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Apalutamide is a nonsteroidal antiandrogen used to treat nonmetastatic castration-resistant prostate cancer. Apalutamide is associated with a low rate of serum enzyme elevation during therapy but has not been linked to cases of clinically apparent liver injury with jaundice.
Apalutamide is a small molecule and androgen receptor (AR) antagonist with potential antineoplastic activity. Apalutamide binds to AR in target tissues thereby preventing androgen-induced receptor activation and facilitating the formation of inactive complexes that cannot be translocated to the nucleus. This prevents binding to and transcription of AR-responsive genes. This ultimately inhibits the expression of genes that regulate prostate cancer cell proliferation and may lead to an inhibition of cell growth in AR-expressing tumor cells.
Apalutamide is a potent androgen receptor (AR) antagonist that selectively binds to the ligand-binding domain of AR and blocks AR nuclear translocation or binding to androgen response elements. It has been used in trials studying the treatment of Prostate Cancer, Hepatic Impairment, Prostatic Neoplasms, Castration-Resistant Prostate Cancer, and Prostatic Neoplasms, Castration-Resistant, among others. Exerting an antitumor action, apalutamide blocks the effect of androgens that promote tumor growth. It targets the AR ligand-binding domain and prevents AR nuclear translocation, DNA binding, and transcription of AR gene targets in prostate tumors. In mice bearing human CRPC xenograft models, apalutamide treatment produced tumor regressions in a dose-dependent manner that was more effective than that of [DB01128] or [DB08899]. Unlike bicalutamide, apalutamide antagonized AR-mediated signaling in AR overexpressing human CRPC cell lines. Androgen deprivation therapy, or hormone therapy, can be used as part of maintenance therapy for patients with non-metastatic prostate cancer. Although most patients achieve therapeutic responses at the initial hormone therapy, many patients progress to non-metastatic castration-resistant (resistance to hormone therapy) prostate cancer which is the second-most common cause of cancer-related deaths in American males. Castration-resistant prostate cancer is often incurable, and poses significant clinical challenges for patients. Approximately 10 to 20 % of prostate cancer cases are castration-resistant, and up to 16% of these patients show no evidence of cancer metastasis at the time of castration-resistant diagnosis. Higher prostate-specific antigen (PSA) and shorter PSA doubling time (PSA DT) are associated with a higher risk for metastases and death. In a phase-2 multicenter open-label study, 89% of patients with non-metastatic, castration-resistant prostate cancer had ≥50% PSA decline at week 12 of apalutamide treatment. In a randomized trial, the median metastasis-free survival for patients taking apalutamide was 40.5 months compared to 16.2 months for patients taking a placebo. Apalutamide displayed good tolerability and safety profile in clinical studies. Apalutamide was approved in February 2018 by the FDA as Erleada for the treatment of patients with non-metastatic prostate cancer that is resistant to treatment with hormone therapy (castration-resistant). It is available as oral tablets. Apalutamide is the first FDA-approved treatment for non-metastatic, castration-resistant prostate cancer.
Mechanism of Action
Persistent androgen receptor (AR) signaling is a common feature of castration-resistant prostate cancer (CRPC), attributed to AR gene amplification, AR gene mutation, increased AR expression, or increased androgen biosynthesis in prostate tumors. Apalutamide is an antagonist of AR that is the binding site in the ligand-binding domain of the receptor with the IC50 of 16 nM. Upon binding, apalutamide disrupts AR signaling, inhibits DNA binding, and impedes AR-mediated gene transcription. Apalutamide impairs the translocation of AR from the cytoplasm to the nucleus thus reducing the concentrations of AR available to interact with the androgen response elements (AREs). Upon treatment with apalutamide, AR was not recruited to the DNA promoter regions. Its main metabolite, N-desmethyl apalutamide, is a less potent inhibitor of AR and exhibited one-third of the activity of apalutamide in an in vitro transcriptional reporter assay.
A small molecule and androgen receptor (AR) antagonist with potential antineoplastic activity. Apalutamide binds to AR in target tissues thereby preventing androgen-induced receptor activation and facilitating the formation of inactive complexes that cannot be translocated to the nucleus. This prevents binding to and transcription of AR-responsive genes. This ultimately inhibits the expression of genes that regulate prostate cancer cell proliferation and may lead to an inhibition of cell growth in AR-expressing tumor cells.
Indications
- Indicated for the treatment of patients with non-metastatic, castration-resistant prostate cancer (NM-CRPC).
- Erleada is indicated in adult men for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC) who are at high risk of developing metastatic disease and in adult men for the treatment of metastatic hormone-sensitive prostate cancer (HSBC) in combination with androgen deprivation therapy (ADT). Apalutamide is a nonsteroidal antiandrogen used to treat nonmetastatic castration-resistant prostate cancer. Apalutamide is associated with a low rate of serum enzyme elevation during therapy but has not been linked to cases of clinically apparent liver injury with jaundice.
- For the treatment of metastatic castration-sensitive prostate cancer (mCSPC)
- For the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC)
- Metastatic Castration Sensitive Prostate Cancer
- Non-Metastatic Castration-Resistant Prostate Cancer
Use in Cancer
Apalutamide is approved to treat:
- Prostate cancer. It is used:
- In patients whose cancer has metastasized (spread to other parts of the body) and is castrate sensitive (has responded to treatments that lower testosterone levels).
- In patients whose cancer has not metastasized and is castrate-resistant (has not responded to treatments that lower testosterone levels).
Contraindications
The following conditions are contraindicated with this drug. Check with your physician if you have any of the following:
- are allergic to apalutamide or any ingredients of the medication
- are female and are or may become pregnant
- a low supply of oxygen-rich blood to the heart
- abnormal EKG with QT changes from birth
- a disorder of the blood vessels of the brain
- pregnancy
Dosage
Strengths: 60 mg
Prostate Cancer
- 240 mg orally once a day
Oral
- 240 mg once daily. In the principal efficacy study, therapy was continued until disease progression or unacceptable toxicity occurred.
Dosage Modification for Toxicity
Oral
- If an intolerable adverse effect or grade 3 or greater toxicity occurs, interrupt therapy until symptoms improve to grade 1 or less or return to baseline; then may resume therapy with or without dosage reduction. If dosage reduction is necessary, reduce dosage to 180 or 120 mg daily.
Dose Adjustments
- If a patient experiences a Grade 3 or greater toxicity or an intolerable side effect, hold dosing until symptoms improve to G
Side Effects
The Most Common
- weakness
- tiredness
- joint pain
- muscle weakness or stiffness
- diarrhea
- nausea
- loss of appetite
- weight loss
- hot flashes
- seizures
- loss of consciousness
- swelling of the arms, legs, hands, or feet
- falling
- chest pain
- shortness of breath
- numbness or weakness of face, arm, or leg, especially on one side of the body; difficulty talking or understanding; difficulty seeing in one or both eyes; dizziness; loss of balance or coordination; or difficulty walking
- rash
- skin blistering, peeling, or redness with or without a fever
More Common
- changed sense of taste
- decreased appetite
- diarrhea
- hot flushes
- itching
- joint pain
- muscle spasms
- nausea
- skin rash
- tiredness
- weight loss
- broken bones
- falls
- high blood pressure
Rare
- signs of heart problems (e.g., fast, irregular heartbeat or pulse; chest pain; sudden weight gain; difficulty breathing; leg swelling)
- swelling of hands, ankles, or feet
- symptoms of irregular heartbeat (e.g., chest pain, dizziness, rapid, pounding heartbeat, shortness of breath)
- symptoms of scarring of the lungs (e.g., shortness of breath at rest, shortness of breath increased with activity, dry cough)
- symptoms of underactive thyroid gland (e.g., dry skin, constipation, weight gain, fatigue, aches, pains and stiffness, intolerance to cold, depression, memory problems)
- seizures
- signs of a heart attack (e.g., chest pain or pressure, pain extending through shoulder and arm, nausea and vomiting, sweating)
- signs of a severe skin reaction such as blistering, peeling, a rash covering a large area of the body, a rash that spreads quickly, or a rash combined with fever or discomfort
- signs of stroke (e.g., sudden or severe headache; sudden loss of coordination; vision changes; dizziness, sudden slurring of speech; or unexplained weakness, numbness, or pain in arm or leg)
Drug Interactions
There may be an interaction between apalutamide and any of the following:
- abiraterone
- aliskiren
- alpha-blockers (e.g., alfuzosin, doxazosin, silodosin, tamsulosin)
- antiarrhythmics (e.g., amiodarone, disopyramide, dronedarone, propafenone, quinidine)
- anticancer medications (e.g., cabazitaxel, docetaxel, doxorubicin, etoposide, ifosfamide, irinotecan, vincristine)
- anticoagulants (e.g., apixaban, clopidogrel, dabigatran, edoxaban, rivaroxaban, ticagrelor)
- antipsychotics (e.g., aripiprazole, clozapine, haloperidol, olanzapine, quetiapine, risperidone)
- aprepitant
- “azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
- benzodiazepines (e.g., chlordiazepoxide, clobazam, clonazepam, diazepam, lorazepam)
- bictegravir
- bisoprolol
- bromocriptine
- buprenorphine
- buspirone
- calcium channel blockers (e.g., amlodipine, diltiazem, felodipine, nifedipine, verapamil)
- cannabis
- clarithromycin
- clindamycin
- clonazepam
- cobicistat
- conivaptan
- corticosteroids (e.g., dexamethasone, hydrocortisone, prednisone)
- cyclosporine
- dapsone
- digoxin
- domperidone
- dronedarone
- eliglustat
- elvitegravir
- enzalutamide
- estrogens (e.g., conjugated estrogen, estradiol, ethinyl estradiol)
- eszopiclone
- everolimus
- exemestane
- fexofenadine
- flibanserin
- gemfibrozil
- “gliptin” diabetes medications (e.g., linagliptin, saxagliptin, sitagliptin)
- guanfacine
- hepatitis C antivirals (e.g., elbasvir, grazoprevir, ledipasvir, letermovir, paritaprevir, voxilaprevir)
- HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs; e.g., doravirine, efavirenz, etravirine, nevirapine, rilpivirine)
- HIV protease inhibitors (e.g., atazanavir, indinavir, ritonavir, saquinavir)
- ivabradine
- ivacaftor
- lemborexant
- lidocaine
- losartan
- lumacaftor and ivacaftor
- macitentan
- maraviroc
- mefloquine
- methadone
- midazolam
- mirtazapine
- naloxegol
- narcotic pain relievers (e.g., codeine, fentanyl, oxycodone, tramadol)
- ondansetron
- praziquantel
- progestins (e.g., dienogest, levonorgestrel, medroxyprogesterone, norethindrone)
- protein kinase inhibitors (e.g., bosutinib, dasatinib, imatinib, nilotinib, tofacitinib)
- proton pump inhibitors (e.g., esomeprazole, lansoprazole, omeprazole)
- quinine
- ranolazine
- remdesivir
- repaglinide
- rifabutin
- roflumilast
- riociguat
- romidepsin
- saxagliptin
- seizure medications (e.g., carbamazepine, oxcarbazepine, perampanel, phenobarbital, phenytoin, primidone)
- selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, escitalopram, fluoxetine, paroxetine, sertraline)
- sildenafil
- solifenacin
- “statin” anticholesterol medications (e.g., atorvastatin, lovastatin, simvastatin)
- stiripentol
- tacrolimus
- tadalafil
- tamoxifen
- thyroid replacements (e.g., desiccated thyroid, levothyroxine)
- tolvaptan
- trazodone
- triazolam
- vitamin D analogues (e.g., calcifediol, calcitriol)
- vortioxetine
- warfarin
- zolpidem
- zopiclone
Pregnancy and Lactation
Pregnancy
May cause fetal harm and potential loss of pregnancy. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)The safety and efficacy of ERLEADA have not been established in females. Based on findings from animals and its mechanism of action, ERLEADA can cause fetal harm and loss of pregnancy when administered to a pregnant female. There are no available data on ERLEADA use in pregnant women to inform a drug-associated risk. In an animal reproduction study, oral administration of apalutamide to pregnant rats during and after organogenesis resulted in fetal abnormalities and embryo-fetal lethality at maternal exposures ≥ 2 times the human clinical exposure (AUC) at the recommended dose
Lactation
Not known whether apalutamide or its metabolites are distributed into milk, affect milk production, or affect nursing infants; drug not indicated for use in women. The safety and efficacy of ERLEADA have not been established in females. There are no data on the presence of apalutamide or its metabolites in human milk, the effect on the breastfed child, or the effect on milk production
What special precautions should I follow?
Before taking apalutamide,
- tell your doctor and pharmacist if you are allergic to apalutamide, any other medications, or any of the ingredients in apalutamide tablets. Ask your pharmacist for a list of the ingredients.
- tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements and herbal products you are taking or plan to take. Be sure to mention any of the following: anticoagulants (‘blood thinners’) such as warfarin (Coumadin), fexofenadine (Allegra), gemfibrozil (Lopid), itraconazole (Onmel, Sporanox, Tolsura), ketoconazole (Nizoral), omeprazole (Prilosec, in Yosprala, Zegerid), midazolam (Nayzilam, Seizalam), rifampin (Rifadin, Rimactane, in Rifamate, in Rifater), rosuvastatin (Crestor, Ezallor). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with apalutamide, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
- tell your doctor if you have or have ever had heart problems such as a heart attack, angina (chest pain), heart failure, or hypertension or a stroke or ministroke. Also, tell your doctor if you have ever had seizures, a brain injury, a brain tumor, high cholesterol, diabetes, or osteoporosis.
- you should know that apalutamide is only for use in men. Women should not take this medication, especially if they are or may become pregnant or are breastfeeding. If taken by pregnant women, apalutamide may harm the fetus. If a pregnant woman takes apalutamide, she should call her doctor immediately.
- if your partner is pregnant, you must use a condom whenever you have sex during your treatment with apalutamide and for three months after your final dose. If your partner is not pregnant but could become pregnant, you must use a condom and another form of birth control whenever you have sex during your treatment and for 3 months after your final dose. Do not donate semen or sperm while you are taking apalutamide and for 3 months after your final dose.
- you should know that apalutamide may cause seizures. Do not drive a car or operate machinery until you know how this medication affects you.
- you should know that apalutamide may cause your muscles and bones to get weak, which may increase your risk of falling and breaking a bone.
Warnings for this medication?
Before you begin using a medication, be sure to inform your doctor of any medical conditions or allergies you may have, any medications you are taking, whether you are pregnant or breast-feeding, and any other significant facts about your health. These factors may affect how you should use this medication.
Abnormal heart rhythm: Apalutamide can cause changes to the normal rhythm of the heart, called QT prolongation. QT prolongation is a serious life-threatening condition. If you are at risk for heart rhythm problems (e.g., have heart failure, angina, low potassium or magnesium levels; have congenital long QT syndrome; or are taking medications that can prolong the QT interval, such as quinidine, procainamide, amiodarone, sotalol, flecainide), discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.
Bone health and fractures: Long-term use of anti-androgen medications such as apalutamide has been shown to cause reduced bone strength and may increase the risk of bone fractures. Apalutamide may also increase the risk of falls. If you have osteoporosis or are at increased risk of developing osteoporosis, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.
Heart disease: The risk of heart attack or heart failure is increased for people taking apalutamide. If you have a high blood pressure or a history of heart disease or risk factors for heart disease (obesity, high blood cholesterol, smoking), discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.
Seizures: There have been rare reports of seizures occurring with apalutamide in studies. The safety of using this medication if you have a seizure disorder has not been determined. If you have a history of epilepsy or medical conditions that increase the risk of seizures, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.
Stroke: Apalutamide may increase the risk of having a stroke or mini-stroke (transient ischemic attack [TIA]) caused by decreased blood flow to parts of the brain. If you have a history of either stroke or TIA, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.
If you experience symptoms of a stroke or TIA, such as confusion, difficulty speaking, loss of coordination, sudden headache, or vision changes, contact your doctor as soon as possible.
Thyroid disease: This medication may cause decreased thyroid gland function. If you have problems with your thyroid gland, apalutamide may make these problems worse. If you experience symptoms of underactive thyroid, such as unexpectedly feeling cold, depression, constipation, or fatigue, let your doctor know. If you have a history of thyroid disease, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.
References
- https://pubchem.ncbi.nlm.nih.gov/compound/Apalutamide
- https://pubchem.ncbi.nlm.nih.gov/compound/Apalutamide-COOH
- https://pubchem.ncbi.nlm.nih.gov/compound/Apalutamide-D4
- https://medlineplus.gov/druginfo/meds/a618018.html
- https://go.drugbank.com/drugs/DB11901
- https://dailymed.nlmhttps://www.drugs.com/apalutamide.html.nih.gov/dailymed/drugInfo.cfm?setid=d1cda4f7-cb33-46ea-b9ac-431f6452b1a5
- https://www.webmd.com/drugs/2/drug-174785/apalutamide-oral/details/list-contraindications
- https://www.cancer.gov/about-cancer/treatment/drugs/apalutamide
- https://www.medbroadcast.com/drug/getdrug/erleada
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Apalutamide [INN]ChemIDplus Chemical Information Classification
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Apalutamide
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CompTox Chemicals Dashboard Chemical Lists
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4-[7-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]-8-oxo-6-sulfanylidene-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide4-[7-[6-cyano-5-(trifluoromethyl)pyridin-3-yl]-8-oxo-6-sulfanylidene-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide
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ChEMBL Protein Target Tree
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NCI Thesaurus Tree
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Erleada (EMEA/H/C/004452)
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ATC Code
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PubChemPFAS and Fluorinated Compounds in PubChem
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LICENSEThe Thieme Chemistry contribution within PubChem is provided under a CC-BY-NC-ND 4.0 license, unless otherwise stated.
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Apalutamide
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apalutamide
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LICENSEAcademic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial licenseTherapeutic category of drugs in JapanUSP drug classificationAnatomical Therapeutic Chemical (ATC) classificationTarget-based classification of drugsDrug Classes
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GHS Classification Tree
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Guide to Pharmacology Target Classification
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LICENSEData: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0NORMAN Suspect List Exchange Classification
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SID 392437718
