6 ADVERSE REACTIONS

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.

Non-Metastatic Castration Resistant Prostate Cancer

The safety of NUBEQA was evaluated in ARAMIS, a randomized (2:1), double-blind, placebo-controlled, multi-center clinical study, that enrolled patients who had non-metastatic castration-resistant prostate cancer (nmCRPC) [see Clinical Studies (14)]. Patients received either NUBEQA at a dose of 600 mg, or a placebo, twice a day. All patients in the ARAMIS study received a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy. Among patients who received NUBEQA, the median duration of exposure was 14.8 months (range: 0 to 44.3 months).

Serious adverse reactions occurred in 25% of patients receiving NUBEQA and in 20% of patients receiving placebo. Serious adverse reactions in ≥1% of patients who received NUBEQA included urinary retention, pneumonia and hematuria. Fatal adverse reactions occurred in 3.9% of patients receiving NUBEQA and 3.2% of patients receiving placebo. Fatal adverse reactions in patients who received NUBEQA included death (0.4%), cardiac failure (0.3%), cardiac arrest (0.2%), general physical health deterioration (0.2%), and pulmonary embolism (0.2%).

Permanent discontinuation of NUBEQA due to adverse reactions occurred in 9% of patients receiving NUBEQA. The most common adverse reactions requiring permanent discontinuation in patients who received NUBEQA included cardiac failure (0.4%), and death (0.4%).

Dosage interruptions due to adverse reactions occurred in 13% of patients treated with NUBEQA. The most common adverse reactions requiring dosage interruption in patients who received NUBEQA included hypertension (0.6%), diarrhea (0.5%), and pneumonia (0.5%).

Dosage reductions due to adverse reactions occurred in 6% of patients treated with NUBEQA. The most common adverse reactions requiring dosage reduction in patients treated with NUBEQA included fatigue (0.7%), hypertension (0.3%), and nausea (0.3%).

The most common (>2% with a ≥2% increase compared to placebo) adverse reactions, including laboratory test abnormalities, were AST increased, neutrophil count decreased, fatigue, bilirubin increased, pain in extremity, and rash.

Table 1 summarizes the adverse reactions in ARAMIS.

Table 1: Adverse Reactions (>2% with a ≥2% increase compared to placebo) in Patients with Non-Metastatic Castration Resistant Prostate Cancer in ARAMIS
* Includes fatigue and asthenia † Includes rash, eczema, rash maculo-papular, dermatitis, erythema multiforme, rash macular, rash papular, rash pustular, skin exfoliation
Adverse Reaction	NUBEQA (n=954)		Placebo (n=554)
Adverse Reaction	All Grades %	Grades 3 or 4 %	All Grades %	Grade 3 or 4 %
Fatigue*	16	0.6	11	1.1
Pain in extremity	6	0	3	0.2
Rash†	4	0.1	1.4	0

Clinically relevant adverse reactions occurring in 2% or more of patients treated with NUBEQA included ischemic heart disease (4%) and heart failure (2.1%).

Table 2 summarizes the laboratory test abnormalities in ARAMIS.

Table 2: Laboratory Test Abnormalities in ARAMIS
Laboratory Abnormality	NUBEQA (N=954)*		Placebo (N=554)*
Laboratory Abnormality	All Grades† %	Grade 3-4 %	All Grades %	Grade 3-4 %
* The denominator used to calculate the rate varied based on the number of patients with a baseline value and at least one post-treatment value. † The denominator used to calculate the rate varied from 470 to 648 based on the number of patients with a baseline value and at least one post-treatment value.
AST increased	23	0.5	14	0.2
Neutrophil count decreased	20	4	9	0.6
Bilirubin increased	16	0.1	7	0

Metastatic Hormone-Sensitive Prostate Cancer

The safety of NUBEQA, in combination with docetaxel, was evaluated in ARASENS, a randomized (1:1), double-blind, placebo-controlled, multi-center clinical study, that enrolled patients who had mHSPC [see Clinical Studies (14)]. Patients were to receive either NUBEQA at a dose of 600 mg, or a placebo, twice a day in combination with docetaxel at a dose of 75 mg/m2 every 21 days for 6 cycles. All patients in the ARASENS study received a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy. Patients with a medical history of seizure were allowed to enter the study. Among patients who received NUBEQA, the median duration of exposure was 41 months (range: 0.1 to 56.5 months) vs. 16.7 months (range 0.3 to 55.8) with placebo. Eighty-eight percent and 86% of patients received the 6 planned cycles of docetaxel, in the NUBEQA with docetaxel arm and placebo with docetaxel arm, respectively.

Serious adverse reactions occurred in 45% of patients receiving NUBEQA with docetaxel and in 42% of patients receiving placebo with docetaxel, respectively. Serious adverse reactions in ≥ 2% of patients who received NUBEQA with docetaxel included febrile neutropenia (6%), neutrophil count decreased (2.8%), musculoskeletal pain (2.6%) and pneumonia (2.6%). Fatal adverse reactions occurred in 4% of patients receiving NUBEQA with docetaxel and 4% of patients receiving placebo with docetaxel. Fatal adverse reactions in patients who received NUBEQA included COVID-19/COVID-19 pneumonia (0.8%), myocardial infarction (0.3%), and sudden death (0.3%).

Permanent discontinuation of NUBEQA due to adverse reactions occurred in 14% of patients treated in the NUBEQA with docetaxel arm. The most common adverse reactions which resulted in permanent discontinuation of NUBEQA were rash (1.1%), musculoskeletal pain (0.9%), and aspartate aminotransferase (AST) increased (0.9%).

Dosage interruptions of NUBEQA due to adverse reactions occurred in 23% of patients treated in the NUBEQA with docetaxel arm. The most common (>2%) adverse reactions requiring dosage interruption of NUBEQA were alanine aminotransferase (ALT) increased (3.2%), AST increased (3.1%) and febrile neutropenia (2.1%).

Dosage reductions of NUBEQA due to adverse reactions occurred in 9% of patients treated in the NUBEQA with docetaxel arm. The most common (>2%) adverse reactions requiring dosage reduction of NUBEQA were ALT increased (2.8%) and AST increased (2.5%).

The most common (>10% with a ≥2% increase over placebo with docetaxel) adverse reactions are constipation, rash decreased appetite, hemorrhage, weight increased, and hypertension. The most common laboratory test abnormalities (≥30%) are anemia, hyperglycemia, lymphocyte count decreased, neutrophil count decreased, AST increased, ALT increased, and hypocalcemia.

Table 3 summarizes the adverse reactions in ARASENS.

Table 3: Adverse Reactions (≥10% with a ≥2% increase compared to placebo with docetaxel) in ARASENS
* Rash includes rash, rash maculo-papular, palmar-plantar erythrodysesthesia syndrome, eczema, dermatitis, skin exfoliation, dermatitis acneiform, drug eruption, rash pruritic, rash erythematous, erythema multiforme, rash macular, dermatitis exfoliative generalized, penile rash, dyshidrotic eczema, rash papular, dermatitis bullous, rash follicular, rash pustular, rash vesicular, toxic skin eruption † Hypertension includes hypertension, blood pressure increased, hypertensive emergency and hypertensive crisis.
Adverse Reaction	NUBEQA with docetaxel (n=652)		Placebo with docetaxel (n=650)
Adverse Reaction	All Grades %	Grades 3 or 4 %	All Grades %	Grades 3 or 4 %
Constipation	23	0.3	20	0.3
Rash*	20	1.8	15	0.2
Decreased Appetite	19	0.2	13	0.6
Hemorrhage	18	1.4	13	1.4
Weight Increased	18	2.1	16	1.2
Hypertension†	14	7	10	3.6

Hemorrhage includes hematuria, epistaxis, anal hemorrhage, hemorrhoidal hemorrhage, rectal hemorrhage, upper gastrointestinal hemorrhage, hemoptysis, hemorrhage urinary tract, hemorrhagic stroke, subarachnoid hemorrhage, lower gastrointestinal hemorrhage, cystitis hemorrhagic, gastrointestinal hemorrhage, hemorrhage subcutaneous, intra-abdominal hemorrhage, nail bed bleeding, subdural hemorrhage

Clinically relevant adverse reactions in < 10% of patients who received NUBEQA with docetaxel included fractures (8%), ischemic heart disease (3.2%), seizures (0.6%), and drug-induced liver injury (0.3%).

Table 4 summarizes laboratory test abnormalities in the ARASENS study.

Table 4: Laboratory Test Abnormalities (≥30%) in ARASENS


* ALT or AST increases to ≥5 x upper limit of normal (ULN) occurred in 5.3% of patients who received NUBEQA with docetaxel. ALT or AST increases to ≥20 x ULN occurred in 0.3% of patients who received NUBEQA with docetaxel. The median time to onset of any grade ALT or AST increases was 2.8 months (range: 0.03 to 46.9).
Laboratory Abnormality	NUBEQA with docetaxel† (N=652)		Placebo with docetaxel† (N=650)
Laboratory Abnormality	All Grades %	Grade 3-4 %	All Grades %	Grade 3-4 %
Anemia	72	6	71	7
Hyperglycemia	57	7	53	10
Lymphocyte count decreased	52	12	49	13
Neutrophil count decreased	49	33	44	31
AST increased*	40	3.6	35	2.3
ALT increased*	37	3.7	31	2.9
Hypocalcemia	31	2.8	28	1.9

Clinically relevant laboratory test abnormalities in < 30% of patients who received NUBEQA with docetaxel included blood bilirubin increased (all grades 20%, Grade 3-4 0.5%) compared to placebo with docetaxel (all grades 10%, grades 3-4 0.3%).