RESULTS FROM THE TERRAIN TRIAL

XTANDI reduced the risk of radiographic progression or death vs bicalutamide in patients with metastatic CRPC1

40% reduction in risk of radiographic progression or death with XTANDI + LHRH therapy* vs bicalutamide + LHRH therapy*1

Radiographic progression-free survival in TERRAIN study1

Radiographic Progression-free Survival, TERRAIN Trial

Radiographic progression was assessed by independent central review per PCWG2 criteria and/or RECIST 1.1 criteria for progression of bone and soft tissue lesions, respectively.1

  • Median radiographic progression-free survival was 19.5 months for patients receiving XTANDI + LHRH therapy* vs 13.4 months for patients receiving bicalutamide + LHRH therapy* (95% CI, 11.8-NR and 8.2-16.4, respectively)1

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Hypertension:  In the two placebo-controlled trials in patients with mCRPC, hypertension was reported in 11% of XTANDI patients and 4% of placebo patients. Hypertension led to study discontinuation in < 1% of patients in each arm. In the placebo-controlled trial in patients with nmCRPC, hypertension was reported in 12% of patients receiving XTANDI and 5% of patients receiving placebo.

The following results are from the TERRAIN trial that contributed to the clinical body of evidence for XTANDI but are not contained in the approved product labeling. The approved product labeling only includes a modified efficacy analysis of the radiographic progression-free survival endpoint, as shown above.

ADDITIONAL RESULTS FROM THE TERRAIN TRIAL

XTANDI improved progression-free survival vs bicalutamide2

  • XTANDI + LHRH therapy* improved progression-free survival, with a 56% reduction in risk of progression event, including death, vs bicalutamide + LHRH therapy* (HR = 0.44 [95% CI, 0.34-0.57]; P < 0.0001)
  • Median progression-free survival was 15.7 months (95% CI, 11.5-19.4) for patients receiving XTANDI + LHRH therapy* and 5.8 months (95% CI, 4.8-8.1) for patients receiving bicalutamide + LHRH therapy*

Progression-free survival in TERRAIN study2

XTANDI® (enzalutamide)+LHRH Therapy Radiographic Progression

Progression-free survival was a composite endpoint defined as the time from randomization to the first progression event, which included 4 components: (1) radiographic disease progression, (2) initiation of a new antineoplastic therapy, (3) skeletal-related event, or (4) death.2 Two of the 4 progression-free survival components as measured in the study (radiographic disease progression and initiation of a new antineoplastic therapy) have limitations that may impact the reliability and objectivity of the progression-free survival endpoint to measure the treatment effects between study drugs.

  • “Radiographic disease progression” criteria were different than the standard Prostrate Cancer Working Group 2 (PCWG2) criteria, which may have led to an inflation of XTANDI’s treatment effect. In the XTANDI Prescribing Information, radiographic progression-free survival was redefined to maintain consistency with the PCWG2
  • “Initiation of a new antineoplastic therapy” was not standardized and the clinical decision on when to initiate a new therapy may have introduced bias

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Effect of Other Drugs on XTANDI:  Administration of strong CYP2C8 inhibitors can increase the plasma exposure to XTANDI. Co-administration of XTANDI with strong CYP2C8 inhibitors should be avoided if possible. If co-administration of XTANDI cannot be avoided, reduce the dose of XTANDI. Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI.

XTANDI PSA changes vs bicalutamide2

PSA Changes in the TERRAIN Study2

  • Median time to a PSA progression event was 19.4 months (95% CI, 16.6-NR) for patients receiving XTANDI + LHRH therapy* and 5.8 months (95% CI, 5.6-8.3) for patients receiving bicalutamide + LHRH therapy* (HR = 0.28 [95% CI 0.20-0.39]; P <0.0001)
  • Reductions in PSA of ≥ 50% were observed in 82% (151/184) of patients receiving XTANDI + LHRH therapy* and 21% (40/191) of patients receiving bicalutamide + LHRH therapy*
Maximum PSA Change from Baseline Per Patient Graph

PSA data are not reported in product labeling because PSA is not a reliable surrogate for overall survival. PSA evaluation should be viewed in the context of patient management and the overall physical condition and clinical course of the patient.

CI, confidence interval; HR, hazard ratio; LHRH therapy, luteinizing hormone-releasing hormone therapy; NR, not reached; PSA, prostate-specific antigen.

*Or after bilateral orchiectomy.1

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Effect of XTANDI on Other Drugs:  XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer in humans. Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

Important Safety Information and Indication

Indication

XTANDI (enzalutamide) is indicated for the treatment of patients with castration-resistant prostate cancer (CRPC).

Important Safety Information

Warnings and Precautions
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.

Posterior Reversible Encephalopathy Syndrome (PRES)   In post approval use, there have been reports of 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.

Ischemic Heart Disease  In the placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (2.7% vs 1.2%). Grade 3-4 ischemic events occurred in 1.2% of patients on XTANDI versus 0.5% on placebo. Ischemic events led to death in 0.4% of patients on XTANDI compared to 0.1% on placebo. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue XTANDI for Grade 3-4 ischemic heart disease.

Falls and Fractures  In the placebo-controlled clinical studies, falls occurred in 10% of patients treated with XTANDI compared to 4% of patients treated with placebo. Fractures occurred in 8% of patients treated with XTANDI and in 3% of patients treated with placebo. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents.

Embryo-Fetal Toxicity  Safety and efficacy of XTANDI have not been established in females. XTANDI can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment with XTANDI and for 3 months after the last dose of XTANDI. XTANDI should not be handled by females who are or may become pregnant.

Adverse Reactions
The most common adverse reactions (≥ 10%) that occurred more frequently (≥ 2% over placebo) in the XTANDI patients from the randomized placebo-controlled trials were asthenia/fatigue, decreased appetite, hot flush, arthralgia, dizziness/vertigo, hypertension, headache and weight decreased. In the bicalutamide-controlled study, the most common adverse reactions (≥ 10%) reported in XTANDI patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, diarrhea, upper respiratory tract infection, and weight loss.

In the placebo-controlled study of metastatic CRPC (mCRPC) patients taking XTANDI who previously received docetaxel, Grade 3 and higher adverse reactions were reported among 47% of XTANDI patients and 53% of placebo patients. Discontinuations due to adverse events were reported for 16% of XTANDI patients and 18% of placebo patients. In the placebo-controlled study of chemotherapy-naïve mCRPC patients, Grade 3-4 adverse reactions were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to adverse events were reported for 6% of both study groups. In the placebo-controlled study of non-metastatic CRPC (nmCRPC) patients, Grade 3 or higher adverse reactions were reported in 31% of XTANDI patients and 23% of placebo patients. Discontinuations with an adverse event as the primary reason were reported for 9% of XTANDI patients and 6% of placebo patients. In the bicalutamide-controlled study of chemotherapy-naïve mCRPC patients, Grade 3-4 adverse reactions were reported in 39% of XTANDI patients and 38% of bicalutamide patients. Discontinuations with an AE as the primary reason were reported for 8% of XTANDI patients and 6% of bicalutamide patients.

Lab Abnormalities:  In the two placebo-controlled trials in patients with mCRPC, Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). In the 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% of patients receiving placebo (0.2% Grade 3-4).

Hypertension:  In the two placebo-controlled trials in patients with mCRPC, hypertension was reported in 11% of XTANDI patients and 4% of placebo patients. Hypertension led to study discontinuation in < 1% of patients in each arm. In the placebo-controlled trial in patients with nmCRPC, hypertension was reported in 12% of patients receiving XTANDI and 5% of patients receiving placebo.

Drug Interactions
Effect of Other Drugs on XTANDI   Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI.

Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI.

Effect of XTANDI on Other Drugs   Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

Indication

XTANDI (enzalutamide) is indicated for the treatment of patients with castration-resistant prostate cancer (CRPC).

Please see Full Prescribing Information for additional safety information.

References: 1. XTANDI [package insert]. Northbrook, IL: Astellas Pharma US, Inc. 2. 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;17(2):153-63.
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Important Safety Information and Indication

Indication

XTANDI (enzalutamide) is indicated for the treatment of patients with castration-resistant prostate cancer (CRPC).

Important Safety Information

Warnings and Precautions
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,