Summary Basis of Decision for Erleada
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Erleada is located below.
Recent Activity for Erleada
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
Post-Authorization Activity Table (PAAT) for Erleada
Updated:
The following table describes post-authorization activity for Erleada, a product which contains the medicinal ingredient apalutamide. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
Drug Identification Number (DIN):
- DIN 02478374 - 60 mg apalutamide tablet, oral
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| Drug product (DIN 02478374) market notification | Not applicable | Date of first sale:2018-07-27 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 211942 | 2017-12-07 | Issued NOC2018-07-03 | Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Erleada
Date SBD issued: 2018-08-27
The following information relates to the new drug submission for Erleada.
Apalutamide
60 mg, tablet, oral
Drug Identification Number (DIN):
- 02478374
Janssen Inc.
New Drug Submission Control Number: 211942
On July 3, 2018, Health Canada issued a Notice of Compliance to Janssen Inc. for the drug product Erleada.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit-harm-uncertainty profile of Erleada is considered favourable for the treatment of patients with non-metastatic castration-resistant prostate cancer at high risk of developing metastases.
1 What was approved?
Erleada, an androgen receptor inhibitor, was authorized for the treatment of patients with non-metastatic castration-resistant prostate cancer. Erleada has not been studied in patients with non-metastatic castration-resistant prostate cancer at low risk of developing metastases. The benefit-risk profile in these patients is unknown.
No overall differences in effectiveness were observed between geriatric patients (over 65 years of age) and younger patients treated with Erleada. Geriatric patients may experience more toxicity and lower tolerability than younger patients. The safety and effectiveness of Erleada in children (under 18 years of age) have not been evaluated.
Erleada is contraindicated in:
- patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
- women who are or may become pregnant.
Erleada was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Erleada (60 mg apalutamide) is presented as tablets. In addition to the medicinal ingredient, the tablet core contains: colloidal anhydrous silica, croscarmellose sodium, hydroxypropyl methylcellulose-acetate succinate, magnesium stearate, microcrystalline cellulose, and silicified microcrystalline cellulose. The following non-medicinal ingredients are present in the tablet coating: iron oxide black (E172), iron oxide yellow (E172), polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.
For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Besponsa Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Erleada approved?
Health Canada considers that the benefit-harm-uncertainty profile of Erleada is favourable for the treatment of patients with non-metastatic castration-resistant prostate cancer at high risk of developing metastases. Erleada has not been studied in patients with the disease at low risk of developing metastases and the benefit-risk profile of Erleada in these patients is unknown.
Prostate cancer is the second most common cancer and the third most common cause of cancer death in men in Canada.
During the early stages of the disease, when cancerous cells are limited to the prostate (localized) or surrounding tissues within the pelvis (locally advanced), patients are often treated with surgery or radiation-based approaches. Approximately 30% of patients experience a biochemical recurrence, defined by increasing prostate-specific antigen (PSA) levels. When there is a biochemical recurrence, patients are usually treated with androgen deprivation therapy (i.e., surgical or medical castration), aimed at lowering blood testosterone concentrations to castration levels and reducing androgen receptor signalling. Most patients initially benefit from androgen deprivation therapy; however, in nearly all patients, the disease eventually progresses after 12 to 48 months depending on the disease burden, host factors, and inherent tumour biology.
When PSA levels begin to rise again despite castration-level serum testosterone and if there is no evidence of metastatic disease, the disease is termed non-metastatic castration-resistant prostate cancer. Patients with non-metastatic castration-resistant prostate cancer and a PSA doubling time of ≤10 months are at high risk of developing metastases, which are associated with serious consequences including skeletal-related events and death. The median time to occurrence of distant metastatic disease is approximately 2 years in this high-risk population.
There are currently no approved therapies for patients with non-metastatic castration-resistant prostate cancer and there is uncertainty regarding optimal management of the disease. These patients are largely asymptomatic, so the burden of long-term toxicities and the potential for negative impact on quality of life are also major considerations in the selection of therapy. The disease phase, previously defined as hormone-refractory prostate cancer, is now understood to still be androgen dependent.
Apalutamide, the medicinal ingredient in Erleada, is a nonsteroidal anti-androgen that binds to the ligand-binding domain of the androgen receptor. In contrast to the first generation of anti-androgens, apalutamide shows no significant agonist properties.
The market authorization of Erleada was primarily based on efficacy and safety data derived from a randomized, double-blind, placebo-controlled Phase III clinical trial, (ARN-509-003, also named SPARTAN), conducted in patients with non-metastatic castration-resistant prostate cancer who were at high risk of developing distant metastases (defined by PSA doubling time of ≤10 months). Treatment with Erleada plus androgen deprivation therapy decreased the risk of distant metastases or death (metastasis-free survival) by 70% compared with placebo plus androgen deprivation therapy. The median metastasis-free survival was 2 years longer in patients treated with Erleada. The improvement in metastasis-free survival was supported by three secondary efficacy endpoints: time to metastases, progression-free survival, and time to symptomatic progression. Overall survival was insignificant at the time of the primary analysis but not detrimental to patients treated with Erleada. Time to initiation of cytotoxic chemotherapy could not be evaluated due to the insignificant overall survival results.
Based on the patient population studied, an indication for patients with non-metastatic castration-resistant prostate cancer at high risk of developing metastases was proposed by Health Canada. The sponsor proposed to include all patients with the disease regardless of the risk of developing metastases. Based on the information provided and the safety profile of Erleada, an indication for patients with non-metastatic castration-resistant prostate cancer was finalized with an inclusion of a caveat statement to capture that patients at low risk of developing metastases have not been studied and the benefit-risk profile of Erleada in these patients is unknown.
The safety profile of Erleada plus androgen deprivation therapy is considered manageable for patients with non-metastatic castration-resistant prostate cancer, and the Erleada Product Monograph has been updated to include most safety results reported in SPARTAN. Overall incidences of treatment emergent adverse events and serious adverse events were comparable between the two treatment arms. However, higher incidences of severe adverse events and adverse events leading to dose modification or discontinuation suggest higher toxicity and lower tolerability of patients treated with Erleada and androgen deprivation therapy over androgen deprivation therapy alone. Erleada also increased risks of known toxicities associated with androgen deprivation therapy, including falls and fractures, cardiac disorders (including QTc prolongation), and serious infections. Deaths due to adverse events (cardiac disorders, infections, and cerebrovascular accidents) were also reported with higher incidences in patients treated with Erleada, but the overall incidence was low. These safety concerns and risk management information are included in the Erleada Product Monograph.
A Risk Management Plan (RMP) for Erleada was submitted by Janssen Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Erleada Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A Look-alike Sound-alike brand name assessment was performed and the proposed name, Erleada, was accepted.
Treatment with Erleada plus androgen deprivation therapy in patients with non-metastatic castration-resistant prostate cancer at high risk of developing metastases demonstrates significant improvement in delaying distant metastases or death over androgen deprivation therapy alone. The efficacy results suggest early intervention with Erleada can delay disease progression in the high-risk patient population. The safety profile of Erleada plus androgen deprivation therapy is manageable with proper monitoring and clinical interventions, when necessary. Overall, the data provided in this submission establish a favourable benefit-harm-uncertainty profile for the use of Erleada in the treatment of patients with high risk non-metastatic castration-resistant prostate cancer.
Appropriate warnings and precautions are in place in the Erleada Product Monograph to address most safety concerns from the clinical trial SPARTAN.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Erleada?
The drug submission for Erleada was reviewed under the Priority Review Policy. Substantial evidence has been provided to demonstrate a significant increase in efficacy such that the overall benefit-risk profile of Erleada is improved over existing therapies for non-metastatic castration-resistant prostate cancer, a disease that is not adequately managed by a drug marketed in Canada.
The submission was assessed through a work-sharing initiative by Health Canada and the Australian regulatory authority for therapeutic goods, Therapeutic Goods Administration (TGA).
Submission Milestones: Erleada
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2017-10-17 |
| Request for priority status | |
| Filed: | 2017-11-01 |
| Approval issued by Director, Bureau of Medical Sciences: | 2017-12-01 |
| Submission filed: | 2017-12-07 |
| Screening | |
| Screening Acceptance Letter issued: | 2018-01-05 |
| Review | |
| Quality Evaluation complete: | 2018-06-27 |
| Clinical Evaluation complete: | 2018-07-03 |
| Review of Risk Management Plan complete: | 2018-03-23 |
| Labelling Review complete, including Look-alike Sound-alike brand name assessment: | 2018-06-20 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate: | 2018-07-03 |
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
The clinical pharmacology data support the use of Erleada for the recommended indication.
Thirteen Phase I/Ib clinical pharmacology studies and simulations were reviewed to characterize the pharmacokinetics of apalutamide (the medicinal ingredient in Erleada) and its major metabolite, N-desmethyl apalutamide, in 83 healthy subjects, 16 subjects with mild or moderate hepatic impairment, and 108 patients with castration-resistant prostate cancer, mostly metastatic disease. Both 30 mg softgel capsules and 60 mg tablets were investigated in the clinical pharmacology program. The tablets are the formulation intended for marketing.
Apalutamide is rapidly absorbed following oral administration with an absolute bioavailability of 100% in healthy subjects. Based on the population pharmacokinetic analysis, healthy subjects exhibit 27% higher bioavailability compared to castration-resistant prostate cancer patients after accounting for body weight and serum albumin concentration. The result may be confounded since healthy subjects were exposed to a single dose compared to castration-resistant prostate cancer patients treated with multiple doses. Apalutamide is 96% bound to plasma proteins, primarily serum albumin, and equally distributes to red blood cells and plasma.
The pharmacokinetics of apalutamide is dose proportional across the dose range of 30 mg to 480 mg. Following the recommended 240 mg daily dosing schedule, steady state was achieved after 4 weeks, with plasma concentrations approximately 5-fold higher than a single dose.
Apalutamide is metabolized in the liver by cytochrome P450 (CYP) enzymes CYP2C8 and CYP3A4. It also induces its own metabolism via CYP3A4 after multiple doses. Thus, accumulation at steady state is lower than predicted by single-dose data. Potent CYP2C8 and CYP3A4 inhibitors and inducers increase and decrease apalutamide steady-state exposure, respectively; however, no initial dose adjustments are necessary.
Apalutamide is a strong inducer of CYP3A4, CYP2C19, and CYP2C9 and substantially reduces exposure to medications metabolized by these enzymes (e.g., midazolam, omeprazole, and warfarin). Therefore, substitution of these medications is recommended to prevent loss of efficacy. Apalutamide was shown clinically to be a weak inducer of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide 1B1 (OATP1B1). Concomitant use of Erleada with medications that are substrates of P-gp, BCRP, or OATP1B1 can result in lower exposure to these medications. Hence, caution is advised if substrates of P-gp, BCRP or OATP1B1 have to be co-administered with Erleada. The established and potential drug-drug interactions are included in the Erleada Product Monograph.
No dose adjustment is recommended based on age, race, body weight, or in patients with mild or moderate hepatic or renal impairment based on population pharmacokinetic analyses. There are no data in subjects with severe hepatic or renal impairment.
Apalutamide may be taken with or without food. However, a high fat meal delayed the median time to reach peak plasma concentration (tmax) by approximately 2 hours compared to the fasting state.
Based on the review of the clinical pharmacology studies provided in the submission, there are no issues to preclude approval of Erleada for the recommended indication.
For further details, please refer to the Erleada Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The efficacy data to support the use of Erleada in patients with non-metastatic, castration-resistant prostate cancer at high risk of developing metastases were primarily derived from the pivotal study, ARN-509-003 (also named SPARTAN). Supportive efficacy data were obtained from a Phase I/II study, ARN-509-001.
Study ARN-509-003 is an ongoing multicentre, randomized, double-blind, placebo-controlled Phase III clinical trial. A total of 1,207 patients with non-metastatic, castration-resistant prostate cancer were randomized in a 2:1 ratio to receive Erleada plus androgen deprivation therapy (gonadotropin-releasing hormone analog or bilateral orchiectomy) or placebo plus androgen deprivation therapy. Patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 74 years and 26% of patients were 80 years of age or older. The majority of patients were Caucasian. Most patients had a Gleason score of 7 or higher at initial diagnosis. At study entry, 23% of patients had nodal disease (<2 cm) located below the iliac bifurcation and 77% of patients had no nodal disease. All patients enrolled were confirmed to have a non-metastatic disease but had a high risk of developing metastases as defined by prostate specific antigen doubling time (PSADT) of ≤10 months.
As of the clinical cut-off date (May 19, 2017), 61% of patients in the Erleada arm and 30% of patients in the placebo arm were continuing study treatment. The median treatment duration was 16.9 months in the Erleada arm and 11.2 months in the placebo arm. The addition of Erleada to an androgen deprivation therapy regimen resulted in statistically significant and clinically meaningful improvement in metastasis-free survival compared with androgen deprivation therapy alone. Treatment with Erleada + androgen deprivation therapy significantly decreased the risk of distant metastasis or death by 70% compared with placebo + androgen deprivation therapy. The median metastasis-free survival was 40.5 months for the Erleada arm and 15.7 months for the placebo arm. This treatment benefit was supported by three secondary endpoints: time to metastasis, progression-free survival, and time to symptomatic progression.
There was no detrimental effect on the overall survival and time to initiation of cytotoxic chemotherapy, although improvement of either of these secondary endpoints was not demonstrated. The overall survival data were not mature at the time of the primary analysis and the p-value did not reach the predefined statistical significance level. The time to initiation of cytotoxic chemotherapy could not be evaluated based on the hierarchical testing scheme.
Overall, patients treated with androgen deprivation therapy alone in Study ARN-509-003 had a median time of 16 months to development of distant metastasis or death, indicative of a high-risk population. Treatment with Erleada plus androgen deprivation therapy demonstrated a better outcome than androgen deprivation therapy alone in delaying the development of metastases or death in patients with high-risk non-metastatic, castration-resistant prostate cancer.
Indication
The New Drug Submission for Erleada was filed with the following indication proposed by the sponsor:
- Erleada (apalutamide) is indicated for the treatment of patients with castration-resistant prostate cancer who have no detectable distant metastases by either computerized tomography (CT) scan, magnetic resonance imaging (MRI) or technetium-99m bone scan.
During the review, Health Canada recommended an indication to reflect the patient population investigated in Study ARN-509-003, i.e., patients with non-metastatic castration-resistant prostate cancer at high risk of developing metastases. However, the sponsor insisted on the initially proposed broad indication which referred to all patients with non-metastatic castration-resistant prostate cancer regardless of the risk of developing metastases. As Erleada has not been studied in patients with the disease at low risk of developing metastases, and given its safety profile, Health Canada recommended a caveat statement inclusion in the broad indication, and approved the following indication:
- Erleada (apalutamide tablets) is indicated for the treatment of patients with non-metastatic castration-resistant prostate cancer (NM-CRPC).
Erleada has not been studied in patients with NM-CRPC at low risk of developing metastases. The benefit and risk profile in these patients is unknown.
For more information, refer to the Erleada Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The safety of 240 mg of Erleada plus androgen deprivation therapy in patients with non-metastatic, castration-resistant prostate cancer was supported primarily by data from Study ARN-509-003 (described in the Clinical Efficacy section). Data from a dedicated QT study in 45 patients treated with Erleada plus androgen deprivation therapy were also provided.
In Study ARN-509-003, median treatment duration was 16.9 months for Erleada-treated patients and 11.2 months for placebo-treated patients. Overall incidences of patients with any treatment emergent adverse events and serious adverse events were similar between the two treatment arms. Higher incidences of severe (Grade 3-4) adverse events and adverse events leading to dose modification were reported in the Erleada arm.
Adverse events of special interest for Erleada were rash, fall, fracture, seizure, and hypothyroidism.
Although the incidences of overall serious adverse events were similar between the two treatment arms, the following serious adverse events were reported more frequently in the Erleada arm: fracture, urinary tract infection, pneumonia, and sepsis. Most serious fractures occurred in weight-bearing bones, suggesting worsening osteopenia and osteoporosis. Higher incidences of serious infections were also noted in the Erleada arm and the rates were still higher after being adjusted for exposure. In addition, six patients treated with Erleada died of infections (sepsis and pneumonia) versus none in the placebo arm.
An imbalance of on-treatment deaths was reported with higher incidences for the Erleada arm than the placebo arm (1.4% vs. 0.5%). The causes of death in the Erleada arm were infections, myocardial infarction, and cerebrovascular accident.
Increased incidences of cardiac disorders including ischemic heart disease (with 3 fatal cases) and cardiac failure were reported in patients treated with Erleada. In addition, the dedicated QT study revealed that Erleada prolonged QTc interval (corrected according to Fridericia, QTcF) in patients treated with androgen deprivation therapy. The mean maximum QTcF change from baseline was 20.2 ms, with the upper bound of the 90% confidence interval being 23.7 ms. A higher incidence of syncope was reported in the Erleada arm in Study ARN-509-003. In addition, apalutamide and its active metabolite, N-desmethyl apalutamide inhibit the human ether-a-go-go-related gene (hERG) potassium channel at a half maximal inhibitory concentration (IC50) that is below the maximum plasma concentration (Cmax) in patients. Based on the seriousness and life-threatening nature, cardiac disorders and QTc prolongation were included in the Warnings and Precautions section of the Erleada Product Monograph.
The increased toxicities with addition of Erleada to androgen deprivation therapy were reported following median treatment duration of 17 months. The long-term safety of the treatment regimen is unknown.
The toxicity of Erleada and androgen deprivation therapy is considered manageable in patients with non-metastatic, castration-resistant prostate cancer, provided that the patients are monitored and managed accordingly. Appropriate warnings and precautions are in place in the approved Erleada Product Monograph to address the identified safety concerns.
For more information, refer to the Erleada Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
Apalutamide, the medicinal ingredient in Erleada, is an androgen receptor inhibitor that binds directly to the ligand-binding domain of the androgen receptor. Preclinical studies have demonstrated that apalutamide prevents androgen receptor nuclear translocation, inhibits deoxyribonucleic acid (DNA) binding, impedes androgen receptor-mediated transcription, and lacks androgen receptor agonist activity. In mouse models of prostate cancer, apalutamide administration causes decreased tumour cell proliferation and increased apoptosis leading to tumour growth inhibition and regression.
Repeat-dose toxicity studies with apalutamide were conducted in mice (2 weeks), rats (up to 26 weeks) and dogs (up to 39 weeks). Most of the toxicities observed were associated with the anti-androgenic pharmacological activity of apalutamide and affected the male and female reproductive organs, mammary glands, pituitary gland, adrenal glands and thymus. Seizures/convulsions were observed in both dogs and mice, probably due to an off-target inhibition of gamma-aminobutyric acid type A (GABAA) current by both apalutamide and its active metabolite, N-desmethyl apalutamide.
Apalutamide and N-desmethyl apalutamide were not genotoxic in the standard battery of tests.
Apalutamide may impair male fertility in patients based on results of repeat-dose and fertility studies. Findings of a reversible decrease in sperm concentration and motility, copulation and fertility rates (upon pairing with untreated females), along with reduced weights of the secondary sex glands and epididymis, were evident at low relative doses in rats and/or dogs.
No embryo-fetal development studies were conducted or warranted to support this submission, as the proposed indication does not include females. Based on its mechanism of action, apalutamide may cause fetal harm if administered during pregnancy.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Erleada Product Monograph. In view of the intended use of Erleada, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Erleada Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The Chemistry and Manufacturing information submitted for Erleada has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the drug product should be stored at room temperature (15ºC to 30ºC) in the original package and protected from light and moisture.
Proposed limits of drug-related impurities are considered adequately qualified, i.e., within International Council for Harmonisation (ICH) limits and/or qualified from toxicological studies.
All sites involved in production are compliant with Good Manufacturing Practices.
All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| ERLEADA | 02478374 | JANSSEN INC | APALUTAMIDE 60 MG |