XTANDI® (Enzalutamide): a Treatment Option for Castration-Resistant Prostate Cancer (CRPC)

XTANDI® (enzalutamide): A Treatment Option for Castration-Resistant Prostate Cancer (CRPC)

XTANDI® (enzalutamide) is approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with castration-resistant prostate cancer (CRPC).1 XTANDI is the first and only oral medication FDA-approved for both non-metastatic and metastatic CRPC.1

ABOUT THE ASTELLAS/PFIZER HOW XTANDI WORKS COLLABORATION

Astellas and Pfizer jointly XTANDI is indicated for the treatment of CRPC, commercialize XTANDI which is defined as disease progression on in the United States. androgen deprivation therapy (luteinizing hormone-releasing hormone (LHRH) therapy Astellas has responsibility or prior bilateral orchiectomy).2 for manufacturing and all additional regulatory In prostate cancer, the androgen receptor (AR) is a key driver filings globally, as well as of progression.3 XTANDI is an AR inhibitor that is thought commercializing XTANDI to act on multiple steps of the androgen receptor signaling 1 outside the United States. pathway within the tumor cell based on in vitro studies.

Select Safety Information Seizure occurred in 0.4% of patients receiving XTANDI in clinical studies. In a study of patients with predisposing factors for seizure, 2.2% of XTANDI-treated patients experienced a seizure. Patients in the study had one or more of the following pre-disposing factors: use of medications that may lower the seizure threshold; history of traumatic brain or head injury, cerebrovascular accident or transient ischemic attack, Alzheimer’s disease, meningioma, or leptomeningeal disease from prostate cancer, unexplained loss of consciousness within the last 12 months, history of seizure, presence of a space occupying lesion of the brain, history of arteriovenous malformation, or history of brain infection. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Advise patients of the risk of developing a seizure while taking XTANDI and of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Please see additional Important Safety Information on pages 3 and 4 and click here for Full Prescribing Information.

August 2018, 076-3315-PM XTANDI® (enzalutamide): A Treatment Option for Castration-Resistant Prostate Cancer (CRPC)

NON-METASTATIC CRPC CLINICAL TRIAL PROSPER

PROSPER was a multinational, randomized, double-blind, placebo-controlled trial that enrolled 1,401 patients with non-metastatic castration-resistant prostate cancer (nmCRPC) that had progressed, based on ≥ 3 rising prostate-specific antigen (PSA) values despite castrate testosterone levels (≤ 50 ng/dL) and a PSA doubling time ≤ 10 months. Patients in this trial were chemotherapy naive and had no symptoms or minimal symptoms and no prior or present evidence of metastatic disease.1,4

Results of the study, which supported the FDA approval of XTANDI for use in patients with nmCRPC,1 demonstrated XTANDI plus LHRH therapy*: • Reduced the risk of metastasis or death by 71 percent (HR=0.29 [95% CI, 0.24-0.35]; P<0.0001).1 • Improved median metastasis-free survival. Median metastasis-free survival (MFS) was 36.6 months (95% CI, 33.1-Not reached (NR)) for men who received XTANDI compared to 14.7 months (95% CI: 14.2-15.0) for men who received placebo plus ADT (HR=0.29 [95% CI: 0.24-0.35]; P < 0.0001).1 Metastasis-free survival was defined as the time from randomization to whichever of the following occurred first 1) loco-regional and/or distant radiographic progression per biochemical recurrence (BICR) or 2) death up to 112 days after treatment discontinuation without evidence of radiographic progression.1

METASTATIC CRPC CLINICAL TRIALS

AFFIRM PREVAIL TERRAIN

AFFIRM was a multinational, randomized, PREVAIL was a multinational, randomized, TERRAIN was a multinational, double- double-blind, placebo-controlled study double-blind, placebo-controlled trial in blind, randomized study in 375 in 1,199 men with metastatic CRPC who 1,717 chemotherapy-naive patients with chemotherapy-naive patients with had previously received docetaxel-based metastatic CRPC and asymptomatic or metastatic CRPC asymptomatic or mildly chemotherapy and had asymptomatic to mildly symptomatic disease. Patients were symptomatic disease. Patients were moderately symptomatic disease. Patients randomized to receive XTANDI plus LHRH randomized to receive XTANDI plus LHRH were randomized to receive XTANDI plus therapy* (n = 872) or placebo plus LHRH therapy* (n = 184) or bicalutamide plus LHRH therapy* (n = 800) or placebo plus therapy* (n = 845).6 LHRH therapy* (n = 191).7 LHRH therapy* (n = 399).5 Results of the study demonstrated Results of the study demonstrated Results of the study demonstrated XTANDI plus LHRH therapy: XTANDI plus LHRH therapy: XTANDI plus LHRH therapy: • Improved overall survival. Median • Reduced the risk of radiographic • Improved overall survival. Median overall survival was 35.3 months progression or death by 40% Overall Survival (OS) post-docetaxel (95% CI, 32.2-NR) for patients receiving compared with bicalutamide plus was 18.4 months (95% CI, 17.3-NR) XTANDI plus LHRH therapy* compared LHRH therapy* (HR = 0.60 [95% CI, compared to 13.6 months (95% CI, to 31.3 months (95% CI, 28.8-34.2) 0.43-0.83]).1 11.3-15.8) with placebo plus LHRH for those receiving placebo plus LHRH therapy,* (HR = 0.63 [95% CI, 0.53- therapy* (HR = 0.77 [95% CI, 0.67- 0.75]; P < 0.0001).1 0.88]).1 • Significantlyreduced the risk of radiographic progression or death by 83% compared with placebo plus LHRH therapy* (HR = 0.17 [95% CI, 0.14-0.21]; P < 0.0001).1

Select Safety Information Posterior Reversible Encephalopathy Syndrome (PRES) In post approval use, there have been reports of Posterior Reversible Encephalopathy Syndrome (PRES) in patients receiving XTANDI. PRES is 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. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.

Hypersensitivity reactions, including edema of the face (0.5%), tongue (0.1%), or lip (0.1%) have been observed with XTANDI in clinical trials. Pharyngeal edema has been reported in post-marketing cases. Advise patients who experience any symptoms of hypersensitivity to temporarily discontinue XTANDI and promptly seek medical care. Permanently discontinue XTANDI for serious hypersensitivity reactions.

Please see additional Important Safety Information on pages 3 and 4 and click here for Full Prescribing Information. *

*Or prior bilateral orchiectomy **Hazard radio (HR) indicates the relative risk of a complication based on comparison of event rates between treatment and control August 2018, 076-3315-PM XTANDI® (enzalutamide): A Treatment Option for Castration-Resistant Prostate Cancer (CRPC)

HELPFUL INFORMATION ABOUT XTANDI DOSING

The recommended XTANDI can be Steroids, for Patients receiving dose of XTANDI taken with or example oral XTANDI should also is four 40 mg without food1 prednisone, are receive an LHRH capsules (160 mg) not required analog concurrently taken orally, once with XTANDI1* or should have a day, at the same had bilateral time each day1 orchiectomy1

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS Falls and Fractures In the placebo-controlled clinical studies, falls occurred in 10% of patients treated with XTANDI compared to 4% of Seizure occurred in 0.4% of patients receiving XTANDI in clinical studies. In a study of patients with predisposing factors for seizure, patients treated with placebo. Fractures occurred in 8% of patients 2.2% of XTANDI-treated patients experienced a seizure. Patients in the treated with XTANDI and in 3% of patients treated with placebo. Evaluate study had one or more of the following pre-disposing factors: use of patients for fracture and fall risk. Monitor and manage patients at risk for medications that may lower the seizure threshold; history of traumatic fractures according to established treatment guidelines and consider use brain or head injury, cerebrovascular accident or transient ischemic of bone-targeted agents. attack, Alzheimer’s disease, meningioma, or leptomeningeal disease Embryo-Fetal Toxicity Safety and efficacy of XTANDI have not been from prostate cancer, unexplained loss of consciousness within the last established in females. XTANDI can cause fetal harm and loss of 12 months, history of seizure, presence of a space occupying lesion pregnancy when administered to a pregnant female. Advise males with of the brain, history of arteriovenous malformation, or history of brain female partners of reproductive potential to use effective contraception infection. It is unknown whether anti-epileptic medications will prevent during treatment with XTANDI and for 3 months after the last dose of seizures with XTANDI. Advise patients of the risk of developing a seizure XTANDI. XTANDI should not be handled by females who are or may while taking XTANDI and of engaging in any activity where sudden loss become pregnant. of consciousness could cause serious harm to themselves or others. ADVERSE REACTIONS Permanently discontinue XTANDI in patients who develop a seizure The most common adverse reactions (≥ 10%) that occurred more during treatment. frequently (≥ 2% over placebo) in the XTANDI patients from the randomized Posterior Reversible Encephalopathy Syndrome (PRES) In post placebo-controlled trials were asthenia/fatigue, decreased appetite, hot approval use, there have been reports of PRES in patients receiving flush, arthralgia, dizziness/vertigo, hypertension, headache and weight XTANDI. PRES is a neurological disorder which can present with rapidly decreased. In the bicalutamide-controlled study, the most common evolving symptoms including seizure, headache, lethargy, confusion, adverse reactions (≥ 10%) reported in XTANDI patients were asthenia/ blindness, and other visual and neurological disturbances, with or without fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, associated hypertension. A diagnosis of PRES requires confirmation constipation, diarrhea, upper respiratory tract infection, and weight loss. by brain imaging, preferably MRI. Discontinue XTANDI in patients who In the placebo-controlled study of metastatic CRPC (mCRPC) patients develop PRES. taking XTANDI who previously received docetaxel, Grade 3 and higher Hypersensitivity reactions, including edema of the face (0.5%), tongue adverse reactions were reported among 47% of XTANDI patients and (0.1%), or lip (0.1%) have been observed with XTANDI in clinical trials. 53% of placebo patients. Discontinuations due to adverse events were Pharyngeal edema has been reported in post-marketing cases. Advise reported for 16% of XTANDI patients and 18% of placebo patients. In the patients who experience any symptoms of hypersensitivity to temporarily placebo-controlled study of chemotherapy-naïve mCRPC patients, Grade discontinue XTANDI and promptly seek medical care. Permanently 3-4 adverse reactions were reported in 44% of XTANDI patients and discontinue XTANDI for serious hypersensitivity reactions. 37% of placebo patients. Discontinuations due to adverse events were Ischemic Heart Disease In the placebo-controlled clinical studies, reported for 6% of both study groups. In the placebo-controlled study ischemic heart disease occurred more commonly in patients on the of non-metastatic CRPC (nmCRPC) patients, Grade 3 or higher adverse XTANDI arm compared to patients on the placebo arm (2.7% vs 1.2%). reactions were reported in 31% of XTANDI patients and 23% of placebo Grade 3-4 ischemic events occurred in 1.2% of patients on XTANDI versus patients. Discontinuations with an adverse event as the primary reason 0.5% on placebo. Ischemic events led to death in 0.4% of patients on were reported for 9% of XTANDI patients and 6% of placebo patients. XTANDI compared to 0.1% on placebo. Monitor for signs and symptoms In the bicalutamide-controlled study of chemotherapy-naïve mCRPC of ischemic heart disease. Optimize management of cardiovascular risk patients, Grade 3-4 adverse reactions were reported in 39% of XTANDI factors, such as hypertension, diabetes, or dyslipidemia. Discontinue patients and 38% of bicalutamide patients. Discontinuations with an AE XTANDI for Grade 3-4 ischemic heart disease. as the primary reason were reported for 8% of XTANDI patients and 6% of bicalutamide patients.

* Please see additional Important Safety Information on page 4 and click here for Full Prescribing Information. *In the PREVAIL trial, 27% of patients in the XTANDI arm and 30% of patients in the placebo arm received glucocorticoids for varying reasons. In the AFFIRM trial, 48% of patients in the XTANDI arm and 46% of patients in the placebo arm received glucocorticoids. In the PROSPER trial, 3.9% of patients in the XTANDI arm and 14% of patients in the placebo arm received glucocorticoids for varying reasons.8 August 2018, 076-3315-PM XTANDI® (enzalutamide): A Treatment Option for Castration-Resistant Prostate Cancer (CRPC)

IMPORTANT SAFETY INFORMATION (CONTINUED)

ADVERSE REACTIONS (CONTINUED) DRUG INTERACTIONS Lab Abnormalities: In the two placebo-controlled trials in patients with Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as mCRPC, Grade 1-4 neutropenia occurred in 15% of XTANDI patients they can increase the plasma exposure to XTANDI. If co-administration is (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). In the necessary, reduce the dose of XTANDI. placebo-controlled trial in patients with nmCRPC, Grade 1-4 neutropenia occurred in 8% of patients receiving XTANDI (0.5% Grade 3-4) and in 5% Avoid strong CYP3A4 inducers as they can decrease the plasma of patients receiving placebo (0.2% Grade 3-4). exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI. Hypertension: In the two placebo-controlled trials in patients with mCRPC, hypertension was reported in 11% of XTANDI patients and Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and 4% of placebo patients. Hypertension led to study discontinuation in CYP2C19 substrates with a narrow therapeutic index, as XTANDI may <1% of patients in each arm. In the placebo-controlled trial in patients decrease the plasma exposures of these drugs. If XTANDI is co- with nmCRPC, hypertension was reported in 12% of patients receiving administered with warfarin (CYP2C9 substrate), conduct additional INR XTANDI and 5% of patients receiving placebo. monitoring.

Please see Full Prescribing Information for additional safety information.

References 1. XTANDI [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc. 2. Saad F, Chi KN, Finelli A, et al. The 2015 CUA-CUOG guidelines for the management of castration-resistant prostate cancer (CRPC). Can Urol Assoc J 2015;9(3-4):90-6. 3. American Urological Association. Castration-resistant prostate cancer: AUA guideline (2018). https://www.auanet.org/Documents/Guidelines/PDF/ CRPC%20website%20050918.pdf. Accessed 5-23-2018. 4. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in men with nonmetastatic castration-resistant prostate cancer. N Engl J Med 2018;378(26):2465-74. 5. 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. 6. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014;371(5):424-33. 7. Shore ND, Chowdhury S, Villers A, et al. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomized, double-blind, phase 2 study. Lancet Oncol 2016;17(2):153-163. 8. Pfizer. XTANDI. Data on file.

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