Darolutamide (Nubeqa): Uses, Dose, Side Effect, MOA

Darolutamide is an androgen receptor inhibitor that is used in the treatment of prostate cancer. It mainly acts by blocking the action of androgens and thereby suppressing the growth of cancer cells.

In this article, we will discuss the mechanism of action, pharmacodynamics, and side effects of Darolutamide.

Drug Name: Darolutamide

Brand Name: Nubeqa

FDA Approval: 5th August 2022.

Company Name: Bayer HealthCare Pharmaceuticals

Primary Indications: Hormone-sensitive metastatic prostatic cancer

On August 5, 2022, the Food and Drug Administration said “yes” to a new medication called Darolutamide (Nubeqa, Bayer HealthCare Pharmaceuticals Inc.).

This medication can be used with another medication called docetaxel to help adult patients who have prostate cancer that has spread to other parts of their body and is sensitive to hormones.

It is recommended for patients who fail to respond to conventional therapies like surgery and hormone therapy.

It is indicated for non-metastatic castration-resistant prostate cancer (nmCRPC) to slow the progression and improve the quality of life of these patients.

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Recommended Dose of Nubeqa:

It is given in a dose of 600 mg twice daily (equivalent to two 300 mg film-coated tablets). The dose is given as two tablets of 300 mg tablet two times a day with food [Ref].

Nubeqa is usually given to patients who are also receiving a gonadotropin-releasing hormone (GnRH) analog, or those who have had a bilateral orchiectomy.

Missed doses should not be covered by taking two doses at one time. The dose can be taken as soon as the patient remembers that he has missed the dose.

Dosage modification in cases of toxicity or side effects:

Severe side effects such as Grade 3 or more can be either managed by temporarily stopping the dose or reducing the dose to 300 mg twice daily.

Once the symptoms improve, the full dose can be re-initiated. Reducing the dose to less than 300 mg twice daily is not recommended.

Dosage adjustment in kidney patients:

For patients with severe renal impairment (eGFR 15-29 mL/min/1.73 m2), the dose should be reduced to 300 mg (single tablet) twice daily.

Dosage modification in Liver disease:

For patients with moderate hepatic impairment (Child-Pugh Class B), the dose should be reduced to 300 mg twice daily.

Dosage Form and Strength:

The tablets of NUBEQA are oval-shaped and come in white to off-white colors. They have a coating on them to make them easier to swallow.

One side of the tablet has the number “300” printed on it, while the other side has the name “Bayer” written on it.

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Side effects caused by Nubeqa:

Adverse Reactions of NUBEQA and Placebo in ARAMIS Clinical Study

Drug Vs Placebo	NUBEQA	Placebo
Patients	Enrolled: unknown	Enrolled: unknown
Condition	nmCRPC	nmCRPC
Dose	600 mg twice a day	placebo
Duration	Median: 14.8 months	unknown
Serious side effects	25%	20%
Serious side effects in ≥ 1% of patients	Urinary retention, pneumonia, and hematuria	Unknown
Death due to adverse reactions	3.9%	3.2%
Adverse reactions leading to permanent discontinuation	9%	9%
Adverse reactions leading to dosage interruptions	13%	Unknown
Adverse reactions leading to dosage reductions	6%	Unknown
Most common side effects that require permanent treatment discontinuation	Cardiac failure (0.4%), and death (0.4%)	Unknown
Most common side effects require treatment interruption	Hypertension (0.6%), diarrhea (0.5%), and pneumonia (0.5%)	Unknown
The most frequent side effect requires dosage reduction	Fatigue (0.7%), hypertension (0.3%), and nausea (0.3%)	Unknown

Summary of the side effects:

The tables show the adverse reactions and laboratory abnormalities observed in patients who were treated with NUBEQA compared to those who received a placebo in the ARAMIS study.

The adverse reactions of the NUBEQA arm with a frequency of at least 2% higher than the placebo, include fatigue, pain in extremities, and rash.

On another side, the laboratory test abnormalities related to NUBEQA treatment, including decreased neutrophil count, increased AST, and increased bilirubin.

Clinically significant side effects that occurred in 2% or more of patients treated with NUBEQA included ischemic heart disease and heart failure.

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Contraindications to Darolutamide:

No contraindications are given in the FDA prescribing information.

Precautions:

Embryo-Fetal Toxicity:

The potential for NUBEQA to cause harm to the embryo or fetus has not been established for females, and therefore, the safety and efficacy of the drug have not been determined for this population.

As per the mechanism of action of NUBEQA, its administration to a pregnant female can result in fetal harm and loss of pregnancy.

Therefore, it is recommended to inform males who have female partners of reproductive potential to utilize effective contraception while undergoing NUBEQA treatment and continue using it for a week after the last dose of the drug.

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Drug interactions:

Drug Interaction	Effect on NUBEQA	Recommended Action
Combined P-gp and Strong or Moderate CYP3A4 Inducer	Decreases Darolutamide exposure	Avoid using these drugs with NUBEQA
Combined P-gp and Strong CYP3A4 Inhibitors	Increases Darolutamide exposure	Monitor patients for side effects. If required, reduce the dose.
Breast Cancer Resistance Protein (BCRP) Substrates	Increases the risk of BCRP substrate-related toxicities	Avoid using it with BCRP substrate drugs if possible; If not, monitor for side effects and reduce the dose of the BCRP substrate drug.

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Use of Nubeqa in Specific Population:

Category	Information
Pregnancy	Limited data.
Lactation	No data available
Females and Males of Reproductive Potential	Nubeqa affects fertility in males. In addition, males should use appropriate contraception during the treatment and for one week after the last dose.
Pediatric Use	Limited data.
Geriatric Use	The safety or efficacy of the drug in younger and older men is the same.
Renal Impairment	No dose adjustment is recommended in mild renal impairment. The dose should be halved to 300 mg twice daily in moderate renal impairment. No data is available on patients with ESRD on dialysis.
Hepatic Impairment	In mild hepatic impairment, the usual dose should be given. In moderate hepatic impairment, the dose should be halved. In severe hepatic impairment, data is limited. It is better to avoid.

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Mechanism of action of Darolutamide:

Darolutamide is an inhibitor of the androgen receptor (AR). Its mechanism of action involves competitive inhibition of androgen binding, AR nuclear translocation, and AR-mediated transcription.

Its major metabolite, keto-darolutamide, is as effective as the original drug.

Furthermore, Darolutamide acts as a progesterone receptor (PR) antagonist in vitro, with an activity level of approximately 1% compared to AR.

The drug reduces prostate cancer volume and cancer cell proliferation

Pharmacokinetic Parameter	Information
Route of Administration	Oral
Dose	600 mg twice daily
Steady-state	2 to 5 days

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Pharmacokinetics of Darolutamide:

Pharmacokinetics	NUBEQA (darolutamide)
Absorption	Maximum concentration: 4 hours after a single 600 mg dose. Absolute bioavailability: 30% under fasted conditions (increases by 2.0 to 2.5 times when taken with food)
Distribution	Protein binding (mainly albumin): 92% for Darolutamide and 99.8% for keto-Darolutamide.
Elimination	Half-life: 20 hours.
Metabolism	Primarily metabolized by CYP3A4, UGT1A9, and UGT1A1.
Excretion	95% is excreted within 7 days (63.4% in urine (including 7% unchanged) and 32.4% in the feces (including 30% unchanged).

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Pharmacokinetics of Darolutamide in a specific population:

Population	Pharmacokinetics
Age (48-95 years)	No significant differences observed
Race (White, Japanese, non-Japanese Asian, Black, or African American)	No significant differences observed
Renal Impairment (eGFR 30-89 mL/min/1.73m2)	No significant differences observed
Mild Hepatic Impairment	No significant differences observed
Severe Renal Impairment (eGFR 15-29 mL/min/1.73 m2) not receiving dialysis	Exposure increased by about 2.5-fold.
Moderate Hepatic Impairment (Child-Pugh Class B)	Exposure increased by about 1.9-fold.
End-stage Renal Disease (eGFR <15 mL/min/1.73 m2)	Not studied
Severe Hepatic Impairment (Child-Pugh C)	Not studied

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Darolutamide Drug Interactions:

Drug Interactions	Result
Rifampicin	Decreased mean Darolutamide AUC0-72 by 72%, and Cmax by 52%
Itraconazole	Increased mean Darolutamide AUC0-72 by 1.7-fold and Cmax by 1.4-fold
Midazolam	Decreased mean AUC and Cmax by 29% and 32% respectively with concomitant use of darolutamide
Rosuvastatin	Increased mean AUC and Cmax by approximately 5-fold with concomitant use of darolutamide
Dabigatran	No significant interactions
In vitro interactions	Darolutamide inhibits CYP2C8 and CYP2C19 at clinically relevant concentrations

Topic	Summary
Nonclinical Toxicology	Darolutamide has not been studied for its long-term effects on causing cancer in animals, but it can damage chromosomes in human blood cells. It did not cause mutations in bacteria or genotoxicity in rats’ liver and duodenum. High doses of Darolutamide damaged the reproductive organs of male rats and dogs. No studies have been done to see if Darolutamide affects fertility in animals.
Clinical Trials	In a trial with 1509 patients with nonmetastatic castration-resistant prostate cancer, Darolutamide improved metastasis-free survival compared to placebo.
Drug Supply	NUBEQA is a medicine that comes in white or off-white oval tablets marked with “300” on one side and “BAYER” on the other. It comes in bottles of 120 tablets with a National Drug Code (NDC) number of 50419-395-01.
Storage	NUBEQA should be kept in a cool and dry place between 20°C to 25°C (68°F to 77°F). It can be kept between 15°C and 30°C (59°F and 86°F) for a short time. The bottle should be tightly closed after the first time it is opened.