RESULTS FROM THE TERRAIN TRIAL

XTANDI reduced the risk of radiographic progression or death vs bicalutamide1

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

Radiographic progression-free survival in TERRAIN study1

Radiographic Progression-free Survival, TERRAIN Trial
  • Median radiographic progression-free survival was 19.5 months for patients receiving XTANDI + GnRH therapy* vs 13.4 months for patients receiving bicalutamide + GnRH therapy* (95% CI, 11.8-NR and 8.2-16.4, respectively) (HR = 0.60 [95% CI, 0.43-0.83])1

Radiographic disease progression was assessed by Independent Central Review (ICR) using the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria and/or Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) criteria for progression of soft-tissue lesions.1

Select Safety Information

In the TERRAIN trial, the most common adverse reactions (≥ 10%) reported in XTANDI patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, upper respiratory tract infection, diarrhea, and weight loss.

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 + GnRH therapy* improved progression-free survival, with a 56% reduction in risk of progression event, including death, vs bicalutamide + GnRH 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 + GnRH therapy* and 5.8 months (95% CI, 4.8-8.1) for patients receiving bicalutamide + GnRH therapy*

Progression-free survival in TERRAIN study2

Progression-free Survival, TERRAIN Trial

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 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

Select Safety Information

In the TERRAIN trial, Grade 3 and higher adverse reactions were reported among 38.8% of XTANDI patients and 37.6% of bicalutamide patients. Discontinuations due to adverse events were reported for 7.6% of XTANDI patients and 6.3% of bicalutamide patients.

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 + GnRH therapy* and 5.8 months (95% CI, 5.6-8.3) for patients receiving bicalutamide + GnRH therapy*2
  • Reductions in PSA of ≥ 50% were observed in 82% (151/184) of patients receiving XTANDI + GnRH therapy* and 21% (40/191) of patients receiving bicalutamide + GnRH therapy*2
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; GnRH therapy, gonadotropin-releasing hormone therapy; HR, hazard ratio; NR, not reached; PSA, prostate-specific antigen.

*Or after bilateral orchiectomy.1

Select Safety Information

Falls (including fall-related injuries) occurred in 9% of XTANDI patients and 4% of placebo patients in the AFFIRM and PREVAIL trials. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients, and included non-pathologic fractures, joint injuries, and hematomas.

Indication

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

Important Safety Information

Contraindications
XTANDI is not indicated for women. XTANDI can cause fetal harm and potential loss of pregnancy.

Warnings and Precautions
Seizure occurred in 0.5% of patients receiving XTANDI in clinical studies. In a study of patients with predisposing factors, seizures were reported in 2.2% of patients. See section 5.1 of the Prescribing Information for the list of predisposing factors. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. 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.

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

In the placebo-controlled study of 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 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 bicalutamide-controlled study of chemotherapy-naïve patients, Grade 3-4 adverse reactions were reported in 38.8% of XTANDI patients and 37.6% of bicalutamide patients. Discontinuations due to adverse events were reported for 7.6% of XTANDI patients and 6.3% of bicalutamide patients.

Lab Abnormalities: In the two placebo-controlled trials, Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). Grade 1-4 thrombocytopenia occurred in 6% of XTANDI patients (0.3% Grade 3-4) and 5% of placebo patients (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of XTANDI patients (0.2% Grade 3-4) and 16% of placebo patients (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients (0.1% Grade 3-4) and 2% of placebo patients (no Grade 3-4).

Infections: In the study of patients taking XTANDI who previously received docetaxel, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In the study of chemotherapy-naïve patients, 1 patient in each treatment group (0.1%) had an infection resulting in death.

Falls (including fall-related injuries) occurred in 9% of XTANDI patients and 4% of placebo patients in the two placebo-controlled trials. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients, and included non-pathologic fractures, joint injuries, and hematomas.

Hypertension occurred in 11% of XTANDI patients and 4% of placebo patients in the two placebo-controlled trials. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm.

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.

Please see Full Prescribing Information for additional safety information.

References: 1. XTANDI [package insert]. Northbrook, IL: Astellas, 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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Indication and Important Safety Information

Indication

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

Important Safety Information

Contraindications
XTANDI is not indicated for women. XTANDI can cause fetal harm and potential loss of pregnancy.