• Nonmetastatic RESULTS

PROSPER TRIAL PRIMARY ENDPOINT

XTANDI significantly extended metastasis-free survival in patients with nonmetastatic CRPC1

Median 3 years of metastasis-free survival* with XTANDI + LHRH therapy vs 14.7 months with placebo + LHRH therapy†1

Metastasis-free survival (primary endpoint)1

Xtandi® (enzalutamide) Median Metastasis Free Survival Graph
71%
REDUCTION IN THE RISK OF METASTASIS OR DEATH with XTANDI + LHRH therapy vs placebo + LHRH therapy in patients with nonmetastatic CRPC (HR = 0.29 [95% CI, 0.24-0.35]; P < 0.0001)1
XTANDI demonstrated consistent metastasis-free survival results in pre-specified and stratified patient sub-groups of PSADT (< 6 months or ≥ 6 months) and use of a prior bone-targeting agent (yes or no).1

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

*The primary endpoint of the study was metastasis-free survival, defined as the time from randomization to whichever of the following occurred first 1) loco-regional and/or distant radiographic progression per BICR (blinded independent central review) or 2) death up to 112 days after treatment discontinuation without evidence of radiographic progression.1

Or after bilateral orchiectomy.1

Select Safety Information

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.

PROSPER TRIAL SECONDARY ENDPOINTS

XTANDI significantly delayed time to first use of subsequent prostate cancer therapy*1

First use of subsequent prostate cancer therapy* was delayed by a median of 3 years with XTANDI + LHRH therapy vs 17.7 months with placebo + LHRH therapy†1

Median time to first use of subsequent prostate cancer therapy (secondary endpoint)1,2

Median Time to Subsequent Therapy in Patients with nmCRPC graph
Overall survival data were not mature at the time of final metastasis-free survival analysis (28% of the required number of events had been reported).1

*Time to subsequent prostate cancer therapy was defined as the time from randomization to first use of a new antineoplastic for prostate cancer. Subsequent prostate cancer therapies included cytotoxic, hormonal (except LHRH agonist/antagonist), or investigational therapies.2

Or after bilateral orchiectomy.1

Select Safety Information

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.

PROSPER SAFETY RESULTS

Safety profile demonstrated in patients with nonmetastatic CRPC1

Adverse reactions that occurred at ≥ 2% higher frequency in the XTANDI arm than in the placebo arm1

ADVERSE REACTIONS PREVAIL
ADVERSE REACTIONS Grade 1-4 (%) Grade 3-4 (%)
XTANDI (n = 930) Placebo (n = 465) XTANDI (n = 930) Placebo (n = 465)
Metabolism and Nutrition Disorders
Decreased Appetite 9.6 3.9 0.2 0.2
Nervous System Disorders
Dizziness* 12 5.2 0.5 0
Headache 9.1 4.5 0.2 0
Cognitive and Attention Disorders 4.6 1.5 0.1 0
Vascular Disorders
Hot Flush 13 7.7 0.1 0
Hypertension 12 5.2 4.6 2.2
Gastrointestinal Disorders
Nausea 11 8.6 0.3 0
Constipation 9.1 6.9 0.2 0.4
General Disorders and Administration Site Conditions
Asthenic Conditions 40 20 4.0 0.9
Investigations
Weight Decreased 5.9 1.5 0.2 0
Injury, Poisoning, and Procedural Complications
Fractures§ 9.8 4.9 2.0 1.7
Fall 11 4.1 1.3 0.6
Psychiatric Disorders
Anxiety 2.8 0.4 0.2 0

Adverse reactions were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.1

*Includes dizziness and vertigo.

Includes amnesia, memory impairment, cognitive disorder, and disturbance in attention.

Includes asthenia and fatigue.

§Includes all osseous fractures from all sites.

  • Median duration of treatment exposure was longer in patients receiving XTANDI + LHRH therapy* than in patients receiving placebo + LHRH therapy* (18.4 months [range: 0.0 to 42 months] and 11.1 months [range: 0.0 to 43 months], respectively)1

Discontinuations with an adverse event as the primary reason were reported for 9.4% of XTANDI-treated patients and 6.0% of placebo-treated patients.1

  • The most common adverse event leading to treatment discontinuation was fatigue, which occurred in 1.6% of the XTANDI-treated patients compared with 0% of the placebo-treated patients1

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

*Or after bilateral orchiectomy.1

 

PROSPER TRIAL DESIGN

PROSPER was a multinational, randomized, double-blind, placebo-controlled phase 3 study of XTANDI + LHRH therapy* in patients with nonmetastatic CRPC who had progressed on LHRH therapy*. 1401 patients with nonmetastatic CRPC were randomized 2:1 to receive XTANDI at a dose of 160 mg once daily (n = 933) or matching placebo once daily (n = 468). Patients in both arms continued to receive LHRH therapy. Stratification factors for treatment randomization included PSA doubling time (< 6 months or ≥ 6 months) and the use of bone-targeting agent (yes or no).1 To be included in the trial, patients were required to have nonmetastatic CRPC (central review), ≥ 3 rising PSA values despite castrate testosterone levels (≤ 50 ng/dL) baseline PSA ≥ 2 ng/mL, PSA doubling time ≤ 10 months, no prior chemotherapy, and ECOG performance status of 0 or 1. Patients were excluded if they had prior abiraterone acetate use, history of seizure, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, or clinically significant cardiovascular disease. Patients were permitted to participate if they had prior antiandrogen therapy with a 4-week washout period prior to randomization. Bicalutamide treatment prior to randomization was received by 55% and 58% of patients in the XTANDI and placebo arms, respectively. The primary endpoint was metastasis-free survival. Key secondary endpoints were time to PSA progression, time to first use of new antineoplastic therapy, and overall survival.1,2

*Or after bilateral orchiectomy.1

Progression was defined as at least 3 rising PSA values (PSA1 < PSA2 < PSA3) taken at least 1 week apart despite castrate levels of testosterone (≤ 50 ng/dL) on LHRH therapy or after bilateral orchiectomy.2

The primary endpoint of the study was metastasis-free survival, defined as the time from randomization to whichever of the following occurred first 1) loco-regional and/or distant radiographic progression per BICR (blinded independent central review) or 2) death up to 112 days after treatment discontinuation without evidence of radiographic progression.1

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. Pfizer. XTANDI. Data on File.
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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,