Camizestrant

Camizestrant is an oral selective oestrogen receptor degrader (SERD) that also acts as an oestrogen receptor (ER) antagonist. Rather than only blocking the receptor, it causes oestrogen receptor alpha (ERα) to be broken down, and it acts on the receptor made from the normal ESR1 gene as well as from a mutated ESR1 gene. This is why treatment is directed at patients whose tumour has been shown to carry an ESR1 mutation.

The authorisation is based on SERENA-6, a randomised, double-blind study guided by circulating tumour DNA (ctDNA) testing. Adults with ER-positive, HER2-negative advanced breast cancer and a detectable ESR1 mutation, who had received at least 6 months of an aromatase inhibitor (letrozole or anastrozole) plus a CDK4/6 inhibitor without progression, were assigned either to switch to camizestrant plus a CDK4/6 inhibitor or to continue the aromatase inhibitor with it. In all, 315 patients were randomised 1:1 (157 to camizestrant 75 mg once daily, 158 to the aromatase inhibitor), with the CDK4/6 inhibitor and its dose unchanged in both groups (palbociclib in 75.6% of patients, ribociclib in 14.9% and abemaciclib in 9.5%). At the data cut-off of 2 January 2026, the primary endpoint, progression-free survival assessed by the investigator (RECIST v1.1), had a median of 16.76 months (95% CI 14.72 to 19.35) with camizestrant plus a CDK4/6 inhibitor against 9.23 months (95% CI 7.23 to 9.66) with the aromatase inhibitor plus a CDK4/6 inhibitor, a hazard ratio of 0.45 (95% CI 0.34 to 0.59; p-value below 0.00001). Overall survival, a key secondary endpoint, was analysed at 30% maturity and gave a hazard ratio of 0.87 (95% CI 0.57 to 1.30).

Mechanism of Action

• Binding: camizestrant binds to the ligand-binding domain of ERα and antagonises its activity.
• Degradation: binding induces proteasome-dependent degradation of ERα, so the amount of receptor in the tumour cell falls.
• No agonist effect: it does not activate (agonise) the receptor.
• Wild-type and mutant receptor: it is active against ERα encoded by both wild-type and mutated ESR1.
• Heart rhythm: in an exposure–response analysis of 30 patients given 75 to 300 mg daily as monotherapy, the predicted mean QTcI prolongation at the mean steady-state peak level on 75 mg daily was 2.99 msec (upper bound of the 90% confidence interval 6.09 msec), and a mean increase above 10 msec was not observed. Bradycardia and QTc prolongation were nevertheless reported when it was combined with CDK4/6 inhibitors (see Special Instructions).

Pharmacokinetics

• Absorption: median time to peak concentration is about 2 to 4 hours. Oral bioavailability at 75 mg is 43%, and steady state is reached by day 5 of once-daily dosing. After a high-fat meal, peak concentration and AUC were about 6% and 10% higher than when fasted (geometric mean ratios 106.2% and 109.8%), so the tablet can be taken with or without food.
• Distribution: plasma protein binding is 75.3% (24.7% free), without concentration dependence; the blood-to-plasma ratio is 0.99. The apparent volume of distribution at steady state is 26.97 L/kg (apparent peripheral volume 8.69 L/kg), showing wide distribution into tissues.
• Metabolism: camizestrant undergoes several oxidation reactions and direct N-glucuronidation, mainly through CYP3A4/5 and UGT1A4. After a radiolabelled 75 mg dose in healthy women, the main circulating materials were the N-glucuronide of camizestrant (20.1% of plasma radioactivity), the N-glucuronide of the acid metabolite (11.2%) and unchanged camizestrant (13.6%).
• Elimination: population pharmacokinetic analysis gives an apparent plasma clearance of 69.1 L/h and a terminal half-life of about 23 hours.
• Special populations: age does not call for a dose change. Because the liver metabolises camizestrant, higher exposure is expected in hepatic impairment (see Administration and Dosage).

Camizestrant is always used together with a CDK4/6 inhibitor.

• Locally advanced or metastatic breast cancer: adults with oestrogen receptor (ER)-positive, HER2-negative locally advanced or metastatic breast cancer in whom an ESR1 mutation has been detected and whose disease has not progressed during first-line endocrine therapy combined with a CDK4/6 inhibitor. The partner is palbociclib, ribociclib or abemaciclib.
• Pre- or perimenopausal women and men: camizestrant plus the CDK4/6 inhibitor is combined with a luteinising hormone-releasing hormone (LHRH) agonist or antagonist.
• Biomarker selection: the ESR1 mutation must be shown by testing plasma or a tumour sample (see Administration and Dosage).

• Breast-feeding (see Pregnancy, Breastfeeding and Fertility).
• Hypersensitivity to camizestrant or to any of the excipients.

The safety profile is based on pooled data from 263 patients who received camizestrant with a CDK4/6 inhibitor in the phase III SERENA-6 and phase I SERENA-1 studies. The most common reactions (≥15%) were neutropenia (59.7%), visual effects (40.7%), infections (38.4%), diarrhoea (21.3%), nausea (21.3%), anaemia (21.3%), fatigue (20.5%), bradycardia (19.8%) and leukopenia (15.6%). Visual effects and bradycardia are the reactions identified for camizestrant itself. Grade 3 or 4 reactions in 2% or more of patients were neutropenia (46.4%), leukopenia (9.1%), anaemia (3.4%), infections (3.4%) and raised alanine aminotransferase (2.3%).

The frequencies below are for any grade. They are based on all-cause adverse events, so some events may be due to the disease, other medicines or other causes. This list gives the main reactions; the full table, with the grade 3 or 4 frequencies, is in section 4.8 of the SmPC.

Very common (≥1/10): infections; neutropenia, anaemia, leukopenia, thrombocytopenia (blood and lymphatic system disorders); dizziness, headache (nervous system disorders); visual effects, dry eye (eye disorders); bradycardia (cardiac disorders); cough (respiratory disorders); diarrhoea, nausea, vomiting (gastrointestinal disorders); back pain (musculoskeletal and connective tissue disorders); fatigue, asthenia (general disorders).

Common (≥1/100 to <1/10): lymphopenia; decreased appetite, hypokalaemia, hypophosphataemia, hypocalcaemia; dysgeusia, syncope; deep vein thrombosis; dyspnoea; constipation, abdominal pain, stomatitis; pruritus, alopecia; pyrexia; increased aspartate and alanine aminotransferase, increased blood creatinine, prolonged QT interval on ECG.

Uncommon (≥1/1,000 to <1/100): febrile neutropenia; embolism, pulmonary embolism; torsades de pointes.

In the SmPC, “visual effects” covers photopsia, blurred vision, visual impairment, diplopia, photophobia and visual perseveration, and “bradycardia” covers bradycardia and sinus bradycardia.

Important serious reactions: serious reactions in at least 1% of patients were infections (3.4%) and pyrexia (1.1%). Bradycardia and QTc prolongation have been reported with the combination, including a non-fatal torsades de pointes in a patient with bradycardia and QTc prolongation who was taking camizestrant with ribociclib. Treatment was stopped because of neutropenia (0.4%) or QT prolongation (0.4%). Dose modifications were most often needed for infections (6.8%), neutropenia (6.5%), bradycardia (4.2%) and QT prolongation (3.4%).

Camizestrant is broken down mainly by CYP3A4/5 and UGT1A4 and is a substrate of P-glycoprotein (P-gp). It is also a reversible inhibitor of CYP3A4/5 and CYP2B6, an irreversible, time-dependent inhibitor of CYP2C9 and CYP2C19, and an inhibitor of the transporters P-gp, BCRP and OATP1B1. The SmPCs of the CDK4/6 inhibitor and of the LHRH agonist or antagonist used with it apply as well.

• Strong CYP3A4/5 inducers (carbamazepine, phenytoin, rifampicin, St John’s wort): with carbamazepine, camizestrant peak concentration and AUC fell to 0.41 and 0.29 times their usual values. Avoid the combination and consider a medicine with no or weak CYP3A4/5 induction.
• Moderate CYP3A4/5 inducers (for example bosentan, nafcillin, modafinil, phenobarbital): exposure is expected to fall. With ribociclib as the partner, no camizestrant dose adjustment is needed; with abemaciclib or palbociclib, avoid them by switching to another medicine.
• CYP3A4/5 inhibitors: the strong inhibitor itraconazole raised camizestrant peak concentration 1.37-fold and AUC 1.90-fold. When ribociclib is the partner, avoid strong CYP3A4/5 inhibitors and use caution with weak (chlorzoxazone, fosaprepitant) and moderate (aprepitant, diltiazem) inhibitors.
• CDK4/6 inhibitor partners: no clinically relevant pharmacokinetic interaction was seen with abemaciclib or palbociclib. With ribociclib, the exposure to camizestrant 75 mg rose to levels comparable to those seen with a 150 mg monotherapy dose.
• CYP2C9 and CYP2C19 substrates: camizestrant irreversibly inhibits both enzymes (laboratory and modelling data; no clinical data), so exposure to their substrates is expected to rise. Sensitive substrates (clobazam, omeprazole, pantoprazole, proguanil) and substrates with a narrow therapeutic index (phenytoin, warfarin) should be stopped at least 2 weeks before the first dose and not used for at least 2 weeks after the last dose. Moderately sensitive substrates (CYP2C9: flurbiprofen, siponimod, glibenclamide; CYP2C19: esomeprazole, voriconazole, lansoprazole) may be used with caution, but alternatives should be considered if possible.
• CYP3A4/5 substrates: camizestrant is a weak inhibitor; it roughly doubled the AUC (1.99-fold) of a sensitive CYP3A4/5 substrate in a study. Use caution with sensitive substrates (budesonide, buspirone, dronedarone, ivabradine, lurasidone, midazolam, quetiapine, sildenafil, simvastatin). Substrates with a narrow therapeutic index (alfentanil, fentanyl) may need a dose adjustment and close monitoring.
• OATP1B1, BCRP and P-gp substrates: camizestrant inhibits these transporters in laboratory studies (no clinical data) and may raise exposure to their substrates, for example glibenclamide and lovastatin (OATP1B1), rosuvastatin, sulfasalazine and sofosbuvir (BCRP), and edoxaban, digoxin, fexofenadine and dabigatran etexilate (P-gp). Sensitive substrates are allowed with caution and close monitoring; those with a narrow therapeutic index should be avoided.
• CYP2B6 substrates: sensitive substrates (bupropion, nevirapine, ketamine, cyclophosphamide) should be avoided; other CYP2B6 substrates are allowed with caution and close monitoring.
• Medicines that prolong the QT interval: avoid other medicines known to prolong the QT interval or to carry a risk of torsades de pointes (for example ciprofloxacin, levofloxacin, moxifloxacin, ondansetron, escitalopram, venlafaxine, fluconazole, chloroquine, halofantrine, clarithromycin, azithromycin, haloperidol, methadone, bepridil and pimozide). If use cannot be avoided, monitor ECGs as clinically indicated. With ribociclib, patients are monitored clinically and doses adjusted as in the ribociclib SmPC.
• Food: the tablet can be taken with or without food.

Treatment should be started and supervised by a physician experienced in anticancer medicines. The tablet is swallowed whole with water, with or without food, at about the same time each day. It must not be chewed, crushed, dissolved or divided, and a tablet that is broken, cracked or otherwise not intact should not be taken.

Patient Selection

• Patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer who are on first-line endocrine treatment are selected by testing for ESR1 mutations in plasma or in a tumour sample, collected every 3 months until a mutation has been detected.
• The test should be a CE-marked in vitro diagnostic device with the corresponding intended purpose; if none is available, an alternative validated test should be used.

Recommended Dose

• 75 mg once daily, in combination with a CDK4/6 inhibitor. The CDK4/6 inhibitor continues at the same dose as when the ESR1 mutation was detected. For the dosing of the CDK4/6 inhibitor and of the LHRH agonist or antagonist, see their own SmPCs.
• Treatment continues for as long as clinical benefit is seen or until unacceptable toxicity occurs.
• If the CDK4/6 inhibitor is permanently discontinued, camizestrant is discontinued as well.

Monitoring

• ECG: before starting, at about day 8 and day 15 of the first cycle, and then as clinically indicated. Afterwards, monitoring follows the SmPC of the CDK4/6 inhibitor. If QTc prolongation occurs, ECGs are done more often.
• With ribociclib: start treatment only if the QTcF value is below 450 msec, and check electrolytes before starting, at day 15 and as clinically indicated. Dose modifications follow the ribociclib SmPC.

Dose Adjustments for Side Effects

Treatment may be interrupted or stopped to manage adverse reactions, as set out in Table 1 of the SmPC (severity graded by NCI CTCAE version 5.0). The table covers holding, restarting and stopping treatment; it does not define a reduced dose level.

• Symptomatic bradycardia, grade 2 or higher: consider holding camizestrant while concomitant medicines known to cause bradycardia are reviewed. If none is found, withhold camizestrant until the symptoms resolve. If a contributing medicine is found, consider stopping it or changing its dose until the symptoms resolve, then restart camizestrant. Consider reassessing the heart rate after restarting, at the next clinical visit or as clinically indicated. Stop camizestrant permanently for persistent symptomatic bradycardia.
• Visual effects, grade 2 or higher (limiting instrumental activities of daily living): consider referral to an eye care professional if visual symptoms are progressive, persistent or interfere with instrumental activities of daily living. The decision on interrupting treatment rests on clinical assessment.
• Any other grade 3 or higher adverse event judged related to camizestrant: hold treatment until it resolves to grade 2 or below, then restart. Permanent discontinuation can be considered if grade 3 or higher events recur.

Special Populations

• Elderly: no dose adjustment.
• Renal impairment: no adjustment in mild or moderate impairment; not recommended in severe impairment.
• Hepatic impairment: no adjustment in mild impairment (NCI criteria). As a precaution, avoid use in moderate and severe impairment.
• 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 straight away if no more than 6 hours have passed since the usual time. After more than 6 hours, skip the dose for that day. Take the next dose at the usual time.
• Vomiting: do not take an extra dose; take the next dose at the usual time.

Bradycardia and QTc Prolongation

Bradycardia and QTc prolongation have been reported with camizestrant plus a CDK4/6 inhibitor. A non-fatal torsades de pointes occurred in a patient with bradycardia and QTc prolongation who was taking camizestrant with ribociclib. Because bradycardia can raise the risk of arrhythmia when the QTc interval is prolonged, caution is needed when camizestrant is given with agents known to prolong the QTc interval, such as ribociclib. The ECG schedule is given under Administration and Dosage, and symptomatic bradycardia of grade 2 or higher calls for holding treatment as described there.

Visual Effects

Visual effects were the most frequent reaction identified for camizestrant (40.7% in the safety pool). They are transient and affect the peripheral vision, mainly as photopsia (perceived flashes of light). Referral to an eye care professional can be considered if symptoms are progressive, persistent or interfere with instrumental activities of daily living.

Hepatic Impairment

Camizestrant is metabolised by the liver, and exposure is expected to be higher when liver function is impaired. As a precaution, use in moderate or severe hepatic impairment should be avoided. Patients with mild impairment may take it without a dose change.

Pregnancy, Breastfeeding and Fertility

• Pregnancy test: for women of childbearing potential, a pregnancy test should be performed and verified as negative before treatment starts, and re-testing should be considered during treatment.
• Contraception: women of childbearing potential and men whose partners are of childbearing potential must use effective contraception during treatment and afterwards for at least 4 weeks (women) or 1 week (men) after the last dose.
• Pregnancy: camizestrant may cause foetal harm. There are no data in pregnant women, and animal studies showed reproductive toxicity, including embryo lethality and dystocia. It should not be used in pregnancy unless the woman’s clinical condition requires it.
• Breastfeeding: contraindicated. It is not known whether camizestrant or its metabolites pass into breast milk, and a risk to the child cannot be excluded. Breastfeeding must be stopped before treatment and not resumed until 4 weeks after the last dose.
• Fertility: there are no data in humans. In mice, rats and dogs, camizestrant had marked effects on the male and female reproductive organs, and in rats it had functional effects on male and female fertility.

Sodium

The tablet contains less than 1 mmol (23 mg) of sodium, that is, it is essentially sodium-free.

Effect on Driving

Camizestrant combined with a CDK4/6 inhibitor has a minor influence on the ability to drive and use machines, because the combination may cause fatigue and dizziness. Camizestrant can also cause transient visual effects, mainly photopsia, which have no or negligible influence on driving. Patients who have these symptoms should take care when driving or operating machinery.

Etcamah tablets need no special storage conditions. They are supplied in aluminium/aluminium perforated unit-dose blisters (28 tablets in 2 blisters of 14). Keep out of the sight and reach of children.

3 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. Camizestrant is a once-daily tablet taken at home together with a CDK4/6 inhibitor, so it is supplied to the patient or to the treating clinic on prescription. Before treatment, the SmPC calls for a documented ESR1 mutation and, in women of childbearing potential, a negative pregnancy test.