6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

Dyslipidemia [see Warnings and Precautions (5.1)]

6.1 Clinical Trials Experience

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.

The safety of ORSERDU was evaluated in 467 patients with ER+/HER2- advanced breast cancer following CDK4/6 inhibitor therapy in EMERALD, a randomized, open-label, multicenter study [see Clinical Studies (14)]. Patients received ORSERDU 345 mg orally once daily (n=237) or standard of care (SOC) consisting of fulvestrant or an aromatase inhibitor (n=230). Among patients who received ORSERDU, 22% were exposed for 6 months or longer and 9% were exposed for greater than one year.

Serious adverse reactions occurred in 12% of patients who received ORSERDU. Serious adverse reactions in >1% of patients who received ORSERDU were musculoskeletal pain (1.7%) and nausea (1.3%). Fatal adverse reactions occurred in 1.7% of patients who received ORSERDU, including cardiac arrest, septic shock, diverticulitis, and unknown cause (one patient each).

Permanent discontinuation of ORSERDU due to an adverse reaction occurred in 6% of patients. Adverse reactions which resulted in permanent discontinuation of ORSERDU in >1% of patients were musculoskeletal pain (1.7%) and nausea (1.3%).

Dosage interruptions of ORSERDU due to an adverse reaction occurred in 15% of patients. Adverse reactions which resulted in dosage interruption of ORSERDU in >1% of patients were nausea (3.4%), musculoskeletal pain (1.7%), and increased ALT (1.3%).

Dosage reductions of ORSERDU due to an adverse reaction occurred in 3% of patients. Adverse reactions which required dosage reductions of ORSERDU in >1% of patients were nausea (1.7%).

The most common (≥10%) adverse reactions, including laboratory abnormalities, of ORSERDU were musculoskeletal pain, nausea, increased cholesterol, increased AST, increased triglycerides, fatigue, decreased hemoglobin, vomiting, increased ALT, decreased sodium, increased creatinine, decreased appetite, diarrhea, headache, constipation, abdominal pain, hot flush, and dyspepsia.

Table 3 summarizes the adverse reactions in EMERALD.

Table 3: Adverse Reactions (>10%) in Patients with ER-positive, HER2-negative, Advanced or Metastatic Breast Cancer Who Received ORSERDU in EMERALDa

aAdverse reactions were graded using NCI CTCAE version 5.0.
bIncludes other related terms
cOnly includes Grade 3 adverse reactions.
Adverse Reaction	ORSERDU (n=237)		Fulvestrant or an Aromatase Inhibitor (n=230)
Adverse Reaction	All Grades (%)	Grade 3 or 4 c (%)	All Grades (%)	Grade 3 or 4 c (%)
Musculoskeletal and connective tissue disorders
Musculoskeletal painb	41	7	39	1
Gastrointestinal disorders
Nausea	35	2.5	19	0.9
Vomitingb	19	0.8	9	0
Diarrhea	13	0	10	1
Constipation	12	0	6	0
Abdominal painb	11	1	10	0.9
Dyspepsia	10	0	2.6	0
General disorders
Fatigueb	26	2	27	1
Metabolism and nutrition disorders
Decreased appetite	15	0.8	10	0.4
Nervous system
Headache	12	2	12	0
Vascular disorders
Hot flush	11	0	8	0

Clinically relevant adverse reactions in < 10% of patients who received ORSERDU included rash, insomnia, dyspnea, cough, dizziness, stomatitis and gastroesophageal reflux disease.

Table 4 summarizes the laboratory abnormalities in EMERALD.

Table 4: Select Laboratory Abnormalities (>10%) That Worsened from Baseline in Patients with ER-positive, HER2-negative, Advanced or Metastatic Breast Cancer Who Received ORSERDU in EMERALDa

aThe denominator used to calculate the rate varied from 29 to 236 for ORSERDU and from 37 to 225 for fulvestrant or an aromatase inhibitor based on the number of patients with a baseline value and at least one post-treatment value.
Laboratory Abnormality	ORSERDUa		Fulvestrant or an Aromatase Inhibitora
Laboratory Abnormality	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
Chemistry
Cholesterol increased	30	1	17	0
Aspartate aminotransferase increased	29	0	34	1
Triglycerides increased	27	2	15	1
Alanine aminotransferase increased	17	0	24	1
Sodium decreased	16	1	15	0
Creatinine increased	16	0	6	0
Hematology
Hemoglobin decreased	26	1	20	2