ERLEADA® (apalutamide) HCP

mCSPC
nmCRPC

INCIDENCE OF ADVERSE REACTIONS¹

Serious adverse reactions occurred in 20% of patients in the ERLEADA^® + ADT arm and 20% of patients in the placebo + ADT arm.¹ The discontinuation rate due to adverse reactions was 8% in the ERLEADA^® + ADT arm.¹

In the combined data of 2 randomized, placebo-controlled clinical studies, rash associated with ERLEADA^® was most commonly described as macular or maculopapular. The onset of rash occurred at a median of 83 days of ERLEADA^® treatment. Rash resolved in 78% of patients within a median of 78 days from onset of rash.¹

Adverse Reactions (All Grades) With ≥10% Incidence in the ERLEADA^® + ADT Arm That Occurred With at Least 2% Greater Frequency Than in the Placebo + ADT Arm in the TITAN Study¹

Adverse Reactions	ERLEADA^® + ADT (n=524)	Placebo + ADT (n=527)
Rash	28%	9%
Hot flush	23%	16%
Hypertension	18%	16%
Arthralgia	17%	15%
Pruritus	11%	4.6%

Grades 3 and 4 Adverse Reactions in the TITAN Study¹

Adverse Reactions	ERLEADA^® + ADT (n=524)	Placebo + ADT (n=527)
Hypertension	8%	9%
Rash	6%	0.6%
Pruritus	0.2%	0.2%
Arthralgia	0.4%	0.9%
Hot flush	0%	0%

Additional Safety Information in the TITAN Study²

Treatment-Emergent Adverse Events	ERLEADA^® + ADT (n=524)	Placebo + ADT (n=527)
Any mental impairment disorder	2.7%	1.5%
Memory impairment	1.3%	1.1%
Amnesia	0.8%	0.2%
Cognitive disorder	0.8%	0.2%
Disturbance in attention	0.2%	0.2%

INCIDENCE OF ADVERSE REACTIONS¹

In the SPARTAN study, 25% of patients in the ERLEADA^® + ADT arm experienced serious adverse reactions and 23% of patients in the placebo + ADT arm.¹

Adverse Reactions (All Grades) With ≥10% Incidence in the ERLEADA^® + ADT Arm That Occurred With at Least 2% Greater Frequency Than in the Placebo + ADT Arm in the SPARTAN Study¹

Adverse Reactions	ERLEADA^® + ADT (n=803)	Placebo + ADT (n=398)
Fatigue	39%	28%
Hypertension	25%	20%
Rash	25%	6%
Diarrhea	20%	15%
Nausea	18%	16%
Weight decreased	16%	6%
Arthralgia	16%	8%
Fall	16%	9%
Hot flush	14%	9%
Decreased appetite	12%	9%
Fracture	12%	7%
Peripheral edema	11%	9%

Grades 3 and 4 Adverse Reactions in the SPARTAN Study¹

Adverse Reactions	ERLEADA^® + ADT (n=803)	Placebo + ADT (n=398)
Hypertension	14%	12%
Rash	5.2%	0.3%
Fracture	2.7%	0.8%
Fall	1.7%	0.8%
Weight decreased	1.1%	0.3%
Diarrhea	1.1%	0.5%
Fatigue	1.4%	0.3%
Decreased appetite	0.1%	0%
Arthralgia	0%	0%
Hot flush	0%	0%
Nausea	0%	0%
Peripheral edema	0%	0%

Additional Safety Information in the SPARTAN Study^3,4

Treatment-Emergent Adverse Events	ERLEADA^® + ADT (n = 803)	Placebo + ADT (n=398)
Any mental impairment disorder*	3.9%^†	3.4%^†
Amnesia	1.9%	1.0%
Memory impairment	1.6%	1.5%
Disturbance in attention	1.2%	0.3%
Cognitive disorder	0.7%	0.8%

To evaluate the potential effect of ERLEADA^® on cognitive deficits, events of amnesia, cognitive disorder, memory impairment, and disturbance in attention were assessed.^3,4

*All mental impairment disorders were Grades 1 or 2.⁴

^†Exposure-adjusted rate. An exposure-adjusted rate is 100 times the number of distinct mental impairment disorder treatment-emergent adverse events divided by total years of exposure.⁴

In the SPARTAN study, 25% of patients in the ERLEADA^® + ADT arm experienced serious adverse reactions and 23% of patients in the placebo + ADT arm.¹

Patient-reported outcomes for health-related quality of life

See patient-reported outcomes

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ADT = androgen deprivation therapy; AE = adverse event; SPARTAN = Selective Prostate Androgen Receptor Targeting with ARN-509; TEAEs = treatment-emergent adverse events; TITAN = Targeted Investigational Treatment Analysis of Novel Anti-androgen.

REFERENCES:

ERLEADA^® [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.
Data on file. Janssen Biotech, Inc.
Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378(15):1408-1418.
U.S. Food and Drug Administration. Drug Approval Package: ERLEADA^® (apalutamide). SPARTAN Clinical Study Report. Accessed December 22, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/rev_210951_arn-509-003_CSR_Redacted.pdf

WARNINGS AND PRECAUTIONS

Cerebrovascular and Ischemic Cardiovascular Events — In a randomized study (SPARTAN) of patients with nmCRPC, ischemic cardiovascular events occurred in 3.7% of patients treated with ERLEADA^® and 2% of patients treated with placebo. In a randomized study (TITAN) in patients with mCSPC, ischemic cardiovascular events occurred in 4.4% of patients treated with ERLEADA^® and 1.5% of patients treated with placebo. Across the SPARTAN and TITAN studies, 4 patients (0.3%) treated with ERLEADA^® and 2 patients (0.2%) treated with placebo died from an ischemic cardiovascular event. Patients with history of unstable angina, myocardial infarction, congestive heart failure, stroke, or transient ischemic attack within 6 months of randomization were excluded from the SPARTAN and TITAN studies.

In the SPARTAN study, cerebrovascular events occurred in 2.5% of patients treated with ERLEADA^® and 1% of patients treated with placebo. In the TITAN study, cerebrovascular events occurred in 1.9% of patients treated with ERLEADA^® and 2.1% of patients treated with placebo. Across the SPARTAN and TITAN studies, 3 patients (0.2%) treated with ERLEADA^®, and 2 patients (0.2%) treated with placebo died from a cerebrovascular event.

Cerebrovascular and ischemic cardiovascular events, including events leading to death, occurred in patients receiving ERLEADA^®. Monitor for signs and symptoms of ischemic heart disease and cerebrovascular disorders. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Consider discontinuation of ERLEADA^® for Grade 3
and 4 events.

Fractures — In a randomized study (SPARTAN) of patients with nmCRPC, fractures occurred in 12% of patients treated with ERLEADA^® and in 7% of patients treated with placebo. In a randomized study (TITAN) of patients with mCSPC, fractures occurred in 9% of patients treated with ERLEADA^® and in 6% of patients treated with placebo. Evaluate patients for fracture risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents.

Falls — In a randomized study (SPARTAN), falls occurred in 16% of patients treated with ERLEADA^® compared with 9% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure. Falls occurred in patients receiving ERLEADA^® with increased frequency in the elderly. Evaluate patients for fall risk.

Seizure — In two randomized studies (SPARTAN and TITAN), 5 patients (0.4%) treated with ERLEADA^® and 1 patient treated with placebo (0.1%) experienced a seizure. Permanently discontinue ERLEADA^® in patients who develop a seizure during treatment. It is unknown whether anti-epileptic medications will prevent seizures with ERLEADA^®. Advise patients of the risk of developing a seizure while receiving ERLEADA^® and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others.

Severe Cutaneous Adverse Reactions — Fatal and life-threatening cases of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) occurred in patients receiving ERLEADA^®.

Monitor patients for the development of SCARs. Advise patients of the signs and symptoms of SCARs (eg, a prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy). If a SCAR is suspected, interrupt ERLEADA^® until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended. If a SCAR is confirmed, or for other Grade 4 skin reactions, permanently discontinue ERLEADA^® [see Dosage and
Administration (2.2)].

Embryo-Fetal Toxicity — The safety and efficacy of ERLEADA^® have not been established in females. Based on findings from animals and its mechanism of action, ERLEADA^® can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ERLEADA^® [see Use in Specific Populations (8.1, 8.3)].

ADVERSE REACTIONS

The most common adverse reactions (≥10%) that occurred more frequently in the ERLEADA^®-treated patients (≥2% over placebo) from the randomized placebo-controlled clinical trials (TITAN and SPARTAN) were fatigue, arthralgia, rash, decreased appetite, fall, weight decreased, hypertension, hot flush, diarrhea, and fracture.

Laboratory Abnormalities — All Grades (Grade 3-4)

Hematology — In the TITAN study: white blood cell decreased ERLEADA^® 27% (0.4%), placebo 19% (0.6%). In the SPARTAN study: anemia ERLEADA^® 70% (0.4%), placebo 64% (0.5%); leukopenia ERLEADA^® 47% (0.3%), placebo 29% (0%); lymphopenia ERLEADA^® 41% (1.8%), placebo 21% (1.6%)
Chemistry — In the TITAN study: hypertriglyceridemia ERLEADA^® 17% (2.5%), placebo 12% (2.3%). In the SPARTAN study: hypercholesterolemia ERLEADA^® 76% (0.1%), placebo 46% (0%); hyperglycemia ERLEADA^® 70% (2%), placebo 59% (1.0%); hypertriglyceridemia ERLEADA^® 67% (1.6%), placebo 49% (0.8%); hyperkalemia ERLEADA^® 32% (1.9%), placebo 22% (0.5%)

Rash — In 2 randomized studies (SPARTAN and TITAN), rash was most commonly described as macular or maculopapular. Adverse reactions of rash were 26% with ERLEADA^® vs 8% with placebo. Grade 3 rashes (defined as covering >30% body surface area [BSA]) were reported with ERLEADA^® treatment (6%) vs placebo (0.5%).

The onset of rash occurred at a median of 83 days. Rash resolved in 78% of patients within a median of 78 days from onset of rash. Rash was commonly managed with oral antihistamines, topical corticosteroids, and 19% of patients received systemic corticosteroids. Dose reduction or dose interruption occurred in 14% and 28% of patients, respectively. Of the patients who had dose interruption, 59% experienced recurrence of rash upon reintroduction of ERLEADA^®.

Hypothyroidism — In 2 randomized studies (SPARTAN and TITAN), hypothyroidism was reported for 8% of patients treated with ERLEADA^® and 1.5% of patients treated with placebo based on assessments of thyroid-stimulating hormone (TSH) every 4 months. Elevated TSH occurred in 25% of patients treated with ERLEADA^® and 7% of patients treated with placebo. The median onset was at the first scheduled assessment. There were no Grade 3 or 4 adverse reactions. Thyroid replacement therapy, when clinically indicated, should be initiated or dose adjusted.

DRUG INTERACTIONS

Effect of Other Drugs on ERLEADA^® — Co-administration of a strong CYP2C8 or CYP3A4 inhibitor is predicted to increase the steady-state exposure of the active moieties. No initial dose adjustment is necessary; however, reduce the ERLEADA^® dose based on tolerability [see Dosage and Administration (2.2)].

Effect of ERLEADA^® on Other Drugs

CYP3A4, CYP2C9, CYP2C19, and UGT Substrates — ERLEADA^® is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9 in humans. Concomitant use of ERLEADA^® with medications that are primarily metabolized by CYP3A4, CYP2C19, or CYP2C9 can result in lower exposure to these medications. Substitution for these medications is recommended when possible or evaluate for loss of activity if medication is continued. Concomitant administration of ERLEADA^® with medications that are substrates of UDP-glucuronosyl transferase (UGT) can result in decreased exposure. Use caution if substrates of UGT must be co-administered with ERLEADA^® and evaluate for loss of activity.

P-gp, BCRP, or OATP1B1 Substrates — Apalutamide is a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1) clinically. Concomitant use of ERLEADA^® with medications that are substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure of these medications. Use caution if substrates of P-gp, BCRP, or OATP1B1 must be co-administered with ERLEADA^® and evaluate for loss of activity if medication is continued.

Please see the full Prescribing Information for ERLEADA^®.

cp-50507v6

ESTABLISHED SAFETY PROFILE1-4

ESTABLISHED SAFETY PROFILE^1-4