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Date Printed: August 22, 2017: 07:09 AM

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09-J1000-85

Original Effective Date: 01/15/13

Reviewed: 03/08/17

Revised: 04/15/17

Subject: Enzalutamide (Xtandi®) Capsules

THIS MEDICAL COVERAGE GUIDELINE IS NOT AN AUTHORIZATION, CERTIFICATION, EXPLANATION OF BENEFITS, OR A GUARANTEE OF PAYMENT, NOR DOES IT SUBSTITUTE FOR OR CONSTITUTE MEDICAL ADVICE. ALL MEDICAL DECISIONS ARE SOLELY THE RESPONSIBILITY OF THE PATIENT AND PHYSICIAN. BENEFITS ARE DETERMINED BY THE GROUP CONTRACT, MEMBER BENEFIT BOOKLET, AND/OR INDIVIDUAL SUBSCRIBER CERTIFICATE IN EFFECT AT THE TIME SERVICES WERE RENDERED. THIS MEDICAL COVERAGE GUIDELINE APPLIES TO ALL LINES OF BUSINESS UNLESS OTHERWISE NOTED IN THE PROGRAM EXCEPTIONS SECTION.

           
Dosage/ Administration Position Statement Billing/Coding Reimbursement Program Exceptions Definitions
           
Related Guidelines Other References Updates  
           

DESCRIPTION:

Prostate cancer remains the most common non-cutaneous malignancy among men worldwide. Prostate cancer is a complex disease, with many controversial aspects of management. Prostate cancer is an androgen dependent disease that initially responds but later becomes resistant to established therapies that reduce circulating testosterone levels (<50 ng/dL) or inhibit androgen binding to androgen receptor (AR). Reactivation of the disease despite castrate levels of testosterone represents a transition to the lethal phenotype of castration-resistant/recurrent prostate cancer (CRPC). This state is now recognized to be driven by AR signaling, in part due to overexpression of the androgen receptor itself.

Enzalutamide (Xtandi®) is an oral AR antagonist that directly inhibits AR by irreversibly binding to the receptor. This interaction impairs AR nuclear translocation, DNA binding, and recruitment of co-activators. Preclinical studies have indicated that enzalutamide is a potent inhibitor and leads to complete suppression of the AR pathway. Additionally, enzalutamide induces tumor shrinkage, whereas conventional agents only retard growth. Moreover, enzalutamide does not display agonistic effects. In the phase III, randomized, double-blind placebo controlled trial, subjects with CRPC who received previous treatment with docetaxel were administered enzalutamide 160 mg or placebo. Enzalutamide was associated with a median overall survival (primary endpoint) of 18.4 months compared with 13.6 months for subjects assigned to placebo. At the time of the prespecified interim analysis, the use enzalutamide resulted in a 37% reduction in the risk of death, as compared to placebo (HR=0.63; 95% CI 0.53-0.75, p<0.001). On the basis of these results, an independent data and safety monitoring committee recommended that the study be halted and unblinded, with eligible subjects in the placebo group offered treatment with enzalutamide. Based principally on the results of this study, enzalutamide was approved by the US Food and Drug Administration (FDA) in August 2012 for the treatment of individuals with metastatic CRPC who have previously received a docetaxel-containing regimen. In September 2014, the indication was expanded to include patients who have not received chemotherapy. This was based on the result of the double-blind, phase 3 PREVAIL study. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide vs. 14% among patients receiving placebo (HR 0.19, 95% CI 0.15 to 0.23, p<0.001). A third study (TERRAIN) was added to the package labeling in 2016 in which enzalutamide was compared to bicalutamide head-to-head in patients with chemotherapy-naïve metastatic CRPC. Radiographic progression-free survival was improved in the patients taking enzalutamide (19.5 months) vs. bicalutamide (13.4 months) [HR 0.60 (0.43, 0.83)].

The National Comprehensive Cancer Network (NCCN) prostate cancer guidelines (Version 1.2017) list enzalutamide as a category 1 first-line option for men with metastatic CRPC with or without visceral metastases. Enzalutamide is also a category 1 option for men who have failed prior docetaxel therapy (with or without visceral metastases) and is a category 2A option for men who have failed prior abiraterone (Zytiga®) treatment (with or without visceral metastases). NCCN notes that two randomized clinical trials (STRIVE and TERRAIN) showed that 160 mg/day enzalutamide improved PFS compared to 50 mg/day bicalutamide in men with treatment-naïve CRPC and, therefore, enzalutamide may be the preferred option in this setting. However, bicalutamide can still be considered in some patients, given the different side-effect profiles of the agents and the increased costs of enzalutamide. The NCCN recommends that patients whose disease progresses to CRPC during primary androgen deprivation therapy (ADT) should receive a laboratory assessment to assure a castrate level of testosterone (<50 ng/dL) has been achieved.

POSITION STATEMENT:

Initiation of enzalutamide (Xtandi®) meets the definition of medical necessity when ALL of the following criteria are met:

1. Member is diagnosed with metastatic, castration-recurrent prostate cancer (CRPC, a.k.a., castration-resistant or hormone-refractory prostate cancer) – lab documentation of a recent (past 90 days) serum testosterone level at castrate level (<50 ng/dL) must be submitted for members receiving medical castration. A chart note documenting a bilateral orchiectomy must be submitted for members who have received surgical castration.

2. The dose does not exceed 160 mg (four 40 mg capsules) once daily

3. Enzalutamide is not used concomitantly with ANY of the following:

a) Abiraterone (Zytiga®)

b) Cabazitaxel (Jevtana®)

c) Docetaxel (Taxotere®)

d) Mitoxantrone (Novantrone®)

e) Radium-223 (Xofigo®)

f) Sipuleucel-T (Provenge®)

Approval duration: 12 months

Continuation of enzalutamide meets the definition of medical necessity when ALL of the following criteria are met:

1. Member has demonstrated a beneficial clinical response to therapy

2. The member has been previously approved by Florida Blue or another health plan in the past 2 years for the treatment of metastatic prostate cancer, OR the member has previously met ALL indication-specific criteria

3. Enzalutamide will not be used concomitantly with ANY of the following:

a) Abiraterone (Zytiga®)

b) Cabazitaxel (Jevtana®)

c) Docetaxel (Taxotere®)

d) Mitoxantrone (Novantrone®)

e) Radium-223 (Xofigo®)

f) Sipuleucel-T (Provenge®)

4. The dose does not exceed 160 mg (four 40 mg capsules) once daily

Approval duration: 12 months

DOSAGE/ADMINISTRATION:

THIS INFORMATION IS PROVIDED FOR INFORMATIONAL PURPOSES ONLY AND SHOULD NOT BE USED AS A SOURCE FOR MAKING PRESCRIBING OR OTHER MEDICAL DETERMINATIONS. PROVIDERS SHOULD REFER TO THE MANUFACTURER’S FULL PRESCRIBING INFORMATION FOR DOSAGE GUIDELINES AND OTHER INFORMATION RELATED TO THIS MEDICATION BEFORE MAKING ANY CLINICAL DECISIONS REGARDING ITS USAGE.

FDA-approved: enzalutamide is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC). The recommended dose is 160 mg (four 40 mg capsules) orally once daily at the same time each day with or without food. The capsules should be swallowed whole and should not be chewed, dissolved, or opened.

Dose Adjustments

Renal Impairment: No initial enzalutamide dosage adjustment is necessary in members with mild or moderate renal impairment (i.e., creatinine clearance [CrCl] 30 ml/min or greater). Enzalutamide has not been evaluated in subjects with severe renal impairment (i.e., CrCl less than 30 ml/min) or end-stage renal disease.

Hepatic Impairment: Based on dedicated hepatic impairment trials no initial enzalutamide dosage adjustment is necessary in members with baseline mild (Child-Pugh class A), moderate (Child-Pugh class B), or severe (Child-Pugh class C hepatic impairment.

Concomitant CYP450 Inducers/Inhibitors

o Strong CYP2C8 Inhibitors (e.g., gemfibrozil): avoid concomitant use; if use cannot be avoided, reduce the enzalutamide dose to 80 mg orally once daily. If strong inhibitor is discontinued, restart enzalutamide at the dose used before the initiation of the strong CYP2C8 inhibitor.

o Strong CYP3A4 Inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine): avoid concomitant use; if use cannot be avoided, increase the enzalutamide dose to 240 mg orally once daily. If strong inducer is discontinued, the enzalutamide dose should be returned to the dose used before the initiation of the strong CYP3A4 inducer.

o CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus and tacrolimus), 2C9 (e.g., phenytoin, warfarin), and 2C19 (e.g., S-mephenytoin) substrates with a narrow therapeutic index (e.g., those whose serum levels are monitored): avoid concomitant use as enzalutamide may decrease their exposure. If co-administration with warfarin cannot be avoided, conduct additional INR monitoring.

Toxicity: If member experiences Grade 3 or higher toxicity or intolerable side effects, hold enzalutamide therapy for 1 week or until symptoms improve to grade 2 or lower toxicity. Therapy can be resumed at the same dose or a reduced dose (e.g., 120- or 80 mg) if warranted.

Drug Availability: enzalutamide is available as a 40 mg capsule.

PRECAUTIONS:

CONTRAINDICATION

• Enzalutamide is contraindicated in women who are or may become pregnant. Based on its mechanism of action, enzalutamide can cause fetal harm when administered to pregnant women. Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the final dose.

WARNINGS AND PRECAUTIONS

Seizure - Seizure occurred in 0.5% of patients receiving enzalutamide in clinical studies. In placebo-controlled studies, 8 of 1671 (0.5%) patients treated with enzalutamide and 1 of 1243 (0.1%) patients treated with placebo experienced a seizure. In patients who previously received docetaxel, 7 of 800 (0.9%) patients treated with enzalutamide experienced a seizure and no patients treated with placebo experienced a seizure. Enzalutamide should be permanently discontinued in members who experience a seizure during therapy. The safety of enzalutamide in subjects with predisposing factors (e.g., history of seizures, underlying brain injury with loss of consciousness, cerebral vascular accident) for seizures is unknown.

Posterior Reversible Encephalopathy Syndrome (PRES) – there have been reports of PRES (a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension) in patients taking enzalutamide. A diagnosis of PRES requires confirmation by brain imaging, preferably magnetic resonance imaging (MRI). Discontinue enzalutamide in patients who develop PRES.

BILLING/CODING INFORMATION:

The following codes may be used to describe:

HCPCS Coding

C9399

Unclassified drugs or biologicals (Hospital Outpatient Use ONLY)

J8999

Prescription drug, oral, chemotherapeutic, not otherwise specified

ICD-10 Diagnoses Codes That Support Medical Necessity

C61

Malignant neoplasm of prostate

REIMBURSEMENT INFORMATION:

Refer to section entitled POSITION STATEMENT.

PROGRAM EXCEPTIONS:

Federal Employee Program (FEP): Follow FEP guidelines.

State Account Organization (SAO): Follow SAO guidelines.

Medicare Advantage Products: No National Coverage Determination (NCD) and/or Local Coverage Determination (LCD) were found at the time of the last guideline review date.

Medicare Part D: Florida Blue has delegated to Prime Therapeutics authority to make coverage determinations for the Medicare Part D services referenced in this guideline.

DEFINITIONS:

Metastatic cancer: when cancer spreads from the primary site (place where it started) to other places in the body.

Castrate-resistant/recurrent prostate cancer (CRPC):disease progression despite androgen deprivation therapy (ADT) with either medication or surgery (i.e., removal/destruction of testicles, and may present as either a continuous rise in serum prostate-specific antigen (PSA) levels, the progression of pre-existing disease, and/or the appearance of new metastases.

RELATED GUIDELINES:

Abiraterone acetate (Zytiga®) 09-J1000-36
Cabazitaxel (Jevtana®) 09-J1000-77

Cryosurgical Ablation of the Prostate (CSAP), 02-54000-14

Docetaxel (Taxotere®) Injection, 09-J0000-95

Gonadotropin Releasing Hormone Analogs and Antagonists, 09-J0000-48

Radium Ra 223 (Xofigo®) IV, 09-J2000-01

Sipuleucel-T (Provenge®) 09-J1000-29

OTHER:

None applicable.

REFERENCES:

  1. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014 Jul 31;371(5):424-33. Epub 2014 Jun 1.
  2. Bianchini D, Lorente D, Rodriguez-Vida A, et al. Antitumour activity of enzalutamide (MDV3100) in patients with metastatic castration-resistant prostate cancer (CRPC) pre-treated with docetaxel and abiraterone. Eur J Cancer. 2014 Jan;50(1):78-84. Epub 2013 Sep 25.
  3. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2017. Available at: www.clinicalpharmacilogy-ip.com. Accessed 2/17/17.
  4. Dayyani F, Gallick GE, Logothetis CJ et al. Novel therapies for metastatic castrate-resistant prostate cancer. J Natl Cancer Inst 2011;103:1665-75.
  5. Fizazi K, Scher HI, Miller K, et al. Effect of enzalutamide on time to first skeletal-related event, pain, and quality of life in men with castration-resistant prostate cancer: results from the randomised, phase 3 AFFIRM trial. Lancet Oncol. 2014 Sep;15(10):1147-56. Epub 2014 Aug 4.
  6. Micromedex® Healthcare Series [Internet Database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Accessed 2/17/17.
  7. National Comprehensive Cancer Network. Cancer Guidelines. Cancer Guidelines and Drugs and Biologics Compendium. Accessed 2/21/17.
  8. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology. Prostate Cancer. Version 1.2017. Available at http://www.nccn.org/professionals/physician_gls/PDF/prostate.pdf. Accessed 2/21/17.
  9. Orphan Drug Designations and Approval [Internet]. Silver Spring (MD): US Food and Drug Administration; 2017 [cited 2017 Feb 17]. Available from: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm/.
  10. Sartor AO, Fitzpatrick JM. Urologists and oncologists: adapting to a new treatment paradigm in castration-resistant prostate cancer (CRPC).BJU Int 2012;110:328-335.
  11. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012;367(13):1187-97.
  12. Siegel R, Naishadham D, Jemal A. Cancer statistics 2012. CA Cancer J Clin 2012;62:10-29.
  13. Shore ND, Chowdhury S, Villers A, et al. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 study. Lancet Oncol. 2016 Feb;17(2):153-63.
  14. Tombal B, Borre M, Rathenborg P, et al. Enzalutamide monotherapy in hormone-naive prostate cancer: primary analysis of an open-label, single-arm, phase 2 study. Lancet Oncol. 2014 May;15(6):592-600.
  15. Xtandi (enzalutamide) [package insert]. Astellas Pharma US, Inc. Northbrook (IL): October 2016.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Coverage Committee on 03/08/17.

GUIDELINE UPDATE INFORMATION:

01/15/13

New Medical Coverage Guideline.

04/15/13

Review and revision to guideline; consisting of revising position statement based on NCCN recommendations for treatment in the pre-docetaxel setting and inclusion of approval duration, revising description section, updating references and coding, adding related guidelines.

07/01/13

Revision to guideline; consisting of revising position statement to require failure or contraindication to abiraterone; Program Exceptions section updated.

04/15/14

Review and revision to guideline; consisting of reformatting position statement and updating references.

04/15/15

Review and revision to guideline; consisting of description section, dosage/administration, definitions, and references.

11/01/15

Revision: ICD-9 Codes deleted.

04/15/16

Review and revision to guideline consisting of description section, position statement, dosage/administration, definitions, and references.

04/15/17

Review and revision to guideline consisting of description section, position statement, precautions section, and references.

Date Printed: August 22, 2017: 07:09 AM