetite, rash, hemorrhage,
increased weight, and hypertension. The most common laboratory test
abnormalities (≥30%) were anemia, hyperglycemia, decreased lymphocyte
count, decreased neutrophil count, increased AST, increased ALT, and
hypocalcemia

.

About NUBEQA® (darolutamide)

NUBEQA is an androgen receptor inhibitor (ARi) with a distinct chemical
structure that competitively inhibits androgen binding, AR nuclear
translocation, and AR-mediated transcription.1

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
adults with nmCRPC and mHSPC.1 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.1 Filings in other regions are underway or planned.

INDICATIONS

NUBEQA® (darolutamide) is an androgen receptor inhibitor indicated for the treatment of adult patients with:

  • Non-metastatic castration-resistant prostate cancer (nmCRPC)
  • Metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel

IMPORTANT SAFETY INFORMATION

Warnings & Precautions

Ischemic Heart Disease – In a study of
patients with nmCRPC (ARAMIS), ischemic heart disease occurred in 3.2%
of patients receiving NUBEQA versus 2.5% receiving placebo, including
Grade 3-4 events in 1.7% vs. 0.4%, respectively. Ischemic events led to
death in 0.3% of patients receiving NUBEQA vs. 0.2% receiving placebo.
In a study of patients with mHSPC (ARASENS), ischemic heart disease
occurred in 2.9% of patients receiving NUBEQA with docetaxel vs. 2%
receiving placebo with docetaxel, including Grade 3-4 events in 1.3% vs.
1.1%, respectively. Ischemic events led to death in 0.3% of patients
receiving NUBEQA with docetaxel vs. 0.1% receiving placebo with
docetaxel. Monitor for signs and symptoms of ischemic heart disease.
Optimize management of cardiovascular risk factors, such as
hypertension, diabetes, or dyslipidemia. Discontinue NUBEQA for Grade
3-4 ischemic heart disease.

Seizure – In ARAMIS, Grade 1-2 seizure
occurred in 0.2% of patients receiving NUBEQA vs. 0.2% receiving
placebo. Seizure occurred 261 and 456 days after initiation of NUBEQA.
In ARASENS, seizure occurred in 0.6% of patients receiving NUBEQA with
docetaxel, including one Grade 3 event, vs. 0.2% receiving placebo with
docetaxel. Seizure occurred 38 to 340 days after initiation of NUBEQA.
It is unknown whether anti-epileptic medications will prevent seizures
with NUBEQA. Advise patients of the risk of developing a seizure while
receiving NUBEQA and of engaging in any activity where sudden loss of
consciousness could cause harm to themselves or others. Consider
discontinuation of NUBEQA in patients who develop a seizure during
treatment.

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

In ARAMIS, serious adverse reactions occurred in 25% of patients
receiving NUBEQA vs. 20% of patients receiving placebo. Serious adverse
reactions in ≥1% of patients who received NUBEQA included urinary
retention, pneumonia, and hematuria. Fatal adverse reactions occurred in
3.9% of patients receiving NUBEQA vs. 3.2% of patients receiving
placebo. Fatal adverse reactions in patients who received NUBEQA
included death (0.4%), cardiac failure (0.3%), cardiac arrest (0.2%),
general physical health deterioration (0.2%), and pulmonary embolism
(0.2%). The most common adverse reactions (>2% with a ≥2% increase
over placebo), including laboratory test abnormalities, were increased
AST, decreased neutrophil count, fatigue, increased bilirubin, pain in
extremity, and rash. Clinically relevant adverse reactions occurring in
≥2% of patients treated with NUBEQA included ischemic heart disease and
heart failure.

In ARASENS, serious adverse reactions occurred in 45% of patients
receiving NUBEQA with docetaxel vs. 42% of patients receiving placebo
with docetaxel. Serious adverse reactions in ≥2% of patients who
received NUBEQA with docetaxel included febrile neutropenia (6%),
decreased neutrophil count (2.8%), musculoskeletal pain (2.6%), and
pneumonia (2.6%). Fatal adverse reactions occurred in 4% of patients
receiving NUBEQA with docetaxel vs. 4% of patients receiving placebo
with docetaxel. Fatal adverse reactions in patients who received NUBEQA
included COVID-19/COVID-19 pneumonia (0.8%), myocardial infarction
(0.3%), and sudden death (0.3%). The most common adverse reactions (≥10%
with a ≥2% increase over placebo with docetaxel) were constipation,
decreased appetite, rash, hemorrhage, increased weight, and
hypertension. The most common laboratory test abnormalities (≥30%) were
anemia, hyperglycemia, decreased lymphocyte count, decreased neutrophil
count, increased AST, increased ALT, and hypocalcemia. Clinically
relevant adverse reactions in <10% of patients who received NUBEQA
with docetaxel included fractures, ischemic heart disease, seizures, and
drug-induced liver injury.

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

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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.7

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.8,9 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.3,5

References

  1. NUBEQA® (darolutamide) tablets [Prescribing Information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, August 2022.
  2. Smith M., Hussain M., Saad F. et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med. 2022.
  3. 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.
  4. 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.
  5. Hahn AW, Higano CS, Taplin ME, Ryan CJ, Agarwal N. Metastatic
    Castration-Sensitive Prostate Cancer: Optimizing Patient Selection and
    Treatment. Am Soc Clin Oncol Educ Book. 2018 May 23;38:363-371. https://doi.org/10.1200/edbk_200967.
  6. 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.
  7. 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 August 2022.
  8. Cancer.Net 2020: Prostate Cancer Statistics. https://www.cancer.net/cancer-types/prostate-cancer/statistics. Accessed August 2022.
  9. American Cancer Society: Hormone Therapy for Prostate Cancer. https://www.cancer.org/cancer/prostate-cancer/treating/hormone-therapy.html. Accessed August 2022.