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Prostate locally advanced or metastatic apalutamide

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Drug Dose Route
Apalutamide 240 mg ONCE a day * PO

*4 x 60 mg tablets

Continuous until disease progression or unacceptable toxicity

Notes:

Androgen deprivation therapy (ADT) should be continued throughout treatment with apalutamide. 

Drug status:

Apalutamide is PBS authority opens in a new tab or window

Apalutamide is available as 60 mg tablets

Cost:
~ $3,490 per month "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, growth factor support etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Continuous treatment
Apalutamide 240 mg (PO) ONCE a day (4 x 60 mg tablets) with or without food.

Continuous until disease progression or unacceptable toxicity

Drug Dose Route
Apalutamide 240 mg ONCE a day * PO

*4 x 60 mg tablets

Continuous until disease progression or unacceptable toxicity

Notes:

Androgen deprivation therapy (ADT) should be continued throughout treatment with apalutamide. 

Drug status:

Apalutamide is PBS authority opens in a new tab or window

Apalutamide is available as 60 mg tablets

Cost:
~ $3,490 per month "How this cost is calculated"

The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes anti-cancer drugs only (not antiemetics, supportive medications or consumables), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au). These costs are reviewed and updated on eviQ at 6 monthly intervals. Anti-cancer drugs that are not included on the PBS do not have a cost included in eviQ protocols.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on a 28 day month.

Where oral drugs are available on the PBS for both 30- and 60-day prescriptions, the unit cost for the 30-day supply is used.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m2; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses and ongoing maintenance doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many anti-cancer drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, growth factor support etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Continuous treatment
Apalutamide 240 mg (PO) ONCE a day (4 x 60 mg tablets) with or without food.

Continuous until disease progression or unacceptable toxicity

Indications:

  • Metastatic castration-sensitive prostate cancer ​
    • ECOG 0-2

Cautions / Exclusions:

  • ischaemic heart disease
  • ischaemic cerebrovascular disease
  • history of seizures
  • brain metastases
  • clinically significant uncontrolled cardiovascular disease
  • uncontrolled hypertension
  • congenital long-QT syndrome
  • arterial or venous thromboembolic events
  • falls risk.

Indications:

  • Castration-resistant prostate cancer with no distant metastasis on conventional imaging
    • ECOG 0-1

Cautions / Exclusions:

  • ischaemic heart disease
  • ischaemic cerebrovascular disease
  • history of seizures
  • clinically significant uncontrolled cardiovascular disease
  • uncontrolled hypertension
  • congenital long-QT syndrome
  • arterial or venous thromboembolic events
  • falls risk.
Caution with oral anti-cancer drugs

Select links for information on the safe prescribing, dispensing and administration of orally administered anti-cancer drugs. 

Read more about at COSA guidelines for the safe prescribing, dispensing and administration of systemic cancer therapy opens in a new tab or window and oral anti-cancer therapy opens in a new tab or window
Emetogenicity MINIMAL

No antiemetics should be routinely administered before treatment in patients without a history of nausea and vomiting. If patients experience nausea and/or vomiting, consider using the low antiemetic prophylaxis regimen.
Prolongation of QT interval

This treatment may prolong the QT interval and increase the risk of cardiac arrhythmia. Use with caution in patients with a congenital long QT syndrome, patients treated with a high cumulative dose of anthracycline therapy, patients taking medications that may prolong the QT interval and those with electrolyte disturbances. Risk factors (e.g. electrolyte abnormalities) should be corrected, where possible, prior to commencement of treatment and the concurrent use of drugs that may prolong the QT interval should be avoided. Baseline and periodic monitoring of electrocardiogram (ECG) and electrolytes (potassium, magnesium, calcium) should be considered in patients at high risk of QT prolongation.

Read more about drugs that may prolong QTc interval at crediblemeds.org opens in a new tab or window (registration required).
Cardiovascular toxicity and cerebrovascular disorders

Ischaemic cardiovascular events and cerebrovascular disorders including those resulting in death have been reported with this treatment. The safety of this treatment in patients with clinically significant cardiovascular disease is unknown.

Any risk factors should be appropriately managed to mitigate risk.

Monitor for signs and symptoms of ischaemic heart disease and cerebrovascular disorders. Consider discontinuation if grade 3 or 4 toxicities occur.

Read more about cardiac toxicity associated with anti-cancer drugs
Seizure risk

Patients with a history of seizures, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous malformation or the use of concomitant medication that may lower the seizure threshold may be at increased risk of seizures with this drug. In patients experiencing seizures this medication should be permanently discontinued.

Read more about drugs that may increase the risk of seizures from the Australian Medicines Handbook (may require login)
Hypothyroidism

Thyroid dysfunction in particular hypothyroidism may occur with this treatment. Monitor for signs and symptoms of thyroid dysfunction and manage as clinically appropriate.
Fatigue

Fatigue is the most common side effect experienced with this treatment.

It is cumulative, can become severe and may require a dose reduction, interruption or change to alternative treatment.
Blood tests

FBC, EUC, eGFR, LFTs, calcium, magnesium and phosphate, TSH and lipid studies at baseline. Repeat as clinically indicated throughout treatment.
Vaccinations

Live vaccines are contraindicated in cancer patients receiving immunosuppressive therapy and/or who have poorly controlled malignant disease. Possible suboptimal response to inactivated vaccines.

For more information about vaccinations in people with cancer refer to the Australian Immunisation Handbook opens in a new tab or window.
Fertility and fathering a child

Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive potential prior to commencing treatment. It is important that all patients of reproductive potential use effective contraception whilst on therapy and after treatment finishes. Effective contraception methods and contraception timeframe should be discussed with all patients of reproductive potential.

Read more about the impact of cancer treatment on fertility opens in a new tab or window
Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the anti-cancer regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences.Suggested dose modifications are based on clinical trial findings, product information, published guidelines and reference committee consensus . The dose reduction applies to each individual dose and not to the total number of days or duration of treatment cycle unless stated otherwise. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) opens in a new tab or window unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.

Note:

  • The dose modifications below are based on a combination of the product information, and reference committee consensus.
  • For any toxicity Grade greater than or equal 3 or intolerable side effect withhold apalutamide until toxicity has resolved to Grade less than or equal 1 or baseline, resume dosing at same dose or reduced dose e.g. 180 mg or 120 mg.
  • For any treatment delay greater than 28 days due to treatment-related adverse events, apalutamide should be discontinued.
Kidney dosing recommendations 
eGFR (mL/min/1.73m2) Recommended dose
≥ 30 No dose modification necessary.
< 30 This drug has not been studied in patients with severe kidney dysfunction.
Hepatic impairment
Hepatic dysfunction
Mild or Moderate

No dose modification necessary
Severe Not studied
Diarrhoea
Grade 3 or Grade 4 Delay treatment until toxicity has resolved to Grade 1 or baseline and reduce the dose for subsequent cycles as follows:
1st occurrence: Reduce apalutamide to 180 mg
2nd occurrence: Reduce apalutamide to 120 mg
3rd occurrence: Cease apalutamide
QT prolongation
Grade 1 or 2

No dose modification necessary

Assess electrolyte and concomitant medications. Correct as appropriate.
Grade 3 Delay treatment until toxicity has resolved to Grade 1 or baseline and reduce the dose for subsequent cycles as follows:
1st occurrence: Reduce apalutamide to 180 mg
2nd occurrence: Cease apalutamide and consider alternative treatment 
Grade 4 Permanently discontinue apalutamide
Ischaemic cardiovascular disease or cerebrovascular disorders
Grade 2 Delay treatment until toxicity has resolved to Grade 1 or baseline and reduce the dose for subsequent cycles as follows:
1st occurrence: Reduce apalutamide to 180 mg
2nd occurrence: Reduce apalutamide to 120 mg
3rd occurrence: Cease apalutamide
Grade 3 or Grade 4 Permanently discontinue apalutamide
Seizures or grade 4 neurotoxicity
Permanently discontinue apalutamide

The drug interactions shown below are not an exhaustive list. For a more comprehensive list and for detailed information on specific drug interactions and clinical management, please refer to the specific drug product information and the following key resources: 

For more information see References & Disclaimer.

Apalutamide
  Interaction Clinical management
CYP2C8 inhibitors (e.g. pazopanib, lapatinib, gemfibrozil, montelukast etc.) Increased levels of apalutamide and active moieties possible due to reduced clearance. No effect expected from mild to moderate CYP2C8 inhibitors. No initial dose adjustment required. Consider reducing apalutamide dose based on tolerability.
CYP3A4 inhibitors (e.g. aprepitant, azole antifungals, clarithromycin, erythromycin, grapefruit juice, ritonavir etc.) Increased levels of apalutamide and active moieties possible due to reduced clearance. No effect expected from mild to moderate CYP3A4 inhibitors. No initial dose adjustment required. Consider reducing apalutamide dose based on tolerability.
CYP2C8 and CYP3A4 inducers (e.g. rifampin) Decreased levels of apalutamide and active moieties possible due to increased clearance.  Dose adjustment not required.
Drugs metabolised by CYP3A4 (e.g. benzodiazepines, calcineurin inhibitors, clarithromycin, dihydroergotamine, statins, ritonavir, apixaban, rivaroxaban, oxycodone, fentanyl etc.), CYP2C9 (e.g. warfarin, phenytoin etc.) or CYP2C19 (e.g. omeprazole) Decreased effect of these drugs due to induction of CYP3A4, CYP2C9 and CYP2C19 by apalutamide, resulting in increased clearance. Avoid combination or monitor for decreased effect of these drugs.
UGT substrates (e.g. estradiol, irinotecan, levothyroxine, thyroxine etc.​) Decreased effect of these drugs due to induction of UGT by apalutamide, resulting in increased clearance. Use with caution if combination cannot be avoided and monitor for decreased effect of these drugs.
P-gp (e.g. antiretrovirals, clopidogrel, digoxin, loperamide etc.), BCRP (e.g. prazosin, sulfasalazine etc.) and OATP1B1 (e.g. statins etc.) substrates Decreased effect of these drugs due to induction of P-gp, BCRP and OATP1B1 by apalutamide, resulting in increased clearance. Use with caution if combination cannot be avoided and monitor for decreased effect of these drugs.
Drugs that may prolong the QTc interval (e.g. azole antifungals, tricyclic antidepressants, antiarrhythmics etc.) Additive effect with apalutamide; may lead to torsades de pointes and cardiac arrest. Avoid combination or minimise additional risk factors (e.g. correct electrolyte imbalances) and monitor ECG for signs of cardiac arrhythmia.

eviQ provides safe and effective instructions on how to administer cancer treatments. However, eviQ does not provide every treatment delivery option, and is unable to provide a comprehensive list of cancer treatment agents and their required IV line giving set/filter or address chemical compatibilities related to IV drug preparation and administration. There may be alternative methods of treatment administration, and alternative supportive treatments that are also appropriate. Please refer to the individual product information monographs via the TGA opens in a new tab or window and Australian Injectable Drugs Handbook opens in a new tab or window websites for further information.

eviQ is currently updating the way information is presented in the administration section, if you notice any discrepancies please let us know, via feedback@eviq.org.au.

Administration

This is a continuous oral treatment

Apalutamide

  • administer orally ONCE a day
  • to be swallowed whole with a glass of water; do not break, crush or chew
  • may be taken with food or without food

​Note: If a dose is forgotten it should be taken as soon as possible on the same day with normal schedule resumed the next day. Missed doses should not be replaced; if a dose is forgotten and not taken on the same day or is vomited, normal dosing should be resumed at the next scheduled dose.

Continue safe handling precautions (reproductive risk only) for 7 days after completion of drug(s).

Discharge information

Apalutamide tablets - with written instructions on how to take them.

Patient information

Ensure patient receives protocol patient information sheet.

The side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.

Early (onset days to weeks)
Ischaemic cardiovascular and cerebrovascular disorders

Ischaemic cardiovascular and cerebrovascular events resulting in death have been associated with this treatment. Ensure optimal management of cardiovascular associated risk factors and closely monitor for signs and symptoms of ischaemic heart disease. 

Read more about cardiac toxicity associated with anti-cancer drugs
QT prolongation

This treatment can cause QTc interval prolongation. QTc prolongation can lead to ventricular arrhythmias that may be fatal.
Hypertension

High blood pressure is commonly associated with many anti-cancer drugs. Pre-existing hypertension should be controlled prior to initiation of drugs capable of causing hypertension.
Skin rash

Anti-cancer drugs can cause a number of changes in the skin with maculo-papular rash the most common type of drug-induced skin reaction. 

Read more about skin rash
Diarrhoea

Read more about treatment induced diarrhoea
Hot flushes
Arthralgia and myalgia

Generalised joint pain or and/or stiffness and muscle aches, often worse upon waking or after long periods of inactivity. Can improve with movement. May be mild or severe, intermittent or constant and accompanied by inflammation. 

Read more about arthralgia and myalgia
Fatigue

Read more about fatigue
Anorexia

Loss of appetite accompanied by decreased food intake.

Read more about anorexia
Nausea and vomiting

Late (onset weeks to months)
Seizures

Read more about drugs that may increase the risk of seizures from the Australian Medicines Handbook (may require login)
Osteoporosis
Hypothyroidism

eviQ is currently updating the way information is presented in the evidence section to improve usability, consistency and facilitate easier update and maintenance. An updated evidence template is being implemented in a staged approach, first across new protocols, then existing protocols as they are reviewed. Find out more

The evidence supporting this protocol is provided by a phase III multicentre international randomised trial TITAN, involving 1,052 patients comparing apalutamide to placebo in patients with metastatic castration-sensitive prostate cancer.1

Between December 2015 and July 2017, 525 patients were randomised to receive apalutamide 240 mg once daily and 527 patients were randomised to placebo, both groups received continuous androgen deprivation therapy (ADT) or had prior bilateral orchiectomy.

The primary end points were radiographic progression free survival (rPFS) and overall survival (OS). Secondary end points were time to the following: initiation of cytotoxic chemotherapy, pain progression, chronic opioid use and a skeletal-related event.

A statistically significant improvement was seen in OS and rPFS in patients randomised to receive apalutamide as compared with subjects randomised to receive placebo. 

Efficacy

After a median follow up of 22.7 months, rPFS at 24 months was 68.2% in the apalutamide group versus 47.5% in the placebo group (HR= 0.48; 95% CI: 0.39-0.60; P<0.0001). OS at 24 months was 82.4% versus 73.5% for the apalutamide compared to the placebo group (HR= 0.67; 95% CI: 0.51-0.89; P=0.005).1

Kaplan-Meier estimate of rPFS1

© N Engl J Med 2019

Kaplan-Meier estimate of OS1

© N Engl J Med 2019

Time to initiation of cytotoxic chemotherapy 24-month event-free rate was 91% (95% CI: 88-93) in the apalutamide group versus 78% (95% CI: 73-82) in the placebo group (HR= 0.39, P<0.0001). Time to prostate specific antigen (PSA) progression was 75% versus 36% for the apalutamide and placebo group respectively at 24 months (HR=0.26, 95% CI: 0.21-0.32). Health related quality of life (HR-QOL) data was collected using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. There was no substantial difference observed in HR-QOL between the apalutamide and placebo groups.1

Toxicity1

© N Engl J Med 2019

eviQ is currently updating the way information is presented in the evidence section to improve usability, consistency and facilitate easier update and maintenance. An updated evidence template is being implemented in a staged approach, first across new protocols, then existing protocols as they are reviewed. Find out more

The evidence supporting this protocol is provided by a phase III multicentre international randomised trial SPARTAN, involving 1,207 patients comparing apalutamide to placebo in patients with castration-resistant prostate cancer with no metastasis (on conventional imaging) and a prostate-specific antigen (PSA) doubling time of 10 months or less during continuous androgen deprivation therapy (bilateral orchiectomy or gonadotropin-releasing hormone analogue agonists or antagonists).2

Between October 2013 and December 2016, 806 patients were randomised to receive apalutamide 240 mg once daily and 401 patients were randomised to receive placebo.

The primary end point was metastasis-free survival (MFS). Secondary end points were time to metastasis, progression-free survival (PFS), time to symptomatic progression, overall survival (OS) and time to initiation of cytotoxic chemotherapy. Unblinding occurred in July 2017 due to evidence of a clinical benefit with apalutamide.

Efficacy

MFS analysis was conducted after distant metastasis or death had been observed in 378 patients. The median MFS was 40.5 months in the apalutamide group versus 16.2 months in the placebo group (HR=0.28; 95% CI: 0.23-0.35; P<0.001).2

Kaplan-Meier estimates of MFS2 

© N Engl J Med 2018

Median PFS was 40.5 months versus 14.7 months for apalutamide versus placebo respectively (HR=0.29; 95% CI: 0.24-0.36; P<0.001). Median OS was not reached in the apalutamide group, compared with 39 months in the placebo group (HR=0.70; 95% CI: 0.47-1.04; P=0.07). Median time to the initiation of cytotoxic chemotherapy was not reached in both groups.2

Kaplan-Meier estimates for secondary and exploratory end points2

© N Engl J Med 2018

Health related quality of life (HR-QOL) data was collected using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire. There was no substantial difference observed in HR-QOL between the apalutamide and placebo groups.2

Toxicity2

© New Engl J Med 2018

1
Chi, K. N., N. Agarwal, A. Bjartell, et al. 2019. "Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer." N Engl J Med 381(1):13-24.
2
Smith, M. R., F. Saad, S. Chowdhury, et al. 2018. "Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer." N Engl J Med 378(15):1408-1418.

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Version 2

Date Summary of changes
27/07/2023

Protocol updated with ADDIKD guideline recommendations. 

PDF of previous protocol.

Version number changed to V.2.
08/03/2024 Protocol reviewed electronically by Urogenital Medical Oncology Reference Committee. No update required. Next review in 2 years. 

Version 1

Date Summary of changes
22/10/2021 New protocol discussed at Medical Oncology Reference Committee Meeting.
11/11/2021 Approved and published on eviQ. Review in 1 year.
02/05/2022 Drug status updated to PBS authority for non-metastatic castration-resistant prostate cancer. Drug cost added.
19/05/2022 Nausea and vomiting added to side effects to align with other prostate anti-androgen protocols.
30/09/2022 Protocol reviewed electronically by Medical Oncology Reference Committee. no changes. Next review in 2 years.
01/06/2023 Drug status updated to reflect PBS authority for metastatic castration sensitive carcinoma of the prostate.

The information contained in this protocol is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to treatment. Any clinician (medical oncologist, haematologist, radiation oncologist, medical physicist, radiation therapist, pharmacist or nurse) seeking to apply or consult this protocol is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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https://www.eviq.org.au/p/4040

20 Jul 2025