PREVAIL Trial Study Design

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

PREVAIL was a multinational, double-blind, randomized, placebo-controlled phase 3 trial of XTANDI + GnRH therapy* in patients with metastatic CRPC who were asymptomatic or mildly symptomatic1,2

Disease progression was confirmed by one or more of the following in the presence of castrate levels of testosterone (≤ 50 μg/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 GnRH therapy or after bilateral orchiectomy
R A N D O M I Z E D 1:11

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

Placebo + GnRH 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:

  • GnRH 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

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

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

PREVAIL: Patient baseline demographics and characteristics were balanced between treatment arms2

All patients were either asymptomatic or mildly symptomatic2

SELECT PATIENT CHARACTERISTICS2,3 XTANDI + GnRH therapy* (n = 872) Placebo + GnRH 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 MEASURES2 XTANDI + GnRH therapy* (n = 872) Placebo + GnRH 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 & 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%

*Or after bilateral orchiectomy.1

§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).2

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.2

#Number of patients included in this analysis: XTANDI (n = 872) and placebo (n = 844).2

**Defined by RECIST 1.1.1

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 placebo-controlled studies, 8 of 1671 (0.5%) patients treated with XTANDI and 1 of 1243 (0.1%) patients treated with placebo experienced a seizure. In patients who previously received docetaxel, 7 of 800 (0.9%) patients treated with XTANDI experienced a seizure and no patients treated with placebo experienced a seizure. In a placebo-controlled study in chemotherapy-naïve patients, 1 of 871 (0.1%) patients treated with XTANDI and 1 of 844 (0.1%) patients treated with placebo experienced a seizure. In bicalutamide-controlled studies conducted in chemotherapy-naïve patients, 3 of 380 (0.8%) patients treated with XTANDI and 1 of 387 (0.3%) patients treated with bicalutamide experienced a seizure. 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 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 a 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 placebo-controlled 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. 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. Medivation, Inc. XTANDI. Data on File.
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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.