The US Food and Drug Administration (FDA) approved enzalutamide (Xtandi; Medivation, Inc., Astellas Pharma US, Inc.) for the treatment of patients with metastatic castration-resistant prostate cancer who had previously received docetaxel. This approval was granted on August 31, 2012. For more information about the FDA approval, see http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm317997.htm.
Prostate cancer is diagnosed second only to skin cancer in men. The American Cancer Society has estimated that more than 238,000 men will be told they have prostate cancer during 2013. Of the men already known to have prostate cancer, almost 30,000 men are projected to die of the disease this year.1,2 Although men are living longer with prostate cancer, our challenge in clinical practice is more often managing men with metastatic disease who are seeking their next treatment options. Until recently, this talk was limited.
Before 2010, our only systemic therapy demonstrating a survival benefit in castration-resistant prostate cancer (CRPC) had been the chemotherapeutic agent docetaxel.3,4 However, in the past few years, 4 new agents have been approved by the US Food and Drug Administration (FDA) for use in the CRPC population, widening the discussion to include not only treatment options, but also sequential treatments.3,5 Enzalutamide was researched clinically against placebo at the same time that the other 3 agents also were in clinical trials. These recently approved therapies differ in their mechanisms of action, reflecting the advances in scientific understanding of CRPC: cabazitaxel is a novel taxane chemotherapeutic agent, abiraterone is an androgen biosynthesis inhibitor, sipuleucel-T is an autologous immunotherapeutic agent, and enzalutamide is an androgen receptor (AR) inhibitor.3,5,6
Androgen deprivation has long been the focus of control of prostate cancer, and responses have been significant. However, despite the reduction of circulating testosterone, and with castrate levels of androgens and medications to limit androgen binding to the AR, reactivation of prostate cancer has signified a more lethal phenotype of CRPC. Traditional therapies have targeted the disruption of ligand binding to the AR. Enzalutamide competes for the inhibition of ligand binding for the AR and appears to have a 5-fold affinity for such binding. Therefore, enzalutamide prevents the cascade of activation of target genes necessary for tumor growth and appears to also cause apoptosis, or cell death.3,5-8
Enzalutamide (Xtandi) received FDA approval in August 2012 for the treatment of men with metastatic CRPC who had previously received chemotherapy with docetaxel. As noted in the AFFIRM (A Study Evaluating the Efficacy and Safety of the Investigational Drug MDV3100) clinical trial, men derived both an overall survival benefit as well as secondary end point benefits of reduced prostate-specific antigen (PSA) levels, soft tissue response rates, improved quality of life, radiographic progression-free survival, and a prolonged time to the first skeletal-related event, compared with placebo.3,7,8 By targeting the AR signaling pathway, enzalutamide provides a novel therapeutic option for this population of men.
The Clinical Picture
Enzalutamide’s current FDA approval is in the setting of CRPC, post- docetaxel chemotherapy. Treatment with docetaxel may have failed and thus patients present with progressive disease, or they may have been intolerant to docetaxel and are unable to continue treatment. As noted, there are several therapeutic options for second-line therapy in this metastatic prostate cancer setting. Although clinical trials are ongoing to determine the benefit of enzalutamide in the prechemotherapy setting (phase 3, PREVAIL [A Safety and Efficacy Study of Oral MDV3100 in Chemotherapy-Naive Patients With Progressive Metastatic Prostate Cancer] trial), in current practice patients may receive enzalutamide as second-line therapy, and this agent can be considered for men with metastatic CRPC who may not be candidates for treatment with docetaxel.9
The approved dose of enzaluta- mide, as administered in the phase 3, global, placebo-controlled, randomized AFFIRM study, is 160 mg daily. Enzalutamide is supplied as a 40-mg capsule; thus the patient swallows 4 capsules to achieve daily dosing. Capsules are swallowed whole, and can be taken with or without food. Dose adjustments are permitted for the management of serious adverse events, such as fatigue or bone pain; a reduction to 120 mg daily is suggested in this setting. Of note, in the research setting, there were no dose adjustments for mild or moderate renal or hepatic impairment. Enzalutamide has not been evaluated in men with severe hepatic or renal impairment or in end-stage renal disease.7,8
Prescriptions are written for #120 capsules (four 40-mg capsules daily) per month. Currently, enzalutamide is available through specialty pharmacies. For assistance in locations and for access programs, Astellas Pharma US, Inc., provides the following contact information: www.XTANDIaccess.com, www.XtandiHCP.com, (800) 888-7704, or email at Customer_Ops@us.astellas.com.
Patients presenting for enzalutamide therapy, who are either postdocetaxel or other hormonal manipulations, will likely be taking steroids. Clinical judgment or patient wishes should be addressed. In clinical trials, 48% of patients receiving enzalutamide 160 mg daily took glucocorticoids continuously. Therefore, patients are permitted but not required to continue steroids.
Guidelines suggest that tapering steroids depends on the clinical picture. Patients who have been taking 10 to 20 mg daily of glucocorticoids for longer than 3 weeks, or those who have taken evening doses of steroids for at least 3 weeks, may experience hypothalamic-pituitary-adrenal (HPA) axis suppression if steroids are stopped without tapering. The patient’s previous dosage, the duration of use, and the potency of the steroids taken are important considerations but not good predictors of the consequences of HPA suppression.
The goal of tapering off steroids is to lessen the possible resurgence of the disease for which the steroids were prescribed, to decrease the symptoms of withdrawal, and to lessen the chance of HPA suppression. Guidelines suggest a 5% to 10% reduction of total dose, every 1 to 2 weeks, until completely tapered.10,11
With second-line therapy, the patient sitting before us has already had experience with cancer. A common thread connecting many with this disease is their likely reliance on PSA readings. Because it is an oral medication, enzalutamide reaches steady state in approximately 28 days. A change in PSA should not be expected within this short time frame. In clinical trials, men were taking enzalutamide for 3 months before their PSA levels showed a decrease, which in turn reinforced their commitment to continuing with the new therapy. Educating patients is key to their quality of life as well as their compliance, especially with oral therapies.
Concomitant use with strong cytochrome P (CYP) 2C8 inhibitors (eg, gemfibrozil) or strong CYP3A4 inhibitors (eg, itraconazole) increases the concentration of enzalutamide—decrease the dose of enzalutamide if these medications are coadministered. CYP2C8 (eg, rifampin) and CYP3A4 (eg, carbamazepine, phenobarbital, phenytoin) inducers may alter or decrease plasma exposure and should be avoided. St. John’s wort, a weaker CYP3A4 inducer, should also be avoided.
Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer. At steady state, enzalutamide reduced the exposure to midazolam, warfarin, and omeprazole. Concomitant use of drugs with narrow therapeutic windows should either be avoided or require more frequent monitoring.8
Warnings and Precautions
Seizures In clinical trials with enzalutamide, 7 of 800 (0.9%) patients taking 160 mg daily experienced a seizure. Of note, no seizures were diagnosed in patients in the placebo arm. Patients with a known history of seizure, known brain metastasis, or ischemic attacks in the previous 12 months were excluded from trials. All patients who had a seizure were taken off the trial and had no further seizures. Patients considering treatment with enzalutamide should be made aware of the data and have their risk of seizures outlined. In men with prostate cancer, clinical practice does not often include evaluation of a brain scan. Thorough patient and family histories are necessary when considering changes to a patient’s therapy.3,5,7,8,12
Pregnancy Enzalutamide is contraindicated in women and could cause fetal harm, based on its mechanism of action. Men able to father children should practice safe sex with barrier methods while taking, and for up to 3 months post- treatment with, enzalutamide.8
Common Adverse Events With Enzalutamide The most common adverse events of enzalutamide, reported in any grade from clinical trials, were fatigue (34%), diarrhea (21%), hot flashes (20%), musculoskeletal pain (14%), and headaches (12%). Men in the placebo arm experienced the same adverse events, although at a somewhat lower percentage. In men taking enzalutamide, these effects should be anticipated, and patient education should include strategies aimed at addressing them.3,7,8
Advances in therapies aimed at metastatic CRPC have greatly aided our discussions of treatment options, particularly over the past 4 to 5 years. To date, 5 treatment options offer a survival benefit for men living with advanced prostate cancer. Going forward, we will consider not only what to offer our patients, but in what sequence. Enzalutamide’s current place is in second-line therapy, postdocetaxel, yet ongoing clinical trials may allow for another option in chemo-naive men. As with all oral therapies, patient education and a keen understanding of anticipatory needs will allow for better compliance with therapy and better patient outcomes.
References 1. American Cancer Society. Cancer Facts and Figures 2013. http://www.cancer.org/research/cancerfacts figures/cancerfactsfigures/cancer-facts-figures-2013. Accessed March 18, 2013. 2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63(1):11-30. 3. Menon MP, Higano CS. Enzalutamide, a second generation androgen receptor antagonist: development and clinical applications in prostate cancer. Curr Oncol Rep. 2013;15:67-75. 4. Berthold DR, Pond GR, Soban F. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol. 2008;26(2):242-245. 5. Ezzell EE, Chang KS, George BJ. New agents in the arsenal to fight castrate-resistant prostate cancer. Curr Oncol Rep. 2013;16(3):239-248. 6. Taneja SS. Re: increased survival with enzalutamide in prostate cancer after chemotherapy [comment]. J Urol. 2013;189(1):123-124. 7. Scher HI, Fizazi K, Saad F, et al; AFFIRM Investigators. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187-1197. 8. Xtandi [package insert]. Northbrook, IL: Astellas Pharma US Inc; 2012. 9. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Prostate cancer. Version 1.2013. www.nccn.org/professionals/physician_gls/pdf/prostate.pdf. Accessed February 19, 2013. 10. Chettle CC. Glucocorticoid drugs: their benefits and risks. http://ce.nurse.com/PrintTopic.aspx?Topi cId=7895. Accessed February 28, 2013. 11. Furst DE, Saag KG, Matteson EL, Romain PL. Glucocorticoid withdrawal. http://www.uptodate.com.ezproxy.med.nyu.edu/contents/glucocorticoid-with drawal?topic. Accessed March 1, 2013. 12. Pal SK, Stein CA, Sartor O. Enzalutamide for the treatment of prostate cancer. Expert Opin Pharmacother. 2013;14(5):679-685.
Mr G, a 74-year-old psychotherapist, had had annual healthcare visits, including prostate-specific antigen (PSA) screening. His first diagnosis of prostate cancer was 11 years previous (age 63 years), at which time his PSA was 12, with a slightly palpable prostate on digital rectal examination. His Gleason score was 3 + 4 = 7, in 2 core biopsies. Bone scan was negative. He opted for curative intent therapy with brachytherapy and external beam radiation. His PSA nadir was 0.7. At the age of 67, his PSA began to rise, and at a PSA of 5, he started bicalutamide and then a luteinizing hormone-releasing hormone agonist, every 3 months. A second bone scan was still negative. While in a foreign country 2 years later, he was treated for a painful urinary tract infection, thought to be nephritis with back pain. Although he improved on antibiotics, the pain returned a month later and he sought medical treatment in a small town away from home. An astute nurse practitioner in the emergency department worked him up for metastatic prostate cancer: his bone scan showed pelvic disease and computed tomography revealed positive lymph nodes. Once home, he started docetaxel 70 mg/m2 every 3 weeks. His pain resolved and his PSA, which had risen to 47, began to decrease. After his 6th cycle of chemotherapy, his repeat scans showed stable disease, but he was having difficulty in picking up his credit card and had noticed foot numbness. He feared that his neuropathy might worsen, and his healthcare team outlined treatment options. He then started enzalutamide 160 mg daily, once he secured the medication from a specialty pharmacy. He was told that although lab work would be performed in 2 weeks and then monthly for safety reasons, his PSA would not always be drawn. This was concerning to him until the pharmacokinetics of enzalutamide was explained. At 3 months, although he was more fatigued, his PSA went from 67 to 42. Bone pain was not an issue, although he says he has aches. Scans are stable and he will continue receiving enzalutamide.
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