ERLEADA® (apalutamide) HCP

Median metastasis free survival, Placebo and ADT 1.4 years, Erleada and ADT 3.4 years

Bar graph showing median metastasis free survival, Placebo and ADT 1.4 years, Erleada and ADT 3.4 years

HR=0.28; 95% CI: 0.23, 0.35; P<0.0001

Consistent results in metastasis-free survival (MFS) were observed across patient subgroups, including¹:

PSA doubling time (≤6 months or >6 months)
Use of a prior bone-sparing agent (yes or no)
Locoregional disease (N0 or N1)

*Metastasis-free survival was defined as the time from randomization to the time of first evidence of blinded independent central review-confirmed distant metastasis, defined as new bone or soft tissue lesions or enlarged lymph nodes above the iliac bifurcation, or death due to any cause, whichever occurred first.¹

At the time of the analysis, 60.9% of patients were still on ERLEADA^® + ADT vs 29.9% of patients still on placebo + ADT²

Secondary endpoints favored the ERLEADA® + ADT arm¹

Progression free survival Erleada and A D T 40.5 months vs Placebo and A D T 14.7 months

^†Time to metastasis was defined as the time from randomization to the time of the scan that showed first evidence of blinded independent central review-confirmed radiographically detectable bone or soft tissue distant metastasis.^2,3

^‡Progression-free survival was defined as the time from randomization to first documentation of blinded independent central review-confirmed radiographic progressive disease or death due to any cause, whichever occurred first.^2,3

Sites of metastasis^§4

Patients with metastasis (%)	ERLEADA^® + ADT (n=175)	Placebo + ADT (n=191)
Bone	57%	52%
Nodal	30%	40%
Visceral	13%	8%

^§As reported in a post hoc analysis of SPARTAN. In the SPARTAN study, 175 patients (22%) in the ERLEADA^® + ADT arm and 191 patients (48%) in the placebo + ADT arm developed metastasis.¹

Secondary endpoint:

The metastasis-free survival (MFS) outcome was supported by a statistically significant improvement in time to symptomatic progression¹

Time to symptomatic progression was defined as the time from randomization to documentation of any of the following (whichever occurred earlier)^2,3

Development of a skeletal-related event: pathologic fracture, spinal cord compression, or need for surgical intervention or radiation therapy to the bone
Pain progression or worsening of disease-related symptoms requiring initiation of a new systemic anticancer therapy
Development of clinically significant symptoms due to locoregional tumor progression requiring surgical intervention or radiation therapy

Examples of symptomatic progression evaluated in the SPARTAN study:

A circular x-ray, showing the spinal cord being pinched by a lump

Spinal cord compression

A circular x-ray, showing a replaced hip joint

The need for surgical intervention

The need for radiation therapy

SPARTAN Final Analysis

Final analysis data from the SPARTAN study are not currently reported in the Prescribing Information for ERLEADA^®.

SPARTAN has the longest follow-up period of the registration trials that supported indications for the treatment of nmCRPC^5-7

October 14, 2013

First patient randomized

SPARTAN Trial Begins

May 19, 2017

Clinical cutoff date

Primary Analysis

Median follow-up time: 20.3 months⁵

19% of patients in the placebo + ADT arm crossed over to receive ERLEADA^® + ADT when the study was unblinded at the primary analysis.⁵

Overall survival data were immature at this time.¹

February 1, 2020

Clinical cutoff date

Final Analysis

Median follow-up time: 52.0 months⁵

At the time of the final analysis, 30% of patients originally randomized to the ERLEADA^® + ADT arm were continuing to receive treatment with ERLEADA^® + ADT.⁵

Prespecified analysis of overall survival was conducted.⁵

Patients receiving ERLEADA^® + ADT stayed on therapy approximately 3 times longer than those receiving placebo + ADT⁵

Median Duration of Exposure at the Final Analysis⁵

Many patients who received ERLEADA^® lived more than 1 year longer:

ERLEADA^® + ADT improved median overall survival by 14 MONTHS vs placebo + ADT⁵

Secondary endpoint:

Overall Survival⁵

Median follow-up time was 52.0 months.⁵

Median overall survival for patients who took ERLEADA^® + ADT was more than 6 years compared with 5 years for patients who took placebo + ADT⁵

ADT = androgen deprivation therapy; CI = confidence interval; HR = hazard ratio; nmCRPC = non-metastatic castration-resistant prostate cancer; PSA = prostate-specific antigen; SPARTAN = Selective Prostate Androgen Receptor Targeting with ARN-509.

References

1. ERLEADA^® [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.

2. Smith MR, Saad F, Chowdhury S, et al; for the SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378(15):1408-1418.

3. U.S. Food and Drug Administration. Drug Approval Package: ERLEADA^® (apalutamide). SPARTAN Clinical Study Report. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/Erleada_210951_toc.cfm. Accessed August 14, 2020.

4. Smith MR, Saad F, Rathkopf DE, et al. Relationship of time to metastasis (TTM) and site of metastases in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC): results from the phase 3 SPARTAN trial [abstract 5033]. J Clin Oncol. 2018;36(15_suppl).

5. Smith MR, Saad F, Chowdhury S, et al. Apalutamide and overall survival in prostate cancer [published online September 6, 2020]. Eur Urol. doi.org/10.1016/j.eururo.2020.08.011

6. Sternberg CN, Fizazi K, Saad F, et al; PROSPER Investigators. Enzalutamide and survival in nonmetastatic castration-resistant prostate cancer. N Engl J Med. 2020;382(23):2197-2206.

7. Fizazi K, Shore ND, Tammela T, et al. Overall survival results of phase III ARAMIS study of darolutamide added to androgen deprivation therapy for non-metastatic castration-resistant prostate cancer. Poster presented at: ASCO Annual Meeting; May 29-31, 2020; Chicago, IL.

WARNINGS AND PRECAUTIONS

Ischemic Cardiovascular Events — In a randomized study (SPARTAN) of patients with nmCRPC, ischemic cardiovascular events occurred in 4% of patients treated with ERLEADA^® and 3% of patients treated with placebo. In a randomized study (TITAN) in patients with mCSPC, ischemic cardiovascular events occurred in 4% of patients treated with ERLEADA^® and 2% of patients treated with placebo. Across the SPARTAN and TITAN studies, 6 patients (0.5%) treated with ERLEADA^® and 2 patients (0.2%) treated with placebo died from an ischemic cardiovascular event. Patients with current evidence of unstable angina, myocardial infarction, or congestive heart failure within 6 months of randomization were excluded from the SPARTAN and TITAN studies.

Ischemic cardiovascular events, including events leading to death, occurred in patients receiving ERLEADA^®. Monitor for signs and symptoms of ischemic heart disease. 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 2 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.

Embryo-Fetal Toxicity — The safety and efficacy of ERLEADA^® have not been established in females. Based on 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

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% (2%), placebo 21% (2%)
Chemistry — In the TITAN study: hypertriglyceridemia ERLEADA^® 17% (3%), placebo 12% (2%). In the SPARTAN study: hypercholesterolemia ERLEADA^® 76% (0.1%), placebo 46% (0%); hyperglycemia ERLEADA^® 70% (2%), placebo 59% (1%); hypertriglyceridemia ERLEADA^® 67% (2%), placebo 49% (0.8%); hyperkalemia ERLEADA^® 32% (2%), placebo 22% (0.5%)

Rash — In 2 randomized studies, 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, hypothyroidism was reported for 8% of patients treated with ERLEADA^® and 2% 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 — 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-50507v2

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Access and Affordability

Patient Resources

Efficacy in nmCRPC

ERLEADA^® + ADT improved median metastasis-free survival (MFS) by 2 YEARS vs placebo + ADT¹

The metastasis-free survival (MFS) outcome was supported by a statistically significant improvement in time to symptomatic progression¹

SPARTAN has the longest follow-up period of the registration trials that supported indications for the treatment of nmCRPC^5-7

ERLEADA^® + ADT improved median overall survival by 14 MONTHS vs placebo + ADT⁵

DOSING

Mechanism of Action

SAFETY

SPARTAN
Primary Publication

SPARTAN
Final Analysis Publication

SPARTAN Patient-Reported Outcomes Publication

You are leaving the HCP website

Locate a Representative

Request Samples

Register for Updates

Frequently Asked Questions

Access and Affordability

Patient Resources

Useful Tools & Info

Efficacy in nmCRPC

ERLEADA® + ADT improved median metastasis-free survival (MFS) by 2 YEARS vs placebo + ADT1

The metastasis-free survival (MFS) outcome was supported by a statistically significant improvement in time to symptomatic progression1

SPARTAN has the longest follow-up period of the registration trials that supported indications for the treatment of nmCRPC5-7

ERLEADA® + ADT improved median overall survival by 14 MONTHS vs placebo + ADT5

DOSING

Mechanism of Action

SAFETY

SPARTANPrimary Publication

SPARTANFinal Analysis Publication

SPARTAN Patient-Reported Outcomes Publication

You are leaving the HCP website

Useful Tools & Info

ERLEADA^® + ADT improved median metastasis-free survival (MFS) by 2 YEARS vs placebo + ADT¹

The metastasis-free survival (MFS) outcome was supported by a statistically significant improvement in time to symptomatic progression¹

SPARTAN has the longest follow-up period of the registration trials that supported indications for the treatment of nmCRPC^5-7

ERLEADA^® + ADT improved median overall survival by 14 MONTHS vs placebo + ADT⁵

SPARTAN
Primary Publication

SPARTAN
Final Analysis Publication