Etcamah 75 mg film-coated tablets

Etcamah in combination with a CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) is indicated for the treatment of adult patients with ER-positive, HER2-negative, locally advanced or metastatic breast cancer upon detection of ESR1‑mutation and without disease progression during first-line endocrine therapy in combination with a CDK4/6 inhibitor (for biomarker based patient-selection, see section 4.2 and 5.1).

In pre- or peri-menopausal women and in men, Etcamah plus a CDK4/6 inhibitor should be combined with a luteinizing hormone releasing hormone (LHRH) agonist or antagonist.

Treatment should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.

Patient selection

Patients with ER-positive, HER2-negative, locally advanced or metastatic breast cancer on first-line endocrine treatment should be selected for treatment based on the presence of ESR1‑mutations in plasma or tumour specimen collected every 3 months until an ESR1-mutation has been detected, and which should be assessed by a CE-marked in vitro diagnostic (IVD) medical device with the corresponding intended purpose (see section 5.1). If a CE-marked IVD is not available, an alternative validated test should be used.

Posology

The recommended dose of Etcamah in combination with a CDK4/6 inhibitor is 75 mg once daily. The CDK4/6 inhibitor should be continued at the same dose at the time of initiation with Etcamah as when the ESR1m was detected.

Please also refer to the summary of product characteristics (SmPC) of the CDK4/6 inhibitor or LHRH agonist or antagonist for the recommended dosing information. If the CDK4/6 inhibitor is permanently discontinued, Etcamah should also be discontinued.

Treatment duration

Treatment with Etcamah should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.

Missed dose

If a dose of Etcamah is missed, it can be taken immediately within 6 hours after the time it is usually taken. After more than 6 hours, the dose should be skipped for that day. The next dose of Etcamah should be taken at the usual time.

Vomiting

If the patient vomits, an additional dose should not be taken. The next dose of Etcamah should be taken at the usual time.

Monitoring for Etcamah in combination with CDK4/6 inhibitors

For the combination of Etcamah with a CDK4/6 inhibitor, ECG should be assessed before initiating treatment, at approximately day 8 and day 15 of the first cycle, and then as clinically indicated. Thereafter, monitoring during combination treatment should be performed according to the recommendations in the SmPC of the co-administered CDK4/6 inhibitor. In case of QTc prolongation during treatment, more frequent ECG monitoring is recommended.

In addition, for the combination of Etcamah with ribociclib, treatment should be initiated only in patients with QTcF values less than 450 msec, and analysis of electrolytes should be performed before initiating combination treatment, at day 15 and as clinically indicated. Refer to the ribociclib SmPC for dose modification guidelines and other relevant safety information.

Dose adjustments

Treatment with Etcamah may be temporarily interrupted and/or discontinued to manage adverse reactions per dose modification guideline provided in Table 1.

Table 1 Recommended dose modification for Etcamah

ADL = Activities of daily living; AE = Adverse Event; CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute.

a. Bradycardia includes bradycardia and sinus bradycardia.

b. Visual effects include photopsia, vision blurred, visual impairment, diplopia, and photophobia of eye disorders MedDRA SOC, and visual perseveration of nervous system disorders MedDRA SOC.

No clinically relevant pharmacokinetic interaction was observed when camizestrant was co-administered with abemaciclib or palbociclib. When camizestrant 75 mg was administered in combination with ribociclib, camizestrant exposure increased to levels comparable to those observed with a 150 mg monotherapy dose (see section 4.9).

Special populations

Elderly

No dose adjustment of camizestrant is required for elderly patients (see section 5.2).

Renal impairment

No dose adjustment of camizestrant is required for patients with mild or moderate renal impairment. Etcamah is not recommended for patients with severe renal impairment (see section 5.2).

Hepatic impairment

No dose adjustment of camizestrant is required for patients with mild (NCI criteria) hepatic impairment. As a precautionary measure, the use of camizestrant in patients with moderate and severe hepatic impairment should be avoided. Patients with mild hepatic impairment are allowed to take camizestrant (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of camizestrant in children aged 0‑18 years has not been established. No data are available.

Method of administration

Oral use.

The tablet should be swallowed whole with water and may be taken with or without food, at approximately the same time each day. Etcamah should not be ingested if it is broken, cracked, or otherwise not intact. The tablet should not be chewed, crushed, dissolved, or divided because these methods have not been studied in clinical studies.

Breast-feeding (see section 4.6).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Bradycardia, when combined with medicinal products known to increase the risk of QTc prolongation

Bradycardia and QTc prolongation have been reported with camizestrant and CDK4/6 inhibitor combination treatment (see section 4.8). A non-fatal Torsades de Pointes was observed in a patient with bradycardia and QTc prolongation for camizestrant in combination with ribociclib. Considering bradycardia in the context of potential QTc prolongation may increase the risk of arrhythmia, caution should be exercised when administering camizestrant in combination with agents known to cause QTc prolongation, e.g. ribociclib. Refer to monitoring recommendations (see section 4.2).

Hepatic impairment

Camizestrant is metabolised by the liver. Patients with impaired hepatic function are expected to have increased exposure to camizestrant. As a precautionary measure, the use of camizestrant in patients with moderate and severe hepatic impairment should be avoided. Patients with mild hepatic impairment are allowed to take camizestrant. No dose adjustment of camizestrant is required for patients with mild (NCI criteria) hepatic impairment (see sections 4.2 and 5.2).

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet, that is to say essentially 'sodium‑free'.

Camizestrant is a reversible inhibitor of CYP3A4/5 and CYP2B6 and cause inhibition of drug transporters P-gp, BCRP and OATP1B1. Camizestrant is a potent, time-dependent, irreversible inhibitor of CYP2C9 and CYP2C19. Camizestrant is a substrate for CYP3A4/5 and P‑gp.

Effects of other medicinal products on camizestrant

CYP3A4/5 inducers

The exposure to camizestrant is expected to decrease if co-administered with moderate and strong CYP3A4/5 inducers. Clinically, a single 75 mg camizestrant dose co-administered orally with repeat doses of carbamazepine, a strong CYP3A4/5 inducer, resulted in camizestrant geometric mean ratios for C_max and AUC of 0.41 [90% CI: 0.37,0.46] and 0.29 [90% CI: 0.28,0.32], respectively. The co-administration of camizestrant and a strong CYP3A4/5 inducer (including but not limited to: carbamazepine, phenytoin, rifampicin and St John's Wort) should be avoided. An alternative medicinal product with no or weak potential to induce CYP3A4/5 should be considered.

When co-administering camizestrant in combination with ribociclib, plus a moderate CYP3A4/5 inducer (including but not limited to: e.g. bosentan, nafcillin, modafinil and phenobarbital), no dose adjustment of camizestrant is necessary. When co-administering camizestrant in combination with abemaciclib or palbociclib, the use of such moderate CYP3A4/5 inducers should be avoided by switching to an alternate concomitant drug product (see section 5.2).

CYP3A4/5 inhibitors

In a clinical study, concomitant use of itraconazole, a strong CYP3A4/5 inhibitor, increased camizestrant geometric mean C_max and AUC_inf by 1.37-fold and 1.90-fold, respectively. Camizestrant in combination with ribociclib should be avoided in patients taking strong CYP3A4/5 inhibitors. In addition, caution should be exercised when combining camizestrant and ribociclib in combination with weak (e.g., chlorzoxazone and fosaprepitant) and moderate (e.g., aprepitant and diltiazem) CYP3A4/5 inhibitors.

Effects of camizestrant on other medicinal products

CYP2C9 and CYP2C19 substrates

In vitro data in conjunction with mechanistic static modelling show that camizestrant is a potent irreversible, time-dependent inhibitor of both CYP2C9 and CYP2C19. This means that the inhibition is irreversible and in order to reinstate functionality, the enzymes need to be synthesised again. Therefore, camizestrant is expected to increase the exposure levels of medicinal products that are substrates of CYP2C9 and/or CYP2C19. No in vivo clinical data is available. Medicinal products that are sensitive substrates (including but not limited to: clobazam, omeprazole, pantoprazole and proguanil) or substrates with narrow therapeutic index of CYP2C9 and/or CYP2C19 (including but not limited to: phenytoin and warfarin) should be stopped at least 2 weeks before the first dose of Etcamah and not used for at least 2 weeks after the last dose of Etcamah.

The co-administration of camizestrant and moderately sensitive substrates of CYP2C9 (including but not limited to: flurbiprofen, siponimod and glyburide) and/or CYP2C19 (including but not limited to: esomeprazole, voriconazole and lansoprazole) may be allowed with caution; however, alternative medicinal products should be considered if possible.

CYP3A4/5 substrates

In a clinical study, concomitant use of camizestrant increased midazolam, a sensitive CYP3A4/5 substrate, geometric mean C_max by 1.50‑fold and AUC by 1.99‑fold respectively, therefore, camizestrant is a weak inhibitor of CYP3A4/5. Camizestrant should be used with caution when co-administered with sensitive CYP3A4/5 substrates (including but not limited to: budesonide, buspirone, dronedarone, ivabradine, lurasidone, midazolam, quetiapine, sildenafil and simvastatin). Narrow therapeutic index CYP3A4/5 substrates (e.g. alfentanil and fentanyl) may require dose adjustment and should be monitored closely.

OATP1B1 sensitive substrates

In vitro data show that camizestrant is an inhibitor of OATP1B1. Therefore, camizestrant may increase the exposure levels of medicinal products that are substrates of OATP1B1 including but not limited to glyburide, and lovastatin. No in vivo clinical data is available. Medicinal products which have a narrow therapeutic index and are sensitive substrates of OATP1B1 should be avoided. Those medicinal products which are sensitive substrates of OATP1B1 are permitted but caution should be exercised and patients monitored closely for possible drug interactions.

BCRP sensitive substrates

In vitro data show that camizestrant is an inhibitor of Breast Cancer Resistance Protein (BCRP). Therefore, camizestrant may increase the exposure levels of medicinal products that are substrates of BCRP. No in vivo clinical data is available. Those medicinal products that are sensitive substrates of BCRP e.g. rosuvastatin, sulfasalazine and sofosbuvir, are permitted but caution should be exercised and patients monitored closely for possible drug interactions. Medicinal products that have a narrow therapeutic index and are sensitive substrates of BCRP should be avoided.

P-gp sensitive substrates

In vitro data show that camizestrant is an inhibitor of P-glycoprotein (P-gp). Therefore, camizestrant may increase the exposure levels of medicinal products that are substrates of P-gp including but not limited to: edoxaban, digoxin, fexofenadine and dabigatran etexilate. No in vivo clinical data is available. Medicinal products which have a narrow therapeutic index and are sensitive substrates of P-gp should be avoided. Those medicinal products which are sensitive substrates of P-gp are permitted but caution should be exercised and patients monitored closely for possible drug interactions.

CYP2B6 sensitive substrates

In vitro data show that camizestrant is an inhibitor of Cytochrome P450 2B6 (CYP2B6). Therefore, camizestrant may increase the exposure levels of medicinal products that are substrates of CYP2B6. No in vivo clinical data are available. Those medicinal products that are sensitive substrates of CYP2B6 including but not limited to: bupropion, nevirapine, ketamine, and cyclophosphamide should be avoided. All other CYP2B6 substrates are permitted but caution should be exercised and patients monitored closely for possible drug interactions.

Medicinal products known to prolong the QT interval

Camizestrant in combination with ribociclib has been studied clinically, a non-fatal Torsades de Pointes was observed in a patient with bradycardia and QTc prolongation for camizestrant in combination with ribociclib. It is recommended to monitor patients clinically and adjust doses as specified in the approved ribociclib SmPC. Co-administration of other medicinal products known to prolong the QT interval and/or have a known risk of Torsades de Pointes (e.g. ciprofloxacin, levofloxacin, ondansetron, escitalopram, venlafaxine, fluconazole, chloroquine, halofantrine, clarithromycin, azithromycin, haloperidol, methadone, moxifloxacin, bepridil, and pimozide) should be avoided. If concomitant use cannot be avoided, monitor ECGs as clinically indicated (see section 4.2).

Women of childbearing potential

Based on its mechanism of action and preclinical data, camizestrant may cause foetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant while receiving camizestrant. A pregnancy test should be performed and verified as negative on women of childbearing potential prior to initiating treatment and re-testing should be considered throughout treatment.

Contraception in males and females

Women of childbearing potential and men with women partners of childbearing potential have to use effective contraception during treatment with camizestrant and for the following periods after completion of treatment with camizestrant: at least 4 weeks for females and 1 week for males.

Pregnancy

There are no data from the use of camizestrant in pregnant women. Studies in animals have shown reproductive toxicity, including embryo lethality and dystocia (see section 5.3). Based on animal data and its mechanism of action, camizestrant should not be used during pregnancy unless the clinical condition of the women requires treatment with camizestrant.

Breast-feeding

It is not known whether camizestrant and its metabolites are excreted in human milk. Based on animal data (see section 5.3), a risk to the breast‑fed child cannot be excluded. Breast-feeding must be discontinued prior to treatment with camizestrant and must not be resumed until 4 weeks following the last dose (see section 4.3).

Fertility

There are no data on the effect of camizestrant on human fertility. Results from animal studies have shown that camizestrant has marked effects on male and female reproductive organs in mice, rats and dogs and functional effects on female and male fertility in rats (see section 5.3).

Etcamah in combination with a CDK4/6 inhibitor, has a minor influence on the ability to drive and use machines as the combination may cause fatigue and dizziness (see section 4.8). Etcamah, may cause transient visual effects in the peripheral vision consisting mainly of photopsia, which has no or negligible influence on the ability to drive. However, patients who experience these symptoms should be advised to observe caution when driving or operating machinery.

Summary of the safety profile

The summary of the safety profile of Etcamah is based on pooled data from 263 patients who received Etcamah in combination with a CDK4/6 inhibitor in phase III (SERENA-6) and phase I (SERENA-1) studies.

The most common adverse reactions (≥ 15%) for Etcamah in combination with a CDK4/6 inhibitor 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%). Among these, ADRs identified for Etcamah were visual effects (40.7%) and bradycardia (19.8%).

The common Grade 3 or 4 adverse reactions (≥ 2%) for Etcamah in combination with a CDK4/6 inhibitor were neutropenia (46.4%), leukopenia (9.1%), anaemia (3.4%), infections (3.4%) and alanine aminotransferase increase (2.3%).

The common serious adverse reactions (≥ 1%) reported in patients receiving Etcamah in combination with a CDK4/6 inhibitor included infections (3.4%) and pyrexia (1.1%).

Adverse reactions leading to treatment discontinuation of Etcamah in patients receiving Etcamah in combination with a CDK4/6 inhibitor were neutropenia (0.4%) and electrocardiogram QT prolonged (0.4%).

The most common adverse reactions (≥ 2%) leading to dose modification of Etcamah in patients receiving Etcamah in combination with a CDK4/6 inhibitor were infections (6.8%), neutropenia (6.5%), bradycardia (4.2%), electrocardiogram QT prolonged (3.4%), diarrhoea (2.3%), vomiting (2.3%) and visual effects (2.3%).

Tabulated list of adverse reactions

Adverse drug reactions identified for Etcamah in the Etcamah and CDK4/6 inhibitors combination are visual effects and bradycardia. Also included in Table 2 are adverse reactions, and their respective incidence, identified for the Etcamah and CDK4/6 inhibitors combination in the Etcamah in combination with a CDK4/6 inhibitor pool (n = 263).

In SERENA-6, the median duration of exposure to Etcamah in combination with a CDK4/6 inhibitor was 15.54 months and to AI in combination with a CDK4/6 inhibitor was 7.36 months.

The adverse reaction frequencies from clinical studies are based on all-cause adverse event frequencies, where a proportion of the events for an adverse reaction may have causes other than the drug, such as the disease, other medication or unrelated causes.

Adverse reactions are listed by MedDRA System Organ Class (SOC) and by descending frequency of the MedDRA grouped term. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000) and not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 2 Adverse drug reactions reported in the Etcamah and CDK4/6 inhibitor combination (n = 263) ^a

^a. Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

^b. Visual effects include photopsia, vision blurred, visual impairment, diplopia, and photophobia of eye disorders MedDRA SOC, and visual perseveration of nervous system disorders MedDRA SOC. In addition to camizestrant, vision blurred is an ADR for palbociclib and photopsia is an ADR for abemaciclib.

^c. Bradycardia includes bradycardia and sinus bradycardia.

^d. All PTs under the Infections and Infestation SOC.

^e. ADR for camizestrant and palbociclib combination.

^f. ADR for camizestrant and abemaciclib combination.

^g. ADR for camizestrant and ribociclib combination.

^h. Neutropenia includes neutropenia and neutrophil count decreased.

^i. Anaemia includes anaemia, anaemia macrocytic and iron deficiency anaemia.

^j. Leukopenia includes leukopenia and white blood cell count decreased.

^k. Thrombocytopenia includes thrombocytopenia and platelet count decreased.

Description of selected adverse reaction

Bradycardia

Among the 19.8% patients with bradycardia reported, 85% patients had bradycardia reported as asymptomatic CTCAE Grade 1, while the remaining 15% had Grade 2 adverse reactions reported. Bradycardia exhibited a time-dependent onset where a gradual decrease in heart rate can reach a stable nadir at approximately 14 days and generally recovered following treatment cessation in a similar time course.

Bradycardia in the presence of drug-induced QTc prolongation has the potential to increase the risk of arrhythmia. QTc prolongation has been reported as an adverse reaction in 18 patients (6.8%) within the Etcamah and CDK4/6 inhibitor combination (see Table 2). Of those, 14 were reported as Grade 1 or Grade 2; 3 were reported as Grade 3 and a Torsades de Pointes (Grade 4) was observed in a patient with bradycardia and QTc prolongation for camizestrant in combination with ribociclib in a phase 1 study. The Grade 3 and 4 events were in combination with ribociclib. Additional monitoring is recommended (see sections 4.2 and 4.4).

Visual effects

Of the 40.7% patients who reported visual effects, the majority (92.5%) experienced CTCAE Grade 1 adverse reactions, while 6.5% patients experienced CTCAE Grade 2 adverse reactions and 0.9% CTCAE Grade 3 adverse reaction (photopsia) occurred. The most common visual effect was photopsia (24.0%). The median time to the onset of the first visual effect was 9 days. Visual effects ADRs were typically intermittent, of brief duration, and not continuous throughout the day. Visual effects were reported not to worsen over time in patients. Ophthalmological review of patients reporting visual effects showed no evidence of structural effects on the eye or clinically meaningful changes in visual acuity attributed to Etcamah (see section 5.1).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

There is no specific treatment in the event of Etcamah overdose. No Maximum Tolerated Dose (MTD) was reached in the phase I studies in which patients received a daily monotherapy dose up to 450 mg. The safety profile of patients treated with once daily doses of 150 mg Etcamah was consistent with the established safety profile of Etcamah at the recommended 75 mg once daily dose (see section 4.8). In case of suspected overdose, patients should be closely monitored and treated symptomatically, if necessary.

Pharmacotherapeutic group: Endocrine therapy, Anti-estrogens, ATC code: L02BA05

Mechanism of action

Camizestrant is an oral selective oestrogen receptor degrader (SERD) and oestrogen receptor (ER) antagonist.

Camizestrant binds to the ligand binding domain of ERα, antagonising the activity of ERα encoded by both wild-type ESR1 and mutated ESR1, and inducing proteasome-dependent degradation of ERα, without agonising ERα.

Cardiac electrophysiology

Exposure response analysis of potential QTcI prolongation of daily 75 mg to 300 mg of camizestrant monotherapy was assessed in 30 patients. The predicted drug related mean QTcI prolongation was 2.99 msec (95% CI: (-0.75, 6.73)) at the mean steady state C_max with an upper bound of 6.09 msec (90% CI) following 75 mg camizestrant daily. At the recommended 75 mg dose of camizestrant, a mean increase in QTcI > 10 msec was not observed.

Clinical efficacy

ER-positive, HER2-negative locally advanced or metastatic breast cancer

SERENA-6

SERENA-6 was a randomised, double-blind, circulating tumour DNA (ctDNA)-guided study to assess the efficacy and safety of switching to Etcamah plus a CDK4/6 inhibitor (palbociclib, ribociclib or abemaciclib) versus continuing AI (letrozole or anastrozole) plus a CDK4/6 inhibitor in adult pre/peri/post-menopausal females and males with ER-positive/HER2-negative, locally advanced or metastatic breast cancer with detectable ESR1‑mutation assessed by ctDNA testing without disease progression during first-line treatment with AI plus a CDK4/6 inhibitor. All patients were required to be currently on treatment and have received ≥ 6 months of AI plus a CDK4/6 inhibitor treatment as the initial endocrine based treatment with no evidence of disease progression as per investigator assessment. Patients could have received one prior line of chemotherapy before the start of AI plus a CDK4/6 inhibitor treatment. Patients with ECOG > 1, presence of widespread symptomatic metastatic visceral disease, early progressors on CDK4/6 inhibitor; severe and uncontrolled cardiac comorbidity, severe hepatic impairment and/or QTc prolongation (defined as > 480 msec for combination with palbociclib or abemaciclib; or ≥ 450 msec for combination with ribociclib were excluded. ESR1-mutation status was prospectively determined through testing of plasma-derived circulating tumour DNA (ctDNA) using Guardant 360 CDx assay. Mutations in ESR1 that cause the indicated amino acids changes were eligible for inclusion E380Q, V422del, S463P, L536H, L536P, L563R, Y537C, Y537D, Y537N, Y537S, D538G. Based on results from the Guardant 360 assay, the most common ESR1 alterations were variants at amino acids D538G, Y537S, and Y537N detected in 44.6%, 38.9% and 18.5% of patients with an eligible ESR1-mutation, respectively.

A total of 315 patients were randomised 1:1 to receive either Etcamah (n = 157, 75 mg once daily) plus a CDK4/6 inhibitor and a placebo of AI or continue AI plus a CDK4/6 inhibitor and placebo of Etcamah (n = 158). The total percentage of randomised patients on palbociclib were 75.6%, ribociclib were 14.9%, and abemaciclib were 9.5%. The choice of CDK4/6 inhibitor and its dose remained the same at the time of randomisation for both arms. Randomisation was stratified by disease site (visceral disease versus non-visceral disease), ESR1m detection (first test versus subsequent ctDNA tests), time from initiation of AI plus CDK4/6 inhibitor to randomisation (< 18 months versus ≥ 18 months), and type of CDK4/6 inhibitor (palbociclib versus ribociclib versus abemaciclib). Pre/perimenopausal female patients and male patients taking concomitant LHRH agonist continued to receive it after randomisation. Treatment with Etcamah continued until disease progression or unacceptable toxicity occurred.

The primary endpoint was progression free survival (PFS) as assessed by investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The key secondary endpoints were time from randomisation to second progression or death (PFS2) and overall survival (OS).

Demographic and baseline characteristics were well balanced between arms. Of the 315 patients, the median age was 61.0 years (range 29.0 to 89.0 years and 36.8% were over 65 years of age); female (99.0%); male (1.0%); White (63.2%), Asian (23.2%), Black (1.9%), and other races (1.0%). Eastern Cooperative Oncology Group (ECOG) performance status 0 (65.1%) or 1 (33.0%); 79.4% were post‑menopausal female and 20.6% were pre‑/peri‑menopausal female or male.

Efficacy results are summarized in Table 3 and Figure 1.

Table 3 Efficacy Results in SERENA-6 (DCO3: 02 Jan 2026)

a. Includes progression events that occur within 2 visits of last evaluable assessment.

b. The calculation is based on the Kaplan-Meier method.

c. A hazard ratio < 1 favours Etcamah plus CDK4/6 inhibitor treatment arm.

d. p value < 0.00001 achieved at DCO1 (28 Nov 2024).

Figure 1 Kaplan‑Meier plot of progression‑free survival by investigator assessment in SERENA-6

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Etcamah in all subsets of the paediatric population in breast cancer (see section 4.2 for information on paediatric use).

Camizestrant pharmacokinetic parameters have been characterized in healthy patients and breast cancer patients. Based on population pharmacokinetic (popPK) analysis, the pharmacokinetics of camizestrant at the 75 mg dose are characterized by an apparent plasma clearance of 69.1 L/h, apparent volume of distribution (V_ss/F) at steady state of 26.97 L/kg and a terminal half‑life of approximately 23 hours. The camizestrant 75 mg dose oral bioavailability is 43% and steady state is reached by Day 5 following once daily dosing.

Absorption

Following oral administration, camizestrant is absorbed with median peak plasma concentrations achieved between approximately 2 to 4 hours after dosing.

Effect of food

Similar exposures were observed following administration with a high fat meal or fasted overnight supporting camizestrant being taken with or without food. Following a high fat meal, the fed to fasted C_max and AUC geometric mean ratios (90% CI) were 106.2% (90% CI: 94.3%, 119.7%) and 109.8% (90% CI: 104.4%, 115.5%), respectively.

Distribution

Based on popPK analysis, camizestrant is distributed in the tissues with an apparent peripheral volume of distribution of 8.69 L/kg. The apparent volume of distribution of camizestrant at steady state is 26.97 L/kg.

Plasma protein binding of camizestrant is 75.3% (24.7% free). There is no evidence of concentration dependent plasma protein binding. The blood to plasma ratio was 0.99.

Biotransformation

Metabolism results from in vitro hepatocytes studies suggest that camizestrant undergoes multiple oxidation reactions in addition to direct N-glucuronidation and is primarily metabolised by CYP3A4/5 and UGT1A4. Human metabolites of camizestrant were detected and quantified in pharmacokinetic samples from healthy female volunteers receiving a single oral dose of 75 mg [14C]-camizestrant (0.67 MBq). The major drug-related circulating materials were the N-glucuronide conjugate of camizestrant, the N-glucuronide of the acid metabolite and camizestrant which accounted for 20.1%, 11.2%, and 13.6% of the circulating radioactivity in plasma. The other eight minor metabolites in plasma, each of which had a relative abundance lower than 10% of the total drug-related materials in plasma, were either oxidative metabolites or glucuronides of oxidative metabolites. No active metabolites have been identified.

In vitro: Camizestrant does not inhibit CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19 or CYP2E1 and is a weak (IC50 > 100 µM) inhibitor of UGT1A1 and UGT2B7. Camizestrant does not cause time-dependent inhibition of CYP1A2, CYP2D6 and CYP3A4/5. Camizestrant has low potential to cause induction of CYP1A2, CYP2B6, and CYP3A4/5. For the drug transporters, camizestrant does not inhibit OATP1B3, OCT2, OAT1, OAT3, MATE1, and MATE2K and is not a substrate of BCRP, OATP1B1 or OATP1B3.

Elimination

Following single oral administration of 75 mg [14C]-camizestrant, mean of 82% of the radioactivity administered was recovered in urine and faeces. Mean total radioactivity (65.1%) was recovered in faeces indicating faecal excretion was the main route of elimination following oral dosing; with 16.8% of the total radioactivity being recovered from the urine.

Linearity/non-linearity

Camizestrant AUC and C_max showed greater than dose-proportional increase over the dose range of 25 to 450 mg.

Special populations

Effect of age, gender, race and weight

Based on popPK analyses (n = 756), no clinically significant relationships were identified between model predicted steady-state exposure, area under the curve at steady state (AUC_ss) and the following covariates: baseline median age 61 years (29 to 89 years) and racial groups. PopPK analysis showed baseline median body weight was 69.9 kg (34.2 to 150 kg) and it affected apparent volume of distribution (V2/F), but this was not clinically relevant; it did not significantly impact apparent total body clearance (CL/F) or AUC_ss. No dose adjustments for camizestrant are required based on age, gender, race, or body weight.

Renal impairment

The popPK analysis used continuous creatinine clearance. Baseline creatinine clearance (CrCL) was calculated using the Cockcroft-Gault equation to evaluate the effect of renal function on camizestrant PK; the median CrCL was 86.2 mL/min (range 22.8-303 mL/min). The analysis showed no clinically meaningful impact of mild and moderate renal impairment at baseline on camizestrant PK, indicating that no dose adjustment is necessary for patients with mild to moderate renal impairment.

There were limited patients with severe renal impairment and no patients on dialysis or with CrCL < 15 mL/min were included in the clinical studies of camizestrant. Therefore, an appropriate dose of camizestrant has not been established for severe renal impairment patients and patients on dialysis (see section 4.2).

Hepatic impairment

Based on a pharmacokinetic study in patients following a single 75 mg dose, camizestrant exposure geometric mean C_max and AUC_0‑INF in patients with moderate (Child-Pugh B) hepatic impairment was 2.4-fold and 2.7-fold, respectively, compared to patients with normal hepatic function. Camizestrant exposure geometric mean C_max and AUC_0-INF in patients with severe (Child-Pugh C) hepatic impairment was 3.1-fold and 3.8-fold, respectively, compared to patients with normal hepatic function.

The exposure to camizestrant is higher than dose-proportional and increases with time until steady state. The increase in exposure to camizestrant from single dose to steady state is not known in subjects with hepatic impairment (Child-Pugh). PopPK modelling did not indicate mild hepatic impairment (NCI) as a significant covariate for camizestrant exposure. As precautionary measures, camizestrant should be avoided in subjects with moderate and severe hepatic impairment. Patients with mild hepatic impairment are allowed to take camizestrant.

Non-clinical/repeat-dose toxicity

In repeat-dose toxicity studies in mice, rats and dogs, the reproductive tract was identified as a target organ with histopathological findings occurring at exposures significantly below (female) or at 2-fold (male) human exposure at Maximum Recommended Human Dose (MRHD). There were related findings in the adrenals (rats and mice) and pituitary (mice) glands. Findings were hormone-driven, based on the pharmacological action of camizestrant and therefore not relevant for post-menopausal women or pre- or peri menopausal women or men administered an LHRH agonist. Findings in the male reproductive tract of clinical relevance are described in the fertility section.

Macrophage aggregation (lung, spleen, thymus and mesenteric lymph nodes) and vacuolation (biliary epithelium of the liver) were noted in the rat and/or mouse. This was confirmed as phospholipidosis in the lung of rat, was reversible following 1-month dosing but was considered adverse in female rats in the 6-month study at a total plasma exposure (AUC) of approximately 60-fold human exposure at MRHD.

In mechanistic studies, camizestrant caused rod bipolar cell dysfunction in the retina of rats at clinically relevant exposures (approximately 5-fold human exposure at MRHD). The retina effects in rats were reversible and are consistent with the transient visual effects observed in humans.

Cardiovascular effects were observed across species (i.e. dogs and rats) and supported by mechanistic studies. Heart rate reduction, related to decreased sinoatrial node pacemaker current activity via HCN4 ion channels, was observed in animals and confirmed clinically (see section 4.4). In dogs and rats, additional delayed-onset cardiovascular functional effects included dose- and time-dependent decreases in diastolic blood pressure, QA interval and PR interval, with increases in pulse pressure, QT/QTc intervals and left ventricular parameters (dP/dt+ and dP/dt-). When assessed in dogs, QTc prolongation persisted for at least 3 days up to 4 weeks. The QTc prolongation was of unknown mechanism, independent of heart rate and unrelated to hERG inhibition and observed at maximum unbound plasma concentrations ≥ 4-fold those at human MRHD. Additional atrial premature complexes (APCs) were observed in one telemetry and one toxicology dog at maximum free plasma levels 12-fold and 33-fold human MRHD, respectively. Cardiomyopathy was observed in female rats following dosing for 6 months at total plasma exposures ≥ 11-fold the human AUC exposure at human MRHD.

In dogs, combination dosing of camizestrant with atropine resulted in a significant increase in plasma and brain exposure of atropine considered to be due to inhibition of atropine metabolism and, therefore, likely dog specific.

Mutagenicity and carcinogenicity

Camizestrant was negative in the in vitro Ames and micronucleus assays, and the in vivo micronucleus study. Findings in the ovaries in chronic repeat-dose studies included hyperplasia at total plasma exposures (AUC) ≥ 2-fold (rat granulosa cell) and 52-fold (dog sex cord stromal) relative to human exposure at MRHD and benign granulosa cell tumours at total plasma exposures (AUC) of approximately 60-fold (rats) and 3.5-fold (dogs) relative to human exposure at MRHD. An interstitial (Leydig) cell adenoma was observed in the testis of a single dog at 13-fold human exposure at MRHD. Findings are considered hormone-driven, based on the pharmacological action of camizestrant and therefore not relevant for post-menopausal women or in pre- or peri menopausal women or men administered an LHRH agonist.

Reproductive toxicity

Embryofoetal/developmental toxicity

Administration of camizestrant in a modified embryofoetal development study in rats resulted in a complete lack of implantation in females when dosing at 0.1 mg/kg/day commenced prior to implantation. When administration was restricted to the phase of organogenesis, camizestrant had no effect on embryofoetal survival or development, but when dosed from implantation through parturition and into lactation, camizestrant resulted in increased length of gestation, dystocia, impaired offspring survival and growth. Maternal exposures in this study were far below human exposure at MRHD.

Fertility

In a fertility study in female rats, camizestrant negatively affected oestrous cycles, mating behaviour, fertility and early embryonic survival which fully reversed following 1 month off dose. Effects were observed at maternal exposures below human exposure at MRHD.

In male rats and dogs, atrophy of the prostate gland, seminal vesicle and seminiferous tubules, tubular dilation of testis and changes in the epididymis (decreased sperm in rats and cell debris in dog) were evident from the lowest dose in chronic studies at exposures ≥ 2-fold (rat) or ≥ 3.5-fold (dog) human exposure at MRHD and were considered of clinical relevance. In male rats following 9 weeks of dosing there were lower spermatid/sperm counts, a higher percentage of sperm abnormalities, lower sperm motility, and lower mating and pregnancy rates indicating an effect on male fertility. Effects were observed at a total plasma exposure (AUC) ≥ 2-fold that observed at a clinical dose of 75 mg, but a no-effect level was not established. In that study, implantation loss and a decrease in number of live foetuses was observed in non-dosed females paired with dosed males suggesting male-mediated reproductive toxicity at a total plasma exposure (AUC) 27-fold the human exposure at MRHD. Reversibility of male fertility findings was not assessed.

Tablet core

Cellulose, microcrystalline (type 102)

Calcium hydrogen phosphate

Sodium starch glycolate (Type A)

Magnesium stearate

Tablet coating

Polyvinyl alcohol

Titanium dioxide (E171)

Macrogol 3350

Talc

Iron oxide red (E172)

Iron oxide yellow (E172)

Iron oxide black (E172)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

28x1 film-coated tablets in aluminium/aluminium perforated unit dose blisters. 2 blisters with 14 film-coated tablets each.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.