Capivasertib

Capivasertib is a potent, selective inhibitor of the kinase activity of all three isoforms of the serine/threonine kinase AKT (AKT1, AKT2 and AKT3). AKT is a pivotal node in the phosphatidylinositol 3-kinase (PI3K) signalling cascade, which regulates cell survival, proliferation, the cell cycle, metabolism, gene transcription and cell migration. In tumours, AKT can be switched on by upstream signalling, by mutations in AKT1, by loss of the phosphatase and tensin homologue (PTEN) and by mutations in the catalytic subunit of PI3K (PIK3CA). This is why patients are selected for treatment by testing for PIK3CA, AKT1 or PTEN alterations.

Mechanism of Action

• AKT inhibition: capivasertib blocks all three AKT isoforms and the phosphorylation of downstream AKT substrates.
• Cell lines: it reduced the growth of cell lines derived from solid tumours and haematological disease, including breast cancer lines with and without PIK3CA or AKT1 mutations or PTEN alterations.
• Breast cancer models: with fulvestrant it showed antitumour activity in a range of ER-positive patient-derived xenograft models, both with and without detectable PIK3CA, PTEN or AKT1 alterations. Alone and with fulvestrant it also slowed tumour growth in mouse xenograft models.
• Exposure and side effects: across doses of 80 to 800 mg, higher exposure was associated with more diarrhoea and rash (grade 2 to 4) and with more severe hyperglycaemia (grade 3 or 4).
• Heart rhythm: in an exposure–response analysis of 180 patients with advanced solid tumours given 80 to 800 mg, the predicted QTcF prolongation at the mean steady-state peak level after 400 mg twice daily was 3.87 ms.

Pharmacokinetics

• Absorption: capivasertib is absorbed rapidly, with peak concentrations after about 1 to 2 hours and a mean absolute bioavailability of 29%. After single doses, exposure rises in proportion to dose from 80 to 800 mg; with repeated twice-daily doses of 80 to 600 mg it rises slightly more than in proportion. On the 4-days-on, 3-days-off schedule at 400 mg twice daily, steady state (AUC 8,069 h·ng/mL, peak 1,371 ng/mL) is predicted on the 3rd and 4th dosing day of each week from week 2. On the off days, plasma levels are low (about 0.5% to 15% of the steady-state peak).
• Food: after a high-fat, high-calorie meal, AUC and peak concentration were 1.32 and 1.23 times those when fasted; after a low-fat meal, 1.14 and 1.21 times. These changes are not clinically relevant, so the tablets can be taken with or without food.
• Distribution: the mean volume of distribution was 2.6 L/kg after intravenous dosing in healthy subjects. The SmPC gives the unbound fraction in plasma as 22%, and the plasma-to-blood ratio is 0.71.
• Metabolism: mainly by CYP3A4 and UGT2B7. The major metabolite in plasma is an ether glucuronide (83% of total drug-related material); a minor oxidative metabolite accounts for 2% and capivasertib itself for 15%. No active metabolites have been identified.
• Elimination: the half-life is about 8 hours (8.3 hours). After a radiolabelled 400 mg dose, about 45% of the radioactivity was recovered in urine and about 50% in faeces. Oral clearance at steady state is about 50 L/h, and renal clearance is about 21% of the total.
• Special populations: no dose change is needed for age or for mild or moderate renal impairment. Hepatic impairment is covered under Administration and Dosage.

• Breast cancer: in combination with fulvestrant, for adults with oestrogen receptor (ER)-positive, HER2-negative locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN alterations, following recurrence or progression on or after an endocrine-based regimen.
• Pre- or perimenopausal women: capivasertib plus fulvestrant should be combined with a luteinising hormone-releasing hormone (LHRH) agonist.
• Men: giving an LHRH agonist according to current clinical practice standards should be considered.
• Biomarker selection: the PIK3CA/AKT1/PTEN alteration must be shown by a CE-marked in vitro diagnostic device with the corresponding intended purpose, or by an alternative validated test if none is available.

• Hypersensitivity to capivasertib or to any of the excipients.

The safety profile is based on 355 patients who received capivasertib plus fulvestrant in the phase III CAPItello-291 study (median exposure to capivasertib 5.4 months; 28.2% of patients exposed for 12 months or more). The most common reactions were diarrhoea (72.4%), rash (40.6%), nausea (34.6%), fatigue (32.1%), vomiting (21.4%), hyperglycaemia (19.2%), stomatitis (18.6%), headache (17.2%), decreased appetite (16.9%) and urinary tract infection (16.6%). The most common grade 3 or 4 reactions were rash (12.4%), diarrhoea (10.4%), anaemia (3.4%), hypokalaemia (2.8%), hyperglycaemia (2.5%) and stomatitis (2.3%).

Serious reactions occurred in 9% of patients, most often rash (2.3%), diarrhoea (2.5%) and vomiting (1.1%). Adverse reactions led to dose reduction in 18.9% of patients (mainly diarrhoea 8.7% and rash 4.5%) and to discontinuation in 10.4% (mainly rash 4.5%, diarrhoea 2.3% and vomiting 2%).

The frequencies below are for any grade.

Very common (≥1/10): urinary tract infection (including cystitis); anaemia; hyperglycaemia (including raised blood glucose and diabetes mellitus), decreased appetite; headache; diarrhoea, nausea, vomiting, stomatitis (including aphthous and mouth ulcers); rash (including erythematous, macular, maculopapular, papular and pruritic rash), pruritus; fatigue (including asthenia).

Common (≥1/100 to <1/10): hypersensitivity; hypokalaemia; dysgeusia, dizziness, syncope; dyspepsia, dry mouth, abdominal pain; dry skin, erythema multiforme; acute kidney injury; mucosal inflammation, pyrexia; increased blood creatinine, weight decrease, raised glycosylated haemoglobin.

Uncommon (≥1/1,000 to <1/100): diabetic ketoacidosis; drug eruption, dermatitis, generalised exfoliative dermatitis, toxic skin eruption.

Important serious reactions: severe hyperglycaemia with diabetic ketoacidosis, including fatal cases, has occurred, and in some cases ketoacidosis developed in less than 10 days. Diarrhoea can lead to dehydration, hypokalaemia and acute kidney injury, and cardiac arrhythmias have been reported (hypokalaemia is a risk factor). Severe skin reactions, including erythema multiforme and generalised exfoliative dermatitis, have been reported.

Capivasertib is metabolised mainly by CYP3A4 and UGT2B7, and in the body it is a weak, time-dependent inhibitor of CYP3A.

• Strong CYP3A4 inhibitors (for example clarithromycin, itraconazole, ketoconazole, posaconazole, voriconazole, ritonavir, cobicistat, idelalisib, ribociclib and tucatinib; the SmPC gives a longer list): they raise capivasertib exposure and the risk of toxicity. Itraconazole increased total exposure (AUC) by 95% and peak concentration by 70%. Avoid the combination; if it cannot be avoided, reduce the capivasertib dose.
• Moderate CYP3A4 inhibitors (aprepitant, ciprofloxacin, ciclosporin, diltiazem, erythromycin, fluconazole, fluvoxamine, tofisopam, verapamil): they also raise exposure, and the capivasertib dose should be reduced.
• Grapefruit and grapefruit juice: listed with the strong CYP3A4 inhibitors; avoid.
• Strong CYP3A4 inducers (carbamazepine, phenytoin, rifampicin, St John’s wort): avoid. The strong inducer enzalutamide lowered capivasertib AUC by about 40% to 50%. The SmPC also advises avoiding moderate CYP3A4 inducers, because exposure may fall.
• Metformin: capivasertib inhibits renal transporters such as OCT2 that clear metformin. Metformin is the preferred oral antidiabetic for managing capivasertib-related hyperglycaemia in studies, but when both are taken, serum creatinine is checked weekly after metformin is started for up to 3 weeks and then on day 1 of each cycle. Metformin should be given only on days when capivasertib is also taken, and withdrawn when capivasertib is withdrawn unless otherwise clinically indicated.
• Other antidiabetic medicines: they can cause hypoglycaemia on days when capivasertib is not taken, and this should be taken into account.
• Corticosteroids: regular oral steroids are a risk factor for diabetic ketoacidosis, so glucose is checked more often.
• Fulvestrant: the combination partner; see its own SmPC.

Treatment should be started and supervised by a physician experienced in anticancer medicines. Patients are selected by testing for PIK3CA/AKT1/PTEN alterations (CE-marked in vitro diagnostic device, or an alternative validated test if none is available). The tablets are taken by mouth, with or without food, and swallowed whole with water. They must not be chewed, crushed, dissolved or divided, and a tablet that is broken, cracked or otherwise not intact should not be taken.

Recommended Dose

• 400 mg (two 200 mg tablets) twice daily, about 12 hours apart (total daily dose 800 mg), for 4 days followed by 3 days off treatment each week. The tablets are taken on days 1 to 4; there is no dosing on days 5, 6 and 7.
• Fulvestrant is given with it: 500 mg on days 1, 15 and 29 and once monthly thereafter (see the fulvestrant SmPC). In pre- or perimenopausal women an LHRH agonist is added.
• Treatment continues until disease progression or unacceptable toxicity.

Dose Reductions

Treatment may be interrupted to manage adverse reactions, and the dose can be reduced up to two times, keeping the 4-days-on, 3-days-off schedule:

• Starting dose: 400 mg twice daily (two 200 mg tablets).
• First reduction: 320 mg twice daily (two 160 mg tablets).
• Second reduction: 200 mg twice daily (one 200 mg tablet).

Dose Modifications for Specific Side Effects

Grades follow NCI CTCAE.

• Hyperglycaemia, grade 1 (fasting glucose above the upper limit of normal to 160 mg/dL, or 8.9 mmol/L): no dose change; consider starting or intensifying oral antidiabetic treatment.
• Hyperglycaemia, grade 2 (above 160 to 250 mg/dL, or above 8.9 to 13.9 mmol/L): withhold capivasertib and start or intensify oral antidiabetic treatment. If glucose falls to 160 mg/dL (8.9 mmol/L) or below within 28 days, restart at the same dose; if it takes longer than 28 days, restart one dose level lower.
• Hyperglycaemia, grade 3 (above 250 to 500 mg/dL, or above 13.9 to 27.8 mmol/L): withhold, consult a diabetologist, start or intensify oral antidiabetic treatment, and consider insulin and intravenous hydration. If fasting glucose falls to 160 mg/dL (8.9 mmol/L) or below within 28 days, restart one dose level lower; if not, stop permanently.
• Hyperglycaemia, grade 4 (above 500 mg/dL, or above 27.8 mmol/L): withhold, consult a diabetologist and treat, considering insulin and intravenous hydration. If glucose falls to 500 mg/dL (27.8 mmol/L) or below within 24 hours, follow the guidance for the relevant grade; if it is still above that after 24 hours, stop permanently.
• Diarrhoea, grade 1: no dose change; start antidiarrhoeal treatment and supportive care.
• Diarrhoea, grade 2: start or intensify antidiarrhoeal treatment and monitor; if clinically indicated, interrupt for up to 28 days until grade 1 or below, then resume at the same dose or one level lower. If grade 2 diarrhoea persists or recurs, restart one level lower. Secondary prophylaxis should be considered for recurrent diarrhoea.
• Diarrhoea, grade 3: interrupt, treat and monitor. If it improves to grade 1 or below within 28 days, resume one level lower; if not, stop permanently.
• Diarrhoea, grade 4: stop permanently.
• Rash and other skin reactions, grade 1: no dose change; start emollients and consider a non-sedating oral antihistamine.
• Rash, grade 2: start or intensify a topical steroid and consider non-sedating antihistamines. If there is no improvement, interrupt, and resume at the same dose level once the rash is clinically tolerable.
• Rash, grade 3: interrupt and treat with a moderate or higher-strength topical steroid, non-sedating antihistamines and/or systemic steroids. If it improves to grade 1 or below within 28 days, restart one level lower; if not, discontinue. Consider permanent discontinuation if intolerable grade 3 or higher rash recurs.
• Rash, grade 4: stop permanently.
• Skin reactions in general: consider consulting a dermatologist at any grade. For persistent rash or a previous grade 3 rash, consider secondary prophylaxis with oral antihistamines and/or topical steroids.
• Other toxicities (apart from hyperglycaemia, diarrhoea and skin reactions): grade 1, no dose change, treat and monitor; grade 2, interrupt until grade 1 or below; grade 3, interrupt until grade 1 or below, then restart at the same dose or one level lower as clinically appropriate; grade 4, stop permanently.

With CYP3A4 Inhibitors

• Strong inhibitors: avoid. If they cannot be avoided, reduce the dose to 320 mg twice daily (total daily dose 640 mg).
• Moderate inhibitors: reduce the dose to 320 mg twice daily.
• After the inhibitor is stopped: after 3 to 5 half-lives of the inhibitor, resume the dose taken before the inhibitor was started.

Special Populations

• Elderly: no dose adjustment; data in patients aged 75 or over are limited.
• Renal impairment: no adjustment in mild or moderate impairment; not recommended in severe impairment, which has not been studied.
• Hepatic impairment: no adjustment in mild impairment. In moderate impairment, data are limited, so use only if the benefit outweighs the risk and monitor closely for toxicity. Not recommended in severe impairment, which has not been studied.
• Children and adolescents: safety and efficacy at 0 to 18 years have not been established; no data are available.

Missed or Vomited Dose

• Missed dose: it can be taken within 4 hours after the usual time. After more than 4 hours, skip it and take the next dose at the usual time. There must be at least 8 hours between doses.
• Vomiting: do not take an extra dose; take the next dose at the usual time.

Hyperglycaemia and Diabetic Ketoacidosis

• Not studied: patients with pre-existing type 1 diabetes, type 2 diabetes needing insulin, or HbA1c above 8.0% (63.9 mmol/mol) were excluded from the phase III study, so safety and efficacy in them are unknown.
• Risk: hyperglycaemia was reported in 38.1% of patients with a baseline HbA1c of 6.5% or more, against 17.8% of those with a lower value. Severe hyperglycaemia with diabetic ketoacidosis (DKA), including fatal cases, has occurred; DKA can arise at any time during treatment and in some cases developed in less than 10 days. Patients with diabetes may need intensified antidiabetic treatment and close monitoring, and consulting a diabetologist is recommended.
• Patient information: before treatment, patients are told that capivasertib can cause hyperglycaemia and to contact their healthcare professional immediately if they develop excessive thirst, pass urine more often or in larger amounts than usual, or have increased appetite with weight loss.
• Recognising DKA: dehydration, malnourishment, concurrent chemotherapy or steroids and sepsis raise the risk that hyperglycaemia progresses to DKA. Consider DKA when nonspecific symptoms appear, such as nausea, vomiting, abdominal pain, difficulty breathing, a fruity odour on the breath, confusion, unusual fatigue or sleepiness. If DKA is suspected, interrupt capivasertib immediately; if it is confirmed, stop permanently.
• Monitoring before and during treatment: fasting glucose and HbA1c are tested before starting, and glucose is optimised. After the start, fasting glucose is checked at weeks 1, 2, 4, 6 and 8 and then monthly, ideally before the dose on day 3 or 4 of the dosing week; HbA1c is checked every 3 months. Patients with diabetes monitor or self-monitor more often, daily for the first 2 weeks and then as often as needed, and have an extra HbA1c test at week 4 if they have diabetes, pre-diabetes or hyperglycaemia at baseline.
• If hyperglycaemia develops: check fasting glucose at least twice a week, on dosing and non-dosing days, until it returns to baseline. During antidiabetic treatment, check at least weekly for 2 months and then every 2 weeks or as clinically indicated. Blood ketones (preferably) and other metabolic parameters are monitored when hyperglycaemia occurs. More frequent testing is advised with diabetes, pre-diabetes, regular oral steroids, infection or other risk factors for DKA. Lifestyle counselling, including a dietitian’s advice, is recommended.

Diarrhoea

Diarrhoea occurred in most patients. Its consequences can include dehydration, hypokalaemia and acute kidney injury, and cardiac arrhythmias have been reported with hypokalaemia as a risk factor. Patients should start antidiarrhoeal treatment at the first sign of diarrhoea and drink more fluids, and normal fluid volume and electrolyte balance must be maintained.

Rash and Other Skin Reactions

Skin reactions, including erythema multiforme and generalised exfoliative dermatitis, have been reported. Patients are monitored for signs of rash or dermatitis, and early consultation with a dermatologist is recommended for accurate diagnosis and management.

Patients Not Studied

Efficacy and safety were not studied in symptomatic visceral disease. CAPItello-291 excluded patients with significant cardiac disease including QTcF above 470 msec, with factors that raise the risk of QTc prolongation, arrhythmia or impaired cardiac function, with type 1 diabetes or insulin-requiring type 2 diabetes, and with HbA1c above 8.0%. This should be borne in mind when prescribing for such patients.

Pregnancy, Breastfeeding and Fertility

• Pregnancy test: for women of childbearing potential, a pregnancy test should be done and verified as negative before treatment, and re-testing should be considered throughout treatment.
• Contraception: effective contraception is needed during treatment and for at least 4 weeks (women) or 16 weeks (men) after the last dose.
• Pregnancy: not recommended during pregnancy or in women of childbearing potential who are not using contraception. There are no data in pregnant women, and animal studies showed reproductive toxicity.
• Breastfeeding: it is not known whether capivasertib or its metabolites pass into breast milk, but exposure was confirmed in suckling rat pups, so a risk to the child cannot be excluded. Breastfeeding should be stopped during treatment.
• Fertility: there are no clinical data. In animals no adverse effect on female reproductive organs was seen, but female fertility in rats was not studied; capivasertib caused testicular toxicity and may impair fertility in men.
• The fulvestrant SmPC should be consulted for the same topics.

Sodium

The tablets contain less than 1 mmol (23 mg) of sodium per dose, that is, they are essentially sodium-free.

Effect on Driving

Capivasertib may have a minor influence on the ability to drive and use machines, because fatigue, dizziness and syncope have been reported.

Truqap tablets need no special storage conditions. They are supplied in aluminium/aluminium blisters of 16 tablets, in packs of 64 tablets (4 blisters). Keep out of the sight and reach of children.

4 years. Do not use after the expiry date on the pack.

Prescription only (Rx), under restricted medical prescription (Annex II B); treatment is started and supervised by a physician experienced in anticancer medicines. Truqap tablets are taken at home (used in combination with fulvestrant), so they are supplied to the patient or to the treating clinic on prescription. Before treatment the SmPC calls for a test showing a PIK3CA, AKT1 or PTEN alteration and for baseline fasting glucose and HbA1c, with glucose monitoring continuing during treatment.