Camizestrant

ETCAMAH in combination with a CDK4/6 inhibitor (abemaciclib, palbociclib, or ribociclib) is indicated for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer upon detection of ESR1 mutation during aromatase inhibitor and CDK4/6 inhibitor therapy, based on an FDA-authorized test [see Dosage and Administration ( 2.1 )] . This indication is approved under accelerated approval based on progression-free survival as measured from detection of ESR1 mutation [see Clinical Studies ( 14 )] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). ETCAMAH is an estrogen receptor antagonist indicated:

• in combination with a CDK4/6 inhibitor (abemaciclib, palbociclib, or ribociclib) for the treatment of adult patients with hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative, locally advanced or metastatic breast cancer upon detection of ESR1 mutation during aromatase inhibitor and CDK4/6 inhibitor therapy, based on an FDA authorized test. ( 1 , 2.1 ) This indication is approved under accelerated approval based on progression-free survival as measured from detection of ESR1 mutation. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). ( 1 )

75 mg tablets: beige, round, bi-convex, film-coated tablets debossed with ‘CM’ above ‘75’ on one side and plain on the reverse. Tablets: 75 mg. (3)

None. None. (4)

• Bradycardia : Monitor heart rate more frequently during the first 30 days. Avoid concomitant use of ETCAMAH with other products known to cause bradycardia. Withhold or permanently discontinue ETCAMAH based on severity. ( 2.2 , 2.4 , 5.2 , 7.4 )
• Embryo-Fetal Toxicity : ETCAMAH can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.3 , 8.1 , 8.3 ) 5.1 QTc Interval Prolongation ETCAMAH in combination with a CDK4/6 inhibitor is associated with QTc interval prolongation [see Clinical Pharmacology ( 12.2 )] . When ETCAMAH is used in combination with ribociclib, a CDK4/6 inhibitor that causes QTc interval prolongation and is a strong CYP3A inhibitor, there is potential for an increased risk of Torsades de Pointes, other ventricular arrhythmias, and sudden death. One case of Torsades de Pointes was observed in a dose-finding trial when ETCAMAH was used with ribociclib [see Drug Interactions ( 7.1 , 7.3 ) and Clinical Pharmacology ( 12.2 )] . In SERENA 6, QTc interval prolongation occurred in 2.6% of patients treated with ETCAMAH in combination with a CDK4/6 inhibitor. QTc interval prolongation led to dose interruption of ETCAMAH in 0.6% of patients. ETCAMAH also causes bradycardia, which increases the risk of QTc interval prolongation. [see Warnings and Precautions ( 5.2 )] . Perform an ECG prior to initiating ETCAMAH, then every week for the first 2 weeks of treatment, and periodically during treatment as clinically indicated [see Dosage and Administration ( 2.2 )] . Obtain serum electrolytes at baseline and during treatment as clinically indicated, and correct electrolyte abnormalities. Avoid concomitant use of ETCAMAH in combination with a CDK4/6 inhibitor with products that can cause QTc interval prolongation, are strong CYP3A inhibitors, and/or drugs known to lower heart rate [see Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7.1 , 7.3 , 7.4 )] . Withhold or permanently discontinue ETCAMAH based on severity [see Dosage and Administration ( 2.4 )].

5.2 Bradycardia ETCAMAH causes a decrease in heart rate. Bradycardia increases the risk for life-threatening arrhythmias and sudden death when concomitant QTc interval prolongation is present, such as when ETCAMAH is used in combination with ribociclib, both a QTc interval prolonging product and a strong CYP3A inhibitor [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7.1 , 7.3 )] . In SERENA-6, bradycardia adverse events occurred in 8% of patients treated with ETCAMAH. The mean heart rate decrease from baseline was approximately 13 beats per minute (bpm) with ETCAMAH with the maximum decrease observed on Day 15. The median time to onset of adverse reaction was 17 days (range 13 to 283) after starting ETCAMAH. Bradycardia led to dose interruption of ETCAMAH in 3.9% of patients. The safety of ETCAMAH has not been established in patients with a baseline resting heart rate less than 55 bpm as these patients were excluded from SERENA-6. Monitor heart rate more frequently during the first 30 days of treatment with ETCAMAH in patients with bradycardia (heart rate less than 60 bpm) at baseline and those on concomitant medications known to lower heart rate (e.g., beta-blockers) [see Dosage and Administration ( 2.2 ), and Drug Interactions ( 7.4 )] . Withhold or permanently discontinue ETCAMAH based on severity [see Dosage and Administration ( 2.4 )] .

5.3 Embryo-Fetal Toxicity Based on findings in animals and its mechanism of action, ETCAMAH can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . In animal reproduction studies, oral administration of camizestrant to rats during pregnancy resulted in adverse developmental outcomes including embryo-fetal/neonatal mortality and alterations to growth at maternal exposures below the human AUC at the recommended dose. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ETCAMAH and for 4 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ETCAMAH and for 1 week after the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] .

The most common adverse reactions (≥ 20%), including laboratory abnormalities, with ETCAMAH in combination with a CDK4/6 inhibitor were decreased neutrophils, decreased leukocytes, decreased hemoglobin, decreased lymphocytes, decreased platelets, visual disturbances, and fatigue. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience The following clinically significant adverse reactions are described elsewhere in the labeling:

• QTc interval prolongation [see Warnings and Precautions ( 5.1 )]
• Bradycardia [see Warnings and Precautions ( 5.2 )] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. HR-positive, HER2-negative Locally Advanced or Metastatic Breast Cancer The safety of ETCAMAH was evaluated in 155 patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer with detectable ESR1 mutation without disease progression during first line treatment with an aromatase inhibitor (AI) in combination with a CDK4/6 inhibitor in SERENA-6 [see Clinical Studies ( 14 )] . Patients received ETCAMAH 75 mg orally once daily in combination with a CDK4/6 inhibitor (N = 157) or AI in combination with a CDK4/6 inhibitor (N = 158). The median duration of exposure to ETCAMAH in combination with a CDK4/6 inhibitor was 10.1 months. Serious adverse reactions occurred in 10% of patients who received ETCAMAH in combination with a CDK4/6 inhibitor. Serious adverse reactions in > 1% of patients included urinary tract infection, pneumonia, and osteonecrosis of jaw (1.3% each). Fatal adverse reactions occurred in 1.3% of patients who received ETCAMAH in combination with a CDK4/6 inhibitor, including acute respiratory distress syndrome and sudden death (0.6% each). Permanent discontinuation of ETCAMAH due to adverse reactions occurred in 1.3% of patients. Adverse reactions that resulted in permanent discontinuation of ETCAMAH included gastroesophageal reflux disease, cholestasis and hepatic cytolysis (0.6% each). Dosage interruption of ETCAMAH due to adverse reactions occurred in 22% of patients. Adverse reactions which required dosage interruption of ETCAMAH in ≥ 2% of patients included bradycardia (3.9%) and visual disturbances (2.6%). The most common (≥ 20%) adverse reactions, including laboratory abnormalities, were decreased neutrophils, decreased leukocytes, decreased hemoglobin, decreased lymphocytes, decreased platelets, visual disturbances, and fatigue. Tables 2 and 3 summarize the adverse reactions and laboratory abnormalities, respectively, in SERENA-6. Table 2. Adverse Reactions in ≥ 10% (All Grades) of Patients with HR-positive, HER2-negative Locally Advanced or Metastatic Breast Cancer Who Received ETCAMAH in SERENA-6 Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Adverse Reaction ETCAMAH with a CDK4/6 Inhibitor N = 155 Aromatase Inhibitor with a CDK4/6 Inhibitor N = 155 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Eye Disorders Visual disturbances Visual disturbances include: photopsia, blurred vision, visual field defect, decreased visual acuity, visual impairment, diplopia, photophobia, and visual perseveration. 34 0.6 16 0 Dry eye 12 0 7 0 General Disorders and Administration Site Conditions Fatigue Fatigue includes: fatigue and asthenia. 23 0 19

0.6 Musculoskeletal and Connective Tissue Disorders Arthralgia 16 0 17

0.6 Back pain 10 0.6 10 0 Gastrointestinal Disorders Nausea 10 0 14

0.6 Clinically relevant adverse reactions (< 10%) in patients who received ETCAMAH included: vitreous floaters, bradycardia, and QTc prolongation. Table 3. Select Laboratory Abnormalities ≥ 10% that Worsened from Baseline in Patients with HR-positive, HER2-negative Locally Advanced or Metastatic Breast Cancer Who Received ETCAMAH in SERENA-6 Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Includes patients with at least one baseline and one post-baseline result. Laboratory Abnormality ETCAMAH with a CDK4/6 Inhibitor N = 155 Aromatase Inhibitor with a CDK4/6 Inhibitor N = 155 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematology Neutrophils decreased 68 42 66 39 Leukocytes decreased 66 23 58 17 Hemoglobin decreased 47 3.9 38 5 Lymphocyte decreased 39 9 37 8 Platelets decreased 36 2.6 30

1.3 Chemistry Aspartate aminotransferase increased 17 2.6 29

1.3 Corrected calcium decreased 17 0 12

0.7 Creatinine increased 16 0.6 20

1.3 Gamma glutamyl transferase increased 12 2.7 23 8 Alanine aminotransferase increased 12 1.3 20 0 Creatine kinase increased 12 0 6 0 Alkaline phosphatase increased 10 0.7 22

0.7 Patient-Reported Outcomes Patient-reported blurred vision was assessed using the Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE) at baseline, every week through Week 12, and then every 8 weeks until treatment discontinuation. For post-baseline time points, completion rates for the patient-reported symptom of blurred vision (severity) ranged between 65% to 80% for patients on ETCAMAH in combination with a CDK4/6 inhibitor and 58% to 72% for patients on AI in combination with a CDK4/6 inhibitor up to Week 52. PRO-CTCAE blurred vision (severity) results are summarized in Table 4. Table 4. Patient-Reported Symptom of Blurred Vision Assessed by PRO-CTCAE Number of Patients The number of patients with score before study treatment and at least one on treatment up to week 52 ETCAMAH in combination with a CDK4/6 inhibitor (N = 102) AI in combination with a CDK4/6 inhibitor (N = 88) Symptoms Any symptoms before study treatment (%) The percentage of patients whose symptom score at baseline assessment (before study treatment) was 1-4 Any Worsening on treatment (%) The percentage of patients whose symptom score increased with respect to their score at baseline assessment (before study treatment) Any Worsening to Score 3 or 4 (%) The percentage of patients whose symptom score increased to 3 or 4 with respect to their score at baseline assessment (before study treatment) ETCAMAH in combination with a CDK4/6 inhibitor (%) AI in combination with a CDK4/6 inhibitor (%) ETCAMAH in combination with a CDK4/6 inhibitor (%) AI in combination with a CDK4/6 inhibitor (%) ETCAMAH in combination with a CDK4/6 inhibitor (%) AI in combination with a CDK4/6 inhibitor (%) Blurred Vision (Severity) 31 25 69 50 10

4.5 The symptom attribute scoring for severity is defined as a score of 0 = ‘none’; 1 = ‘mild’; 2 = ‘moderate’; 3 = ‘severe’; 4 = ‘very severe’. Patient-reported overall impact of visual disturbances was assessed using the Visual Symptom Assessment Questionnaire [VSAQ]. The VSAQ was assessed at baseline, in Weeks 2, 6 and 24, and then every 12 weeks. For post-baseline timepoints, completion rates ranged from 69% to 81% for patients on ETCAMAH in combination with a CDK4/6 inhibitor and 60% to 73% for patients on AI in combination with a CDK4/6 inhibitor. Among patients who reported experiencing a visual disturbance and completed a baseline and at least one post baseline assessment, 12% of patients on ETCAMAH in combination with a CDK4/6 inhibitor versus 13% of patients on AI in combination with a CDK4/6 inhibitor reported “I am bothered by visual disturbances from my cancer treatment”. With respect to baseline, the proportion of patients with VSAQ responses of "quite a bit" or "extremely" bothered was 4.9% of patients on ETCAMAH in combination with a CDK4/6 inhibitor and 1.2% of patients on AI in combination with a CDK4/6 inhibitor. […]

• CYP3A Inhibitors : Monitor for increased adverse reactions to ETCAMAH with strong CYP3A inhibitors and modify the dosage as recommended. ( 7.1 )
• CYP3A Inducers : Avoid concomitant use of strong and moderate CYP3A inducers. If concomitant use with a moderate CYP3A inducer cannot be avoided, dose adjustment is needed when ETCAMAH is given in combination with abemaciclib or palbociclib. ( 2.6 , 7.1 )
• CYP2C9 and/or CYP2C19 Substrates : Avoid concomitant use of ETCAMAH with CYP2C9 substrates or CYP2C19 substrates during treatment with ETCAMAH and at least 2 weeks after the last dose of ETCAMAH, unless otherwise recommended in the Prescribing Information of the CYP2C9 substrate or CYP2C19 substrate. ( 7.2 )
• CYP3A Substrates : Refer to the Prescribing Information for CYP3A substrates where minimal increases in the concentration may lead to serious adverse reactions. ( 7.2 )

7.1 Effect of Other Drugs on ETCAMAH Table 5 describes drug interactions where concomitant use of another drug affects ETCAMAH. Table 5. Drug Interactions involving ETCAMAH and Other Drug Products Strong CYP3A Inhibitors Prevention or Management

• Monitor for increased adverse reactions to ETCAMAH and modify the dosage as recommended [see Dosage and Administration ( 2.4 )]. Mechanism and Clinical Effect
• Camizestrant is a CYP3A substrate. Concomitant use with strong CYP3A inhibitors increases camizestrant plasma concentrations [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of adverse reactions related to ETCAMAH.
• ETCAMAH is indicated to be used in combination with CDK4/6 inhibitors, including ribociclib, which is a strong CYP3A inhibitor and can prolong the QT interval [see Warnings and Precautions ( 5.1 ) and Drug Interactions ( 7.3 )] . Strong and Moderate CYP3A Inducers Prevention or Management
• Avoid concomitant use of strong CYP3A inducers.
• The co-administration of ETCAMAH and a moderate CYP3A inducer is allowed with caution.
• The dosage recommendations for concomitant use of moderate CYP3A inducers differ depending on the CDK4/6 inhibitor used in combination with ETCAMAH. o Avoid concomitant use of moderate CYP3A inducers for patients who are receiving ETCAMAH in combination with abemaciclib or palbociclib. If concomitant use cannot be avoided, increase the ETCAMAH dosage from 75 mg once daily to 150 mg once daily for patients who are receiving ETCAMAH in combination with abemaciclib or palbociclib [see Dosage and Administration ( 2.6 )] . After the moderate CYP3A inducer has been discontinued for at least 14 days, resume the ETCAMAH dosage used prior to initiation of the moderate CYP3A inducer. o For patients who are receiving ETCAMAH in combination with ribociclib concomitantly with a moderate CYP3A inducer, no ETCAMAH dosage modification is recommended. Mechanism and Clinical Effect
• Camizestrant is a CYP3A substrate. Concomitant use with strong or moderate CYP3A inducers decreases camizestrant plasma concentrations [see Clinical Pharmacology ( 12.3 )] which may reduce ETCAMAH effectiveness.

7.2 Effect of ETCAMAH on Other Drugs Table 6 describes drug interactions where concomitant use of ETCAMAH affects another drug. Table 6. Drug Interactions involving ETCAMAH and Other Drug Products CYP2C9 Substrates or CYP2C19 Substrates Prevention or Management

• Avoid concomitant use of ETCAMAH with CYP2C9 substrates or CYP2C19 substrates during treatment with ETCAMAH and at least 2 weeks after the last dose of ETCAMAH, unless otherwise recommended in the Prescribing Information of the CYP2C9 substrate or CYP2C19 substrate. Mechanism and Clinical Effect
• ETCAMAH is a strong CYP2C9 inhibitor and a strong CYP2C19 inhibitor.
• ETCAMAH is predicted to increase the exposure of both CYP2C9 substrates and CYP2C19 substrates [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of adverse reactions related to these substrates. Certain CYP3A Substrates Prevention or Management
• Refer to the Prescribing Information for CYP3A substrates where minimal increases in the concentration may lead to serious adverse reactions. Mechanism and Clinical Effect
• ETCAMAH is a CYP3A inhibitor.
• ETCAMAH increases exposure of CYP3A substrates [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of adverse reactions related to these substrates.

7.3 Drugs That Prolong the QTc Interval ETCAMAH is indicated in combination with a CDK4/6 inhibitor and there is increased risk of QTc interval prolongation with ribociclib, a strong CYP3A inhibitor that can prolong the QTc interval [see Drug Interactions ( 7.1 )] . Refer to the ribociclib prescribing information for dosage modifications. Avoid concomitant use of ETCAMAH with products (other than ribociclib) known to prolong the QTc interval and/or have a known risk of Torsades de Pointes. If concomitant use with other products cannot be avoided, monitor the QTc interval more frequently [see Warnings and Precautions ( 5.1 )] . ETCAMAH in combination with a CDK4/6 inhibitor is associated with QTc interval prolongation [see Clinical Pharmacology ( 12.2 )].

7.4 Drugs That Cause Bradycardia Avoid concomitant use of ETCAMAH with other products known to cause bradycardia. Monitor for signs and symptoms of bradycardia if concomitant use cannot be avoided [see Warnings and Precautions ( 5.2 )] . ETCAMAH causes decreases in heart rate that are dose and baseline heart rate dependent [see Clinical Pharmacology ( 12.2 )] .

Lactation: Advise not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action, ETCAMAH can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . There are no available human data on ETCAMAH use in pregnant women to inform the drug-associated risk. In animal reproduction studies, oral administration of camizestrant to rats during pregnancy resulted in adverse developmental outcomes including embryo-fetal/neonatal mortality and alterations to growth at maternal exposures below the human AUC at the recommended dose (see Data) . Advise pregnant women and females of reproductive potential of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively. Data Animal Data In an embryo-fetal development study with pre- and post-natal assessments, female rats received camizestrant at doses of 0.1 mg/kg from gestation Day (GD) 2 to 20, doses up to 0.091 mg/kg from GD 6 to 16, or doses of 0.075 and 0.75 mg/kg from GD 6 to lactation day (LD) 6. Administration of 0.1 mg/kg camizestrant during GD 2 to 20 resulted in no pregnancies. Camizestrant at doses ≥ 0.075 mg/kg administered from GD 6 to LD 6 resulted in increased length of gestation, dystocia, and decreased pup survival and pup weight. At all doses, maternal exposures were below the human AUC at the recommended dose.

8.2 Lactation Risk Summary There are no data on the presence of camizestrant or its metabolites in human milk, its effects on milk production, or on the breastfed child. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ETCAMAH and for 1 week after the last dose.

8.3 Females and Males of Reproductive Potential ETCAMAH can cause fetal harm when administered to pregnant women [see Use in Specific Populations ( 8.1 )] . Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiating ETCAMAH treatment. Contraception Females Advise females of reproductive potential to use effective non-hormonal contraception during treatment with ETCAMAH and for 4 weeks after the last dose. Males Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ETCAMAH and for 1 week after the last dose. Refer to the Prescribing Information of the CDK4/6 inhibitor palbociclib, if used in combination with ETCAMAH, for contraception information. Advise patients to use effective contraception during treatment and for the longest post-treatment duration as recommended in the Prescribing Information. Infertility Based on findings from animal studies, ETCAMAH may impair fertility in females and males of reproductive potential. Findings in female animals were reversible. The reversibility of effects on male fertility in animals is unknown [see Nonclinical Toxicology ( 13.1 )] .

8.4 Pediatric Use The safety and effectiveness of ETCAMAH have not been established in pediatric patients.

8.5 Geriatric Use Of the 155 patients who received ETCAMAH in SERENA-6, 62 (39%) patients were ≥ 65 years of age and 5 (3.2%) patients were ≥ 75 years of age [see Clinical Studies ( 14 )] . No overall differences in safety and effectiveness were observed between patients ≥ 65 years of age and younger patients. There are insufficient number of patients ≥ 75 years of age to assess differences in safety or effectiveness.

8.6 Hepatic Impairment The recommended dosage for patients with hepatic impairment differs depending on the CDK4/6 inhibitor used in combination with ETCAMAH. Reduce the dosing frequency of ETCAMAH for patients with severe (Child-Pugh C) hepatic impairment who are receiving ETCAMAH in combination with ribociclib [see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 )] . No dosage modification of ETCAMAH is recommended for patients with mild or moderate (Child-Pugh A or B) hepatic impairment who are receiving ETCAMAH in combination with ribociclib or for patients with mild, moderate, or severe (Child-Pugh A, B, or C) hepatic impairment who are receiving ETCAMAH in combination with abemaciclib or palbociclib. Monitor patients with moderate or severe hepatic impairment receiving ETCAMAH in combination with any CDK4/6 inhibitor for increased adverse reactions and modify the dosage as recommended [see Dosage and Administration ( 2.4 )] .

Camizestrant is an estrogen receptor (ER) antagonist. In vitro, camizestrant binds to the ligand binding domain of ERα, antagonizing the activity of ERα encoded by both wild-type ESR1 and mutated ESR1 and inducing proteasome-dependent degradation of ERα, without agonizing ERα. Camizestrant demonstrated anti-tumor activity in ER-positive cell lines, in vitro, and patient derived xenograft (PDX) models, in vivo, including those with wild-type or mutated ESR1 genes. Treatment with camizestrant and CDK4/6 inhibitors (abemaciclib, palbociclib, or ribociclib) demonstrated greater anti-tumor activity than single agent treatment in ER-positive cell lines and PDX models.