XYTOVA

Enzalutamide is an androgen receptor (AR) inhibitor for the treatment of castration-resistant prostate cancer (CRPC), both metastatic and non-metastatic.

It is a second-generation antiandrogen agent that the FDA approved on August 31, 2012. 8, 7 Although androgen deprivation therapy (ADT) is the first-line treatment of prostate cancer and remission can be achieved, arising resistance is inevitable, becoming castration-resistant prostate cancer.

Until recently, docetaxel is the only treatment available for metastatic CRPC; however, AR inhibitors have been developed for more targeted therapy, although first-generation AR inhibitors like bicalutamide did not substantially increase the survival rate.

Second-generation such as enzalutamide is more efficacious due to a higher affinity to AR and no partial agonist activity compared to bicalutamide. 7, 1 Due to a favorable pharmacological profile, a phase 1 study of enzalutamide was initiated in July 2007.

Compared to the average time of 10-15 years for a drug to go from pre-clinical to clinical studies, enzalutamide was developed relatively rapidly.

Enzalutamide is indicated for the treatment of castration-resistant prostate cancer, metastatic castration-sensitive prostate cancer (mCSPC), and non-metastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk for metastasis (high-risk BCR). 13, 14 It is also used in combination with talazoparib for the treatment of adult patients with HRR gene-mutated mCRPC. 12,

Enzalutamide is a second-generation antiandrogen that blocks the activity of androgen and androgen receptor (AR) in prostate cancer.

AR activity and prostate cancer progression are closely related due to the normal physiology of prostate cells, providing the rationale for androgen deprivation therapy (ADT).

However, resistance will eventually arise after the commencement of ADT in 2-3 years due to the accumulation of mutations, including constitutively active mutation, AR overexpression, and changes in AR splicing variants. 5, 1 Enzalutamide was therefore designed to exploit these mutations.

In vitro experiments in human prostate cancer cell line VCaP showed that enzalutamide can suppress cell growth and induce apoptosis while other antiandrogens like bicalutamide did not.

Clinical trials on prostate cancer patients indicated that enzalutamide can lead to a decrease in serum PSA for at least 12 weeks, although this response can be short-lived and thus resulting in enzalutamide resistance. 6, 3 Patients receiving enzalutamide also had a 37% decreased in the risk of death compared to placebo.

The median

Tmax is 1 hour (0.5-3 hours) following a single 160 mg dose of capsules and 2 hours (0.5-6 hours)

Enzalutamide achieves steady-state by Day and its AUC accumulates approximately 8.3-fold relative to a single dose.

At steady-state, the mean (%CV) maximum concentration (Cmax) for enzalutamide and N-desmethyl enzalutamide is 16.6 µg/mL (23%) and 12.7 µg/mL (30%), respectively, and the mean (%CV) minimum concentrations (Cmin) are 11.4 µg/mL (26%) and 13.0 µg/mL (30%), respectively.

The mean (%CV) volume of distribution after a single oral dose is 110 L (29%).

Enzalutamide is metabolized by

CYP2C8 is primarily responsible for the formation of the active metabolite (N-desmethyl enzalutamide). the inactive carboxylic acid metabolite.

Hover over products below to view reaction partners Enzalutamide M6 enzalutamide N-desmethyl enzalutamide Carboxyl metabolite enzalutamide (M1) Carboxyl metabolite enzalutamide (M1).

Enzalutamide is primarily eliminated by hepatic metabolism. 71% of the dose is recovered in urine (including only trace amounts of enzalutamide and N-desmethyl enzalutamide), and 14% is recovered in feces (0.4% of the dose as unchanged enzalutamide and 1% as N-desmethyl enzalutamide).

The mean terminal half-life (t1/2) for enzalutamide in patients after a single oral dose is 5.8 days (range 2.8-10.2 days).

Following a single 160 mg oral dose of enzalutamide in healthy volunteers, the mean terminal t1/2 for N-desmethyl enzalutamide is approximately 7.8-8.6 days.

The mean apparent clearance (CL/F) of enzalutamide after a single dose is 0.56 L/h (0.33-1.02 L/h).

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In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15).

Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day, and cleft palate and absent palatine bone at 30 mg/kg/day. Doses of 30 mg/kg/day caused maternal toxicity.

The doses tested in mice (1, 10, and 30 mg/kg/day) resulted in systemic exposures (AUC) of approximately 0.04, 0.4, and 1.1 times, respectively, the exposures in patients.

Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC).

In a pharmacokinetic study in pregnant rats with a single oral 30 mg/kg enzalutamide administration on gestation day 14 enzalutamide and/or its metabolites were present in the fetus at a Cmax that was approximately 0.3 times the concentration found in maternal plasma and occurred 4 hours after administration.

Based on animal studies, XTANDI may impair fertility in males of reproductive potential.

Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of XTANDI.

The most common adverse reactions (≥ 5%) are asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension.

• Take XTANDI 160 mg administered orally once daily with or without food.

• Advise patients to take each capsule or tablet whole with a sufficient amount of water to ensure that all medication is successfully swallowed.

• Patients receiving XTANDI for castration-resistant prostate cancer, or metastatic castration sensitive prostate cancer should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy.

• Patients with non-metastatic castration-sensitive prostate cancer with biochemical recurrence at high risk for metastasis may be treated with or without a GnRH analog. 2.1 Recommended Dosage The recommended dosage of XTANDI is 160 mg administered orally once daily with or without food until disease progression or unacceptable toxicity.

Advise patients to take each capsule or tablet whole with a sufficient amount of water to ensure that all medication is successfully swallowed.

Do NOT chew, dissolve, or open the capsules.

Do NOT cut, crush, or chew the tablets.

Patients with CRPC or mCSPC receiving

XTANDI should also receive a gonadotropic-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy.

Patients with nmCSPC with high-risk BCR may be treated with XTANDI with or without a GnRH analog.

For patients who receive XTANDI with or without a GnRH analog, treatment can be suspended if PSA is undetectable (< 0.2 ng/mL) after 36 weeks of therapy.

Reinitiate treatment when

PSA has increased to ≥ 2.0 ng/mL for patients who had prior radical prostatectomy or ≥ 5.0 ng/mL for patients who had prior primary radiation therapy. 2.2 Dosage Modifications for Adverse Reactions If a patient experiences a ≥ Grade 3 or an intolerable adverse reaction, withhold XTANDI for one week or until symptoms improve to ≤ Grade 2, then resume at the same or a reduced dose (120 mg or 80 mg) if warranted. 2.3 Dosage Modifications for Drug Interactions Strong CYP2C8 Inhibitors Avoid the coadministration of strong CYP2C8 inhibitors.

If the coadministration of a strong

CYP2C8 inhibitor cannot be avoided, reduce the XTANDI dosage to 80 mg once daily.

If the coadministration of the strong inhibitor is discontinued, increase the XTANDI dosage to the dosage used prior to initiation of the strong CYP2C8 inhibitor.

CYP3A4 Inducers Avoid the coadministration of strong CYP3A4 inducers.

CYP3A4 inducer cannot be avoided, increase the XTANDI dosage from 160 mg to 240 mg orally once daily.

If the coadministration of the strong

CYP3A4 inducer is discontinued, decrease the XTANDI dosage to the dosage used prior to initiation of the strong CYP3A4 inducer.

(enzalutamide) 40 mg capsules are supplied as white to off-white oblong soft gelatin capsules imprinted in black ink with ENZ and are available in the following package size:

• Bottles of 60 tablets with child resistant closures (NDC 0469-0725-60) Store XTANDI capsules and tablets at 20°C to 25°C (68°F to 77°F) in a dry place and keep the container tightly closed.

Excursions permitted from 15°C to 30°C (59°F to 86°F).

Risk Summary The safety and efficacy of XTANDI have not been established in females.

Based on animal reproductive studies and mechanism of action, XTANDI can cause fetal harm and loss of pregnancy.

There are no human data on the use of XTANDI in pregnant females.

In animal reproduction studies, oral administration of enzalutamide in pregnant mice during organogenesis caused adverse developmental effects at doses lower than the maximum recommended human dose.

In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15).

Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day, and cleft palate and absent palatine bone at 30 mg/kg/day. Doses of 30 mg/kg/day caused maternal toxicity.

The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients.

Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC).

In a pharmacokinetic study in pregnant rats with a single oral 30 mg/kg enzalutamide administration on gestation day 14, enzalutamide and/or its metabolites were present in the fetus at a C max that was approximately 0.3 times the concentration found in maternal plasma and occurred 4 hours after administration.

Safety and effectiveness of

XTANDI in pediatric patients have not been established.

Of 5110 patients who received XTANDI in eight randomized, controlled clinical trials, 78% were and over, while 33% were and over.

No overall differences in safety or effectiveness were observed between these patients and younger patients.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.