Description
Prostate cancer is a leading cause of non-cutaneous cancer in men. Although most will be diagnosed at an early localized stage, up to 30% of cases will recur following curative surgical or radiation therapy. Androgen deprivation therapy with either surgical castration or gonadotropin releasing hormone (GnRH) analogs is commonly initiated to control disease in those who have developed metastases. Unfortunately, nearly all of these cases will continue to progress; when patients recur on androgen deprivation therapy in the setting of “castrate” levels of testosterone, patients are termed “castration-resistant” or “castration-recurrent.” Current treatment options for metastatic castration-resistant/recurrent prostate cancer (CRPC) include both systemic and bone-targeted therapies. While systemic therapies (e.g., abiraterone, cabazitaxel, docetaxel, enzalutamide, mitoxantrone, sipuleucel-T) are not targeted to a specific organ, bone-targeted therapies are active predominantly in the bone and leave lymph node and visceral metastases untreated. Available agents include zoledronic acid (Zometa^®), denosumab (Xgeva^®), and the radioisotopes strontium 89 (Metastron^®) and samarium 153 (Quadramet^®), none of which has been shown to possess a survival advantage (zoledronic acid and denosumab were approved based on a delay in time to skeletal related events; radioisotopes were approved for palliation of bone pain).

Radium 223 (Xofigo^®), an alpha emitting radiopharmaceutical, was approved by the U.S. Food and Drug Administration (FDA) on May 15, 2013, for the treatment of CRPC patients with symptomatic bone metastases and no evidence of visceral metastatic disease. Radium 223 mimics calcium and forms complexes with hydroxyapatite at areas of increased bone turnover; this leads to a high frequency of double-strand DNA breaks in adjacent cells and results in an anti-tumor effect on bone metastases and, ultimately, extended patient survival. While radium 223 is not intended to be used in combination with chemotherapy due to the potential for additive myelosuppression, concomitant use of denosumab or zoledronic acid does not interfere with any beneficial effects.

The safety and efficacy of radium 223 were evaluated in subjects with CRPC and symptomatic bone metastases in a randomized, double-blind, placebo-controlled Phase III study. Individuals with visceral metastatic disease were excluded from the study. Subjects were randomized 2:1 to receive radium 223 (dose: 50 kBq/kg IV) every 28 days for six injections plus best supportive care or placebo plus best supportive care. The primary endpoint was overall survival with one predefined interim analysis; a secondary endpoint was time to symptomatic skeletal events. At the predefined interim analysis, the primary endpoint of overall survival met the boundary for statistical significance, revealing a decrease in the risk of death in the radium 223 group with a hazard ratio of 0.695 (95% CI: 0.522, 0.875; p = 0.00185). The median overall survival was 14 months in the radium 223 group (n = 809 patients) compared to 11.2 months in the placebo group (n = 268 patients). The time to symptomatic skeletal events was also delayed in the radium 223 arm, with a hazard ratio of 0.610 (95% CI: 0.461, 0.807; p = 0.00046). The median time to symptomatic skeletal events was 13.5 months, compared with 8.4 months for radium 223 and placebo, respectively. The most common adverse reactions (> 10%) in patients receiving radium 223 were nausea, diarrhea, vomiting and peripheral edema. The most common hematologic laboratory abnormalities (> 10%) were anemia, lymphocytopenia, leukopenia, thrombocytopenia, and neutropenia.

The National Comprehensive Cancer Network (NCCN) Guidelines for Prostate Cancer (Version 1.2017) designate radium 223 as a category 1 first-line or second-line (i.e., after failure of enzalutamide, abiraterone, or docetaxel) therapeutic option for symptomatic bone metastases in patients with CRPC without visceral metastases. The NCCN states that radium 223 alone has not been shown to extend survival in men with visceral metastases or bulky lymph node metastases (> 3 to 4 cm) and is not recommended in this setting. 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.

Policy
Xofigo is an alph particle-emitting radioactive therapeutic agent indicated for the treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease.  

Xofigo is considered NOT MEDICALLY NECESSARY for all indications other than those listed above.

Policy Guidelines
The dose regimen of Xofigo is 55 kBq (1.49 microcurie) per kg body weight, given at 4 week intervals for 6 injections.

Single-use vial at a concentration of 1,100 kBq/mL (30 microcurie/mL) at the reference date with a total radioactivity of 6,600 kBq/vial (178 microcurie/vial) at the reference date.

References 

1. Clinical Pharmacology [Internet]. Tampa (FL): Gold Standard, Inc.; 2017 [cited 2017 Feb 17]. Available from: http://www.clinicalpharmacology.com/.
2. DRUGDEX® System [Internet]. Greenwood Village (CO): Thomson Micromedex; Updated periodically [cited 2017 Feb 17]. Available from: http://www.thomsonhc.com/.
3. Hoskin P, Sartor O, O'Sullivan JM, et al. Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial. Lancet Oncol. 2014 Nov;15(12):1397-406. Epub 2014 Oct 17.
4. National Comprehensive Cancer Network. Cancer Guidelines. Cancer Guidelines and Drugs and Biologics Compendium. Accessed 2/20/17.
5. 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 02/20/2017.
6. Orphan Drug Designations and Approval [Internet]. Silver Spring (MD): US Food and Drug Administration; 201 [cited 2017 Feb 17]. Available from: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm/.
7. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013 Jul 18;369(3):213-23.
8. Sartor O, Coleman R, Nilsson S, et al. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol. 2014 Jun;15(7):738-46. Epub 2014 May 13.
9. Xofigo (radium chloride ra-223) [package insert]. Bayer HealthCare. Wayne (NJ): March 2016.

Coding Section 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

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