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†‡
- 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
- Metastatic disease
- Disease progression despite receiving GnRH therapy or after bilateral orchiectomy
XTANDI 160 mg daily + GnRH therapy* (n = 872)1
Placebo + GnRH therapy* (n = 845)1
Baseline characteristics and eligibility1-3
- GnRH therapy* maintained
- Chemotherapy naïve
- Asymptomatic or mildly symptomatic
- 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
- 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
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)||
|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%|
*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
XTANDI (enzalutamide) capsules is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).
Important Safety Information
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.
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.
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.