• TRIAL DESIGNS

XTANDI has been evaluated in randomized, controlled prostate cancer clinical trials comprising 3291 patients with metastatic CRPC worldwide1

PREVAIL TRIAL STUDY DESIGN

For patients on LHRH therapy* who have progressed to metastatic CRPC1

PREVAIL was a multinational, double-blind, randomized, placebo-controlled phase 3 trial of XTANDI + LHRH therapy* in patients with metastatic CRPC who were asymptomatic or mildly symptomatic.2

Disease progression was confirmed by one or more of the following in the presence of castrate levels of testosterone (≤ 50 ng/dL)3:

  • Two consecutive PSA rises (≥ 1 week apart)
  • A new positive scan for metastases such as soft-tissue or bone metastases†‡
Co-primary endpoints2
Radiographic progression-free survival
Overall survival
Secondary endpoints2
  • Time to initiation of chemotherapy
  • Time to first skeletal-related event
  • Soft-tissue response rate, PSA response rate (≥ 50% decrease from baseline), and time to PSA progression

Patients had2:

  • Metastatic disease
  • Disease progression despite receiving LHRH therapy or after bilateral orchiectomy
R A N D O M I Z E D 1:11

XTANDI 160 mg daily + LHRH therapy* (n = 872)1

Placebo + LHRH therapy* (n = 845)1

Treatment continued until confirmed radiographic disease progression or skeletal-related event and the initiation of either a cytotoxic chemotherapy or other agent, or until unacceptable toxicity or withdrawal1

Baseline characteristics and eligibility1-3

Included:

  • LHRH therapy* maintained
  • Chemotherapy naïve
  • Asymptomatic or mildly symptomatic

Excluded:

  • Prior abiraterone acetate use
  • History of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, and brain metastasis
  • Eastern Cooperative Oncology Group (ECOG) Performance Status ≥ 2
  • Clinically significant cardiovascular disease

Allowed:

  • Prior anti-androgen treatment
  • Concomitant corticosteroid use
  • Concomitant sipuleucel-T treatment
  • Concomitant bisphosphonate or denosumab use
  • Palliative radiation therapy
  • Medications known to lower the seizure threshold
  • Presence of visceral metastases
PREVAIL: Patient baseline demographics and characteristics were balanced between treatment arms2

All patients were either asymptomatic or mildly symptomatic2

SELECT PATIENT CHARACTERISTICS2,3 XTANDI + LHRH therapy* (n = 872) Placebo + LHRH therapy* (n = 845)
Median age (range) 72 (43-93) 71 (42-93)
Gleason score ≤ 7 at initial diagnosis§ 49.4% 47.6%
ECOG Performance Status = 0 or 1 100% 100%
Baseline mean pain score 0-1, asymptomatic
(Brief Pain Inventory Short Form Q3)||
66.2% 67.5%
Prior anti-androgen use (eg, bicalutamide) 87.2% 86.4%
Prior corticosteroid use (> 7 days) 4.0% 4.3%
Prior bisphosphonate or denosumab use 25.6% 27.2%
SELECT DISEASE MEASURES3 XTANDI + LHRH therapy* (n = 872) Placebo + LHRH therapy* (n = 845)
PSA, median, µg/L# 54.1 44.2
Bone metastases only 39.9% 39.6%
Soft-tissue metastases only** 14.2% 17.6%
Bone and soft-tissue metastases 45.1% 42.0%
Visceral metastases (liver and/or lung) 11.2% 12.5%
Liver metastases 4.6% 4.0%
Lung metastases 7.3% 8.9%

LHRH therapy, luteinizing hormone-releasing hormone therapy; PSA, prostate-specific antigen.

*Or after bilateral orchiectomy.1

Defined by Prostate Cancer Clinical Trials Working Group 2 (PCWG2).2

Defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).2

§Number of patients included in this analysis: XTANDI (n = 838) and placebo (n = 808).2

||Number of patients included in this analysis: XTANDI (n = 859) and placebo (n = 840).3

Includes all steroid use for prostate cancer on the date of the first dose of study drug and with continuous exposure for at least 7 days.3

#Number of patients included in this analysis: XTANDI (n = 872) and placebo (n = 844).3

**Defined by RECIST 1.1.1

TERRAIN TRIAL STUDY DESIGN

For patients on LHRH therapy* who have progressed to metastatic CRPC†1

TERRAIN was a multinational, double-blind, randomized trial comparing XTANDI + LHRH therapy* with bicalutamide + LHRH therapy* in patients with metastatic CRPC who were asymptomatic or mildly symptomatic.4

Xtandi mCRPC Overall Survival Graph, PREVAIL Trial

Baseline characteristics and eligibility4

Included:

  • Asymptomatic or mildly symptomatic
  • Not using opiate analgesics for prostate cancer-related pain
  • ECOG Performance Status of 0-1

Excluded:

  • Prior progression on anti-androgen therapy
  • Prior chemotherapy
  • Brain metastasis
  • History of seizure or a condition that might predispose to seizure
  • Clinically significant cardiovascular disease

Allowed:

  • No age restrictions

CT, computed tomography; ECOG, Eastern Cooperative Oncology Group; ICR, Independent Central Review; LHRH therapy, luteinizing hormone-releasing hormone therapy; MRI, magnetic resonance imaging; PSA, prostate-specific antigen; RECIST, Response Evaluation Criteria in Solid Tumors.

*Or after bilateral orchiectomy.1

Castration resistance, or disease progression, was confirmed by one or more of the following4:

  • A minimum of 3 consecutive PSA rises (≥ 1 week apart)
  • Soft tissue disease progression defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  • Bone disease progression defined by 2 or more new lesions on bone scan

Even though bicalutamide is not approved for the treatment of metastatic castration-resistant prostate cancer, it is widely used in this setting despite evidence of only a short-lived effect in a minority of patients.4

§Progression-free survival was defined as the time from randomization to the first progression event, which includes4:

  • Radiographic disease progression
  • Skeletal-related event
  • Initiation of a new antineoplastic therapy
  • Death

||Radiographic progression-free survival was defined as the time from randomization until first objective evidence of radiographic disease progression based on the assessments by ICR or death, whichever occurred first.1

AFFIRM TRIAL STUDY DESIGN

For patients on LHRH therapy* who have progressed to metastatic CRPC1

In AFFIRM, XTANDI was evaluated in the post-docetaxel setting.1

AFFIRM enrolled 1199 patients with metastatic CRPC who had previously received docetaxel therapy. The treatment group of 800 patients received XTANDI 160 mg daily, compared to the placebo group of 399 patients.1

At baseline, the majority of patients had few or no restrictions on activity (Eastern Cooperative Oncology Group [ECOG] Performance Status 0-1) and a median age of 69 years.1

The primary endpoint in AFFIRM was overall survival, and patients were first assessed for disease progression at 13 weeks.5

AFFIRM was a randomized (2:1), double-blind, placebo-controlled study for patients on LHRH therapy* who had progressed to metastatic CRPC. Patients with predisposing factors for seizure history were excluded. Patients were excluded if they had clinically significant cardiovascular disease. All patients continued ADT. Patients were allowed but not required to take glucocorticoids.1,3,5

ADT, androgen deprivation therapy.

*Or after bilateral orchiectomy.1

92% had an ECOG Performance Status score of 0 or 1. ECOG Performance Status scores range from 0 to 5, with 0 indicating full activity, and 1 indicating a restriction in strenuous activity but the ability to be ambulatory and do light work.1,5

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. Beer TM, Armstrong AJ, Rathkopf DE, et al; for the PREVAIL Investigators. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014;371(5):424-33. [Also supplementary appendix: http://www.nejm.org/doi/suppl/10.1056/NEJMoa1405095/suppl_file/nejmoa1405095_appendix.pdf.] 3. Pfizer Inc. XTANDI. Data on File. 4. 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. 5. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamlde in prostate cancer after chemotherapy. N Engl J Med 2012;367(13):1187-97.
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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,