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FDA Alerts

Pharmacist's Applications to Practice

HOPA, through the Publications Committee, will review new drug updates and provide analysis and research on the application of these new drugs or indications.

The letters “PAP” after drugs listed below indicates that they include this additional analysis.  


February 14, 2018

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210951s000lbl.pdf

On February 14, 2018, the Food and Drug Administration approved apalutamide (Erleada™, Janssen Biotech, Inc.) for patients with non-metastatic castration-resistant prostate cancer (NM-CRPC).

Approval was based on a multicenter, double-blind, clinical trial (SPARTAN, NCT01946204) randomizing 1,207 patients with NM-CRPC (2:1) to receive either apalutamide, 240 mg orally once daily in combination with ADT (medical castration or surgical castration) (n=806), or placebo once daily with ADT (n=401).

The major efficacy endpoint was metastasis-free survival (MFS). MFS was defined as the time from randomization to the time of first evidence of distant metastasis (new bone or soft tissue lesions or enlarged lymph nodes outside the pelvis), or death due to any cause, whichever occurred first. The estimated median MFS was 40.5 months for patients receiving apalutamide and 16.2 months for those receiving placebo (hazard ratio 0.28; 95% CI: 0.23, 0.35; p<0.0001).

The most common adverse reactions in at least 10% of patients were fatigue, hypertension, rash, diarrhea, nausea, weight decreased, arthralgia, fall, hot flush, decreased appetite, fracture, and peripheral edema.

The recommended apalutamide dose is 240 mg (four 60 mg tablets) administered orally once daily.

Full prescribing information is available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210951s000lbl.pdf

FDA granted this application priority review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics, available at:
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

 

Pharmacist’s Applications to Practice

Apalutamide for the Treatment of Patients with Nonmetastatic Castration-Resistant Prostate Cancer

Authors
Kourtney D. LaPlant, PharmD BCOP
Clinical Pharmacy Program Manager for Oncology
Veterans Integrated Service Network 8 Pharmacy Benefits Management
Department of Veterans Affairs
Gainesville, FL
 
Tanja Lepir, PharmD BCOP
Clinical Oncology Pharmacist
Miami VA Healthcare System
Miami, FL

What is the potential role for apalutamide in the treatment of nonmetastatic castration-resistant prostate cancer (nmCRPC)?1-5

  • Apalutamide is an androgen receptor inhibitor approved by the U.S. Food and Drug Administration (FDA) in February 2018 for the treatment of patients with nmCRPC.
  • Findings from the phase 3 placebo-controlled SPARTAN trial led to the approval of apalutamide in combination with androgen deprivation therapy (ADT) as an effective treatment for men with nmCRPC who are at high risk for developing metastatic disease (i.e., their prostate specific antigen [PSA] score rises rapidly despite ADT) when compared to placebo with ADT.
  • Men who received apalutamide had a 72% lower risk of metastasis or death than those who received placebo. The major efficacy end point that contributed to the approval of apalutamide was metastasis-free survival (MFS), defined as the time from randomization to the time of first evidence of distant metastasis (new bone or soft-tissue lesions or enlarged lymph nodes outside the pelvis) or death due to any cause, whichever occurred first. The estimated median MFS was 40.5 months for patients receiving apalutamide and 16.2 month for those receiving placebo (hazard ratio [HR] 0.28; 95% confidence interval [CI]: 0.23–0.35, p < .001).
  • Apalutamide was superior to placebo for the secondary end points, including time to metastasis, progression-free survival, and time to symptomatic progression.1
  • The rate of adverse events leading to discontinuation of the trial regimen was 10.6% in the apalutamide group and 7% in the placebo group. The adverse events reported at a higher rate with apalutamide than with placebo were rash (23.8% vs. 5.5%), hypothyroidism (8.1% vs. 2%), and fracture (11.7% vs. 6.5%).
  • Based on the National Comprehensive Cancer Network guidelines, apalutamide is a category 1 treatment option as a systemic therapy for nonmetastatic (M0) CRPC for patients with a PSA doubling time of 10 months or less.
  • Apalutamide is the first FDA-approved agent for the treatment of nmCRPC in men with a rapidly rising PSA score while they are on ADT. Rapid rise is defined as PSA doubling time of less than 8–10 months and is associated with a significantly increased risk of developing metastases or death.
  • Like enzalutamide, apalutamide is a second-generation antiandrogen; however, apalutamide is indicated in the nonmetastatic setting. Enzalutamide is indicated for metastatic (M1) disease and is currently being studied in the nonmetastatic setting. According to an ASCO Post item in February 2018, enzalutamide is also emerging as a treatment option for nmCRPC.3 The interim results of the phase 3 PROSPER trial have shown that enzalutamide plus ADT reduced the risk of developing metastasis or death by 71% compared to ADT alone. The median for MFS was 36.6 months for men who received enzalutamide, compared to 14.7 months with ADT alone (N = 1,401; HR 0.29; 95% CI, 0.24–0.35; p = .0001).

What role can the pharmacist play in the management of patients on apalutamide?1,4

  • Counsel patients to store apalutamide in the original package.
  • Advise patients that medication dosing is four 60 mg tablets (240-mg dose) once a day with or without food.
  • Advise males with female partners of reproductive potential to use effective contraception.
  • Identify patients at risk for falls because falls and fractures occurred in 16% and 12% of patients receiving apalutamide, respectively. ADT is associated with decreased bone mineral density and greater risk for clinical fractures. Treatment with apalutamide appears to further increase the risk for fracture in men receiving long-term ADT. Patients should be evaluated for fracture risk and managed according to clinical practice guidelines and labeled uses of approved drugs.
  • Screen patients for risk of seizure because seizure occurred in 0.2% of patients receiving apalutamide.
  • Patients receiving apalutamide should concurrently receive a gonadotropin-releasing hormone analog unless they have had a documented bilateral orchiectomy.
  • No clinically significant differences have been observed in the pharmacokinetics of apalutamide or N-desmethyl apalutamide on the basis of age, race, mild-to-moderate renal impairment, or mild-to-moderate hepatic impairment. The effect of severe renal impairment or end-stage renal disease or severe hepatic impairment on apalutamide pharmacokinetics is unknown.
  • Identify concomitant use with medications that are sensitive substrates of CYP3A4, CYP2C18, CYP2C9, UGT, P-glycoprotein, BCRP, or OATP1B1 that may result in loss of activity of these medications. The following medications can affect the concentration of apalutamide: strong CYP2C8 inhibitors, strong CYP3A4 inhibitors, CYP3A4/CYP2C8 inducers, acid-lowering agents, and drugs affecting transporters. Refer to the prescribing information for more details.4
  • Co-administration of a strong CYP2C8 or CYP3A4 inhibitor is predicted to increase the steady-state exposure of the active moieties, and the manufacturer recommends reduction of the apalutamide dose “based on tolerability.”4
  • The most common adverse reactions (occurring in 10% or more of cases) are fatigue, hypertension, rash, diarrhea, nausea, weight decrease, arthralgia, fall, hot flush, decreased appetite, fracture, and peripheral edema.        
  • Skin rash was reported in 23.8% of patients in the apalutamide group versus 5.5% in the placebo group.
    • Grade 3 rashes (covering more than 30% of body surface area) were reported with apalutamide (5.2%) versus placebo (0.3%). Rashes are commonly described as macular or maculopapular.
    • The onset of skin rash occurred at a median of 82 days of treatment and resolved within a median of 60 days for 80.6% of patients.
    • Skin rash led to treatment discontinuation, dose reduction, and dose interruption in 19 (2.4%), 22 (2.7%), and 55 (6.8%) patients, respectively, in the apalutamide group and 0 (0%), 1 (0.3%), and 5 (1.3%) patients, respectively, in the placebo group.
    • Rash management included topical corticosteroids, oral antihistamines, systemic corticosteroids, drug interruption, and dose reduction.
  • Hypothyroidism (grade 1 and grade 2) was reported for 8.1% of patients in the apalutamide group versus 2% in the placebo group.
    • Hypothyroidism also led to treatment discontinuation in 1 patient and dose reduction in 1 patient in the apalutamide group.
    • Hypothyroidism in patients treated with apalutamide worsened in patients who were already receiving thyroid replacement therapy.
    • Elevations in thyroid-stimulating hormone (TSH) occurred early in treatment; median time to first TSH elevation in the apalutamide group was 113 days.
    • Hypothyroidism can be managed with increases or initiation of thyroid replacement therapy.
  • Patient assistance program information can be found at https://www.janssencarepath.com.

Clinical Pearls1,2

  • Treatment options may be considered on the basis of these patient-specific factors: (1) evidence of metastasis by imaging or the presence of nmCRPC or metastatic CRPC; (2) whether the patient has a rapid rise in PSA despite ADT; (3) whether the patient is symptomatic (if the patient has minimal or no symptoms, the treatment options may include flutamide, bicalutamide, nilutamide, enzalutamide, apalutamide, ketoconazole + hydrocortisone, or diethylstilbestrol); (4) toxicities or potential drug-interactions; (5) comorbidities (e.g., seizure, high risk for falls); and (6) cost.
  • Monitor the patient closely for increase in PSA, decrease in thyroid function (from baseline), and signs and symptoms of seizure.
  • Discontinue any first-generation antiandrogens (including bicalutamide, nilutamide, and flutamide) at the time of apalutamide initiation.
  • Continue luteinizing hormone-releasing hormone agonist (goserelin, histrelin, leuprolide, or triptorelin) or antagonist (degarelix) to maintain castrate serum levels of testosterone (less than 50 ng/dl).
  • Erleada (apalutamide) is available as 60-mg film-coated, slightly yellowish to greyish- green, oblong-shaped tablets debossed with “AR 60” on one side in bottles of 120 tablets with silica gel desiccant.
  • The medication should be stored in the original package, protected from light and moisture at 20°C to 25°C (68°F to 77°F) with excursions permitted to 15°C to 30°C (59°F to 86°F).

References

  1. Smith MR, Saad F, Chowdhury S, et al. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018;378:1408-1418.
  2. National Comprehensive Cancer Network. Prostate Cancer. Version 2.2018. Available at https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed April 6, 2018.
  3. 2018 GU Cancers Symposium: Antiandrogenic Therapy in Nonmetastatic Castration-Resistant Prostate Cancer. The ASCO Post, February 9, 2018. Available at www.ascopost.com/News/58527.
  4. Erleada (apalutamide) [package insert]. Horsham, PA: Janssen Biotech, Inc.; February 2018.
  5. Xtandi (enzalutamide) [package insert]. Northbrook, IL: Astellas Pharma US, Inc.; 2012.
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