Efficacy of XTANDI (enzalutamide) in mCSPC: ARCHES Trial

XTANDI + GnRH therapy* demonstrated significantly improved efficacy in mCSPC vs placebo + GnRH therapy*1

  • Median: NR in XTANDI + GnRH therapy* (95% CI, NR-NR) vs 19.4 months with placebo + GnRH therapy* (95% CI, 16.6-NR)1
  • Number of events: 89 (15.5%) with XTANDI + GnRH therapy* vs 198 (34.4%) with placebo + GnRH therapy*1
  • Median: NR in XTANDI + GnRH therapy* (95% CI, NR-NR) vs NR with placebo + GnRH therapy* (95% CI, 49.7 months-NR)1
  • Number of events: 154 (26.8%) with XTANDI + GnRH therapy* vs 202 (35.1%) with placebo + GnRH therapy*1

CI, confidence interval; GnRH, gonadotropin-releasing hormone; HR, hazard ratio; NR, not reached.

*Or after bilateral orchiectomy.1

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Adverse Reactions (ARs) (cont’d) In PROSPER, the placebo-controlled study of nonmetastatic CRPC (nmCRPC) patients, Grade 3 or higher ARs were reported in 31% of XTANDI patients and 23% of placebo patients. Discontinuations with an AR as the primary reason were reported for 9% of XTANDI patients and 6% of placebo patients.

XTANDI + GnRH therapy* significantly extended radiographic progression-free survival† in patients with mCSPC1

Primary Endpoint: Radiographic Progression-free Survival
  • Number of events: 89 (15.5%) with XTANDI + GnRH therapy* vs 198 (34.4%) with placebo + GnRH therapy*1
  • Consistent radiographic progression-free survival results were observed in patients with low and high§ volume of disease and patients with and without prior docetaxel therapy1
mCSPC (ARCHES)
Adverse Reactions mCSPC (ARCHES)
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*Or after bilateral orchiectomy.1

†Radiographic progression-free survival was defined as the time from randomization to radiographic disease progression at any time or death within 24 weeks after study drug discontinuation.1

‡At the time of analysis, the median follow-up was 14.4 months.2

§Defined as metastases involving the viscera or, in the absence of visceral lesions, ≥ 4 bone lesions, ≥ 1 of which must be in a bony structure beyond the vertebral column and pelvic bone.1

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Adverse Reactions (ARs) (cont’d) In ARCHES, the placebo-controlled study of metastatic CSPC (mCSPC) patients, Grade 3 or higher ARs were reported in 24% of XTANDI-treated patients. Permanent discontinuation due to ARs as the primary reason was reported in 5% of XTANDI patients and 4% of placebo patients.

XTANDI + GnRH therapy* significantly extended overall survival in patients with mCSPC1

Key Secondary Endpoint: Overall Survival.
  • Number of events: 154 (26.8%) with XTANDI + GnRH therapy* vs 202 (35.1%) with placebo + GnRH therapy*1
  • At 24, 36, and 48 months, 86%, 78%, and 71% of patients randomized to XTANDI + GnRH therapy* were alive according to Kaplan-Meier calculations, respectively, compared with 82%, 69%, and 57% of patients randomized to placebo + GnRH therapy*†.3. This was not a prespecified analysis and is not in the US Full Prescribing Information for XTANDI
mCSPC (ARCHES)
Adverse Reactions mCSPC (ARCHES)
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and Administration

*Or after bilateral orchiectomy.1

†In ARCHES, after unblinding, 184 patients (31.9%) randomly assigned to placebo + GnRH therapy* remained progression free and consented to crossover, 180 (31.3%) of whom received treatment with XTANDI + GnRH therapy*. The median time to crossover was 21.5 months.3

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Adverse Reactions (ARs) (cont’d) In EMBARK, the placebo-controlled study of nonmetastatic CSPC (nmCSPC) with high-risk biochemical recurrence (BCR) patients, Grade 3 or higher adverse reactions during the total duration of treatment were reported in 46% of patients treated with XTANDI plus leuprolide, 50% of patients receiving XTANDI as a single agent, and 43% of patients receiving placebo plus leuprolide. Permanent treatment discontinuation due to adverse reactions during the total duration of treatment as the primary reason was reported in 21% of patients treated with XTANDI plus leuprolide, 18% of patients receiving XTANDI as a single agent, and 10% of patients receiving placebo plus leuprolide.

The information below is not included in the US Full Prescribing Information for XTANDI. Subgroups were prespecified but not alpha protected and should be considered exploratory analyses. These subgroup analyses are presented for descriptive purposes and cannot be interpreted as a demonstration of efficacy in any particular subgroup.

Subgroup analyses for overall survival3

Overall survival subgroup analyses
mCSPC (ARCHES)
Adverse Reactions mCSPC (ARCHES)
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*Or after bilateral orchiectomy.2

†In ARCHES, after unblinding, 184 patients (31.9%) randomly assigned to placebo + GnRH therapy* remained progression free and consented to crossover, 180 (31.3%) of whom received treatment with XTANDI + GnRH therapy*. The median time to crossover was 21.5 months.3

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Lab Abnormalities: Lab abnormalities that occurred in ≥ 5% of patients, and more frequently (> 2%) in the XTANDI arm compared to placebo in the pooled, randomized, placebo-controlled studies are hemoglobin decrease, neutrophil count decreased, white blood cell decreased, hyperglycemia, hypermagnesemia, hyponatremia, hyperphosphatemia, and hypercalcemia.

XTANDI + GnRH therapy* significantly delayed time to start of new antineoplastic therapy† in patients with mCSPC1

Key Secondary Endpoint: Time to start of new antineoplastic therapy
  • Number of events: 46 (8.0%) with XTANDI + GnRH therapy* vs 133 (23.1%) with placebo + GnRH therapy*4
mCSPC (ARCHES)
Adverse Reactions mCSPC (ARCHES)
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and Administration

*Or after bilateral orchiectomy.1

†Time to start of new antineoplastic therapy was defined as the time from randomization to the initiation of antineoplastic therapy subsequent to the study treatments.5

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Hypertension: In the combined data from five randomized placebo-controlled clinical trials, hypertension was reported in 14.2% of XTANDI patients and 7.4% of placebo patients. Hypertension led to study discontinuation in < 1% of patients in each arm.

The information below is not included In the US Full Prescribing Information for XTANDI. An update to the analysis of time to start of new antineoplastic therapy was performed at the time of the final overall survival analysis. There was no assessment of statistical significance for this updated analysis and it should be understood as descriptive information.

An updated analysis of time to start of new antineoplastic therapy was performed at the time of final overall survival analysis3

Time to start of new antineoplastic therapy (updated analysis)
  • Number of events: 131 (22.82%) with XTANDI + GnRH therapy† vs 236 (40.97%) with placebo + GnRH therapy†5
mCSPC (ARCHES)
Adverse Reactions mCSPC (ARCHES)
Publication XTANDI Dosing
and Administration

NE, not evaluable.

Time to start of new antineoplastic therapy was defined as the time from randomization to the initiation of antineoplastic therapy subsequent to the study treatments.5

*For the analysis of time to start of new antineoplastic therapy, crossover to XTANDI after the primary radiographic progression-free survival analysis was not counted as a subsequent therapy.6

†Or after bilateral orchiectomy.1

‡In ARCHES, after unblinding, 184 patients (31.9%) randomly assigned to placebo + GnRH therapy† remained progression free and consented to crossover, 180 (31.3%) of whom received treatment with XTANDI + GnRH therapy†. The median time to crossover was 21.5 months.3

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Drug Interactions

Effect of Other Drugs on XTANDI Avoid coadministration with strong CYP2C8 inhibitors. If coadministration cannot be avoided, reduce the dosage of XTANDI.

Avoid coadministration with strong CYP3A4 inducers. If coadministration cannot be avoided, increase the dosage of XTANDI.

Effect of XTANDI on Other Drugs Avoid coadministration with certain CYP3A4, CYP2C9, and CYP2C19 substrates for which minimal decrease in concentration may lead to therapeutic failure of the substrate. If coadministration cannot be avoided, increase the dosage of these substrates in accordance with their Prescribing Information. In cases where active metabolites are formed, there may be increased exposure to the active metabolites.

XTANDI is the #1 prescribed branded androgen receptor inhibitor (ARi) in mCSPC*1,5,7

*IQVIA, Global Syndicated Prostate Cancer Tracker, Patient Share captured among Oncologists’ & Urologists’ mCSPC patients, October 2023.5,7
THIS INFORMATION DOES NOT IMPLY SAFETY OR EFFICACY OF ANY PRODUCT; NO COMPARISONS SHOULD BE MADE.

Both the NCCN Clinical Practice Guidelines in Oncology® (NCCN Guidelines®) and American Urological Association (AUA) guideline include enzalutamide (XTANDI) as a treatment option for patients with mCSPC based on high-level evidence8,9

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NCCN Guidelines® recommend enzalutamide (XTANDI) with androgen deprivation therapy as an NCCN Category 1 treatment option* for patients with mCSPC8

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AUA Strong Recommendation† based on Evidence Level Grade A‡ for patients with mCSPC in combination with androgen deprivation therapy9

NCCN, National Comprehensive Cancer Network® (NCCN®).

*A Category 1 recommendation is based on high-level evidence and indicates uniform NCCN consensus that the intervention is appropriate.8

†Strong Recommendations are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken because net benefit or net harm is substantial.9

‡A Grade A rating means the AUA is very confident that the true effect lies close to that of the estimate of the effect.9

Time to PSA progression was also evaluated in patients with mCSPC2

The information below is not included in the US Full Prescribing Information for XTANDI. 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.

Key Secondary Endpoint: Time to PSA progression chart. Xtandi (enzalutamide) Risk info.
  • Number of events: 45 (7.84%) with XTANDI + GnRH therapy† vs 189 (32.81%) with placebo + GnRH therapy†5
mCSPC (ARCHES)
Adverse Reactions mCSPC (ARCHES)
Publication XTANDI Dosing
and Administration

PSA, prostate-specific antigen.

*Time to PSA progression was defined as the time from randomization to PSA progression, which was a ≥ 25% increase and an absolute increase of ≥ 2 μg/L (≥ 2 ng/mL) above the nadir (ie, the lowest PSA value observed post baseline or at baseline), which was confirmed by a second consecutive value at least 3 weeks later.4

†Or after bilateral orchiectomy.1

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Seizure occurred in 0.6% of patients receiving XTANDI in eight randomized clinical trials. In a study of patients with predisposing factors for seizure, 2.2% of XTANDI-treated patients experienced a seizure. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Patients in the study had one or more of the following predisposing factors: use of medications that may lower the seizure threshold, history of traumatic brain or head injury, history of cerebrovascular accident or transient ischemic attack, and 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. 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.

The information below is not included in the US Full Prescribing Information for XTANDI. An update to the analysis of time to PSA progression was performed at the time of the final overall survival analysis. There was no assessment of statistical significance for this post-hoc analysis and it should be understood as descriptive information.

A post-hoc analysis of time to PSA progression was performed at the time of final overall survival analysis6

Key Secondary Endpoint: Time to PSA progression (post-hoc analysis) chart. Xtandi (enzalutamide) Risk info.
  • Number of events: 117 (20.4%) with XTANDI + GnRH therapy† vs 259 (45.0%) with placebo + GnRH therapy†5
mCSPC (ARCHES)
Publication Reactions mCSPC (ARCHES)
Publication XTANDI Dosing
and Administration

ITT, intent to treat.

*Time to PSA progression was defined as the time from randomization to PSA progression, which was a ≥ 25% increase and an absolute increase of ≥ 2 μg/L (≥ 2 ng/mL) above the nadir (ie, the lowest PSA value observed post baseline or at baseline), which was confirmed by a second consecutive value at least 3 weeks later.4

†Or after bilateral orchiectomy.1

‡In ARCHES, after unblinding, 184 patients (31.9%) randomly assigned to placebo + GnRH therapy† remained progression free and consented to crossover, 180 (31.3%) of whom received treatment with XTANDI + GnRH therapy†. The median time to crossover was 21.5 months.3

Select Safety Information

Posterior Reversible Encephalopathy Syndrome (PRES) There have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder that 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.

PSA undetectable rate and time to deterioration of urinary symptoms were also evaluated in patients with mCSPC1,5

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.

Significantly higher PSA undetectable rate vs placebo + GnRH therapy* (key secondary endpoint from primary analysis)
  • XTANDI in addition to androgen deprivation therapy reduced PSA levels to undetectable levels (< 0.2 ng/mL) in 68% of patients with mCSPC1
  • The PSA undetectable rate was 68.1% (95% CI, 63.9-72.1) in the XTANDI + GnRH therapy† group and 17.6%‡ (95% CI, 14.4-21.2) in the placebo + GnRH therapy† group5
  • In patients with a detectable PSA level at baseline, treatment with XTANDI + GnRH therapy† significantly increased the chance of a PSA decline to an undetectable level (< 0.2 ng/mL) compared to treatment with placebo + GnRH therapy† by 50.5% (95% CI, 45.3-55.7; P < 0.0001)‡5

Key secondary endpoint from primary analysis: Time to deterioration of urinary symptoms§5

Treatment with XTANDI + GnRH therapy† was not associated with a statistically significant change in the time to deterioration of urinary symptoms compared with placebo + GnRH therapy† (HR = 0.88 [95% CI, 0.72-1.08]; P = 0.2162)‡.

*PSA undetectable rate was defined as the percentage of patients with undetectable (< 0.2 ng/mL) PSA values at any time during study treatment of those patients with detectable (≥ 0.2 ng/mL) PSA values at baseline.5

†Or after bilateral orchiectomy.1

‡This information is not included in the US Full Prescribing Information for XTANDI.

§A deterioration in urinary symptoms was defined as an increase in the urinary symptoms subscale score by ≥ 50% of the standard deviation observed in the urinary symptoms subscale score at baseline.2

Select Safety Information

Hypersensitivity reactions, including edema of the face (0.5%), tongue (0.1%), or lip (0.1%) have been observed with XTANDI in eight randomized 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.

This information below is not included in the US Full Prescribing Information for XTANDI. This secondary endpoint was prespecified but not alpha protected and should be considered descriptive information.

Time to castration resistance was also evaluated in patients with mCSPC4

Key Secondary Endpoint: Time to castration resistance. Xtandi (enzalutamide) Risk info.
  • Number of events: 90 (15.68%) with XTANDI + GnRH therapy* vs 257 (44.62%) with placebo + GnRH therapy*5
mCSPC (ARCHES)
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Time to castration resistance was defined as the time from randomization to the first castration-resistant event (radiographic disease progression, PSA progression, or symptomatic skeletal event with castrate levels of testosterone [< 50 ng/dL]), whichever occurred first.4

*Or after bilateral orchiectomy.1

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Ischemic Heart Disease In the combined data of five randomized, placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (3.5% vs 2%). Grade 3-4 ischemic events occurred in 1.8% of patients on XTANDI versus 1.1% 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.

The information below is not included in the US Full Prescribing Information for XTANDI. An update to the analysis of time to castration resistance was performed at the time of the final overall survival analysis. There was no assessment of statistical significance for this post-hoc analysis and it should be understood as descriptive information.

A post-hoc analysis of time to castration resistance was performed at the time of final overall survival analysis6

Other Secondary Endpoint: Time to castration resitance. Xtandi (enzalutamide) Risk info.
  • Number of events: 202 (35.2%) with XTANDI + GnRH therapy* vs 327 (56.8%) with placebo + GnRH therapy*5
mCSPC (ARCHES)
Adverse Reactions mCSPC (ARCHES)
Publication XTANDI Dosing
and Administration

*Or after bilateral orchiectomy.1

†In ARCHES, after unblinding, 184 patients (31.9%) randomly assigned to placebo + GnRH therapy* remained progression free and consented to crossover, 180 (31.3%) of whom received treatment with XTANDI + GnRH therapy*. The median time to crossover was 21.5 months.3

Select Safety Information

Falls and Fractures occurred in patients receiving XTANDI. 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. In the combined data of five randomized, placebo-controlled clinical studies, falls occurred in 12% of patients treated with XTANDI compared to 6% of patients treated with placebo. Fractures occurred in 13% of patients treated with XTANDI and in 6% of patients treated with placebo.

References: 1. XTANDI [package insert]. Northbrook, IL: Astellas Pharma US, Inc. 2. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol 2019;37(32):2974-86. 3. Armstrong AJ, Azad AA, Iguchi T, et al. Improved survival with enzalutamide in patients with metastatic hormone-sensitive prostate cancer. J Clin Oncol 2022;40(15):1616-22. 4. Supplement to: Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: a randomized, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol 2019;37(32):2974-86. 5. Astellas. XTANDI. Data on File. 6. Supplement to: Armstrong AJ, Azad AA, Iguchi T, et al. Improved survival with enzalutamide in patients with metastatic hormone-sensitive prostate cancer. J Clin Oncol 2022;40(15):1616-22. 7. Pfizer. XTANDI. Data on File. 8. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Prostate Cancer V.3.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed March 8, 2024. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. 9. Lowrance W, Dreicer R, Jarrard DF, et al. Updates to advanced prostate cancer: AUA/SUO guideline (2023). J Urol 2023;209(6):1082-90.

Important Safety Information

Warnings and Precautions

Seizure occurred in 0.6% of patients receiving XTANDI in eight randomized clinical trials. In a study of patients with predisposing factors for seizure, 2.2% of XTANDI-treated patients experienced a seizure. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Patients in the study had one or more of the following predisposing factors: use of medications that may lower the seizure threshold, history of traumatic brain or head injury, history of cerebrovascular accident or transient ischemic attack, and 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. 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) There have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder that 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 eight randomized 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 combined data of five randomized, placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (3.5% vs 2%). Grade 3-4 ischemic events occurred in 1.8% of patients on XTANDI versus 1.1% 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 occurred in patients receiving XTANDI. 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. In the combined data of five randomized, placebo-controlled clinical studies, falls occurred in 12% of patients treated with XTANDI compared to 6% of patients treated with placebo. Fractures occurred in 13% of patients treated with XTANDI and in 6% of patients treated with placebo.

Embryo-Fetal Toxicity The 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.

Adverse Reactions (ARs)

In the data from the five randomized placebo-controlled trials, the most common ARs (≥ 10%) that occurred more frequently (≥ 2% over placebo) in XTANDI-treated patients were musculoskeletal pain, fatigue, hot flush, constipation, decreased appetite, diarrhea, hypertension, hemorrhage, fall, fracture, and headache. In the bicalutamide-controlled study, the most common ARs (≥ 10%) reported in XTANDI-treated patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, diarrhea, upper respiratory tract infection, and weight loss.

In AFFIRM, the placebo-controlled study of metastatic CRPC (mCRPC) patients who previously received docetaxel, Grade 3 and higher ARs were reported among 47% of XTANDI-treated patients. Discontinuations due to ARs were reported for 16% of XTANDI-treated patients. In PREVAIL, the placebo-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to ARs were reported for 6% of XTANDI-treated patients. In TERRAIN, the bicalutamide-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 39% of XTANDI patients and 38% of bicalutamide patients. Discontinuations with an AR as the primary reason were reported for 8% of XTANDI patients and 6% of bicalutamide patients.

In PROSPER, the placebo-controlled study of nonmetastatic CRPC (nmCRPC) patients, Grade 3 or higher ARs were reported in 31% of XTANDI patients and 23% of placebo patients. Discontinuations with an AR as the primary reason were reported for 9% of XTANDI patients and 6% of placebo patients.

In ARCHES, the placebo-controlled study of metastatic CSPC (mCSPC) patients, Grade 3 or higher ARs were reported in 24% of XTANDI-treated patients. Permanent discontinuation due to ARs as the primary reason was reported in 5% of XTANDI patients and 4% of placebo patients.

In EMBARK, the placebo-controlled study of nonmetastatic CSPC (nmCSPC) with high-risk biochemical recurrence (BCR) patients, Grade 3 or higher adverse reactions during the total duration of treatment were reported in 46% of patients treated with XTANDI plus leuprolide, 50% of patients receiving XTANDI as a single agent, and 43% of patients receiving placebo plus leuprolide. Permanent treatment discontinuation due to adverse reactions during the total duration of treatment as the primary reason was reported in 21% of patients treated with XTANDI plus leuprolide, 18% of patients receiving XTANDI as a single agent, and 10% of patients receiving placebo plus leuprolide.

Lab Abnormalities: Lab abnormalities that occurred in ≥ 5% of patients, and more frequently (> 2%) in the XTANDI arm compared to placebo in the pooled, randomized, placebo-controlled studies are hemoglobin decrease, neutrophil count decreased, white blood cell decreased, hyperglycemia, hypermagnesemia, hyponatremia, hyperphosphatemia, and hypercalcemia.

Hypertension: In the combined data from five randomized placebo-controlled clinical trials, hypertension was reported in 14.2% of XTANDI patients and 7.4% of placebo patients. Hypertension led to study discontinuation in < 1% of patients in each arm.

Drug Interactions

Effect of Other Drugs on XTANDI Avoid coadministration with strong CYP2C8 inhibitors. If coadministration cannot be avoided, reduce the dosage of XTANDI.

Avoid coadministration with strong CYP3A4 inducers. If coadministration cannot be avoided, increase the dosage of XTANDI.

Effect of XTANDI on Other Drugs Avoid coadministration with certain CYP3A4, CYP2C9, and CYP2C19 substrates for which minimal decrease in concentration may lead to therapeutic failure of the substrate. If coadministration cannot be avoided, increase the dosage of these substrates in accordance with their Prescribing Information. In cases where active metabolites are formed, there may be increased exposure to the active metabolites.

Indications

XTANDI® (enzalutamide) is indicated for the treatment of patients with:

  • nonmetastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk for metastasis (high-risk BCR)
  • metastatic castration-sensitive prostate cancer (mCSPC)
  • castration-resistant prostate cancer (CRPC)

Please see Full Prescribing Information.

Important Safety Information

Warnings and Precautions

Seizure occurred in 0.6% of patients receiving XTANDI in eight randomized clinical trials. In a study of patients with predisposing factors for seizure, 2.2% of XTANDI-treated patients experienced a seizure. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Patients in the study had one or more of the following predisposing factors: use of medications that may lower the seizure threshold, history of traumatic brain or head injury, history of cerebrovascular accident or transient ischemic attack, and 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. 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) There have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder that 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 eight randomized 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 combined data of five randomized, placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (3.5% vs 2%). Grade 3-4 ischemic events occurred in 1.8% of patients on XTANDI versus 1.1% 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 occurred in patients receiving XTANDI. 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. In the combined data of five randomized, placebo-controlled clinical studies, falls occurred in 12% of patients treated with XTANDI compared to 6% of patients treated with placebo. Fractures occurred in 13% of patients treated with XTANDI and in 6% of patients treated with placebo.

Embryo-Fetal Toxicity The 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.

Adverse Reactions (ARs)

In the data from the five randomized placebo-controlled trials, the most common ARs (≥ 10%) that occurred more frequently (≥ 2% over placebo) in XTANDI-treated patients were musculoskeletal pain, fatigue, hot flush, constipation, decreased appetite, diarrhea, hypertension, hemorrhage, fall, fracture, and headache. In the bicalutamide-controlled study, the most common ARs (≥ 10%) reported in XTANDI-treated patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, diarrhea, upper respiratory tract infection, and weight loss.

In AFFIRM, the placebo-controlled study of metastatic CRPC (mCRPC) patients who previously received docetaxel, Grade 3 and higher ARs were reported among 47% of XTANDI-treated patients. Discontinuations due to ARs were reported for 16% of XTANDI-treated patients. In PREVAIL, the placebo-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to ARs were reported for 6% of XTANDI-treated patients. In TERRAIN, the bicalutamide-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 39% of XTANDI patients and 38% of bicalutamide patients. Discontinuations with an AR as the primary reason were reported for 8% of XTANDI patients and 6% of bicalutamide patients.

In PROSPER, the placebo-controlled study of nonmetastatic CRPC (nmCRPC) patients, Grade 3 or higher ARs were reported in 31% of XTANDI patients and 23% of placebo patients. Discontinuations with an AR as the primary reason were reported for 9% of XTANDI patients and 6% of placebo patients.

In ARCHES, the placebo-controlled study of metastatic CSPC (mCSPC) patients, Grade 3 or higher ARs were reported in 24% of XTANDI-treated patients. Permanent discontinuation due to ARs as the primary reason was reported in 5% of XTANDI patients and 4% of placebo patients.

In EMBARK, the placebo-controlled study of nonmetastatic CSPC (nmCSPC) with high-risk biochemical recurrence (BCR) patients, Grade 3 or higher adverse reactions during the total duration of treatment were reported in 46% of patients treated with XTANDI plus leuprolide, 50% of patients receiving XTANDI as a single agent, and 43% of patients receiving placebo plus leuprolide. Permanent treatment discontinuation due to adverse reactions during the total duration of treatment as the primary reason was reported in 21% of patients treated with XTANDI plus leuprolide, 18% of patients receiving XTANDI as a single agent, and 10% of patients receiving placebo plus leuprolide.

Lab Abnormalities: Lab abnormalities that occurred in ≥ 5% of patients, and more frequently (> 2%) in the XTANDI arm compared to placebo in the pooled, randomized, placebo-controlled studies are hemoglobin decrease, neutrophil count decreased, white blood cell decreased, hyperglycemia, hypermagnesemia, hyponatremia, hyperphosphatemia, and hypercalcemia.

Hypertension: In the combined data from five randomized placebo-controlled clinical trials, hypertension was reported in 14.2% of XTANDI patients and 7.4% of placebo patients. Hypertension led to study discontinuation in < 1% of patients in each arm.

Drug Interactions

Effect of Other Drugs on XTANDI Avoid coadministration with strong CYP2C8 inhibitors. If coadministration cannot be avoided, reduce the dosage of XTANDI.

Avoid coadministration with strong CYP3A4 inducers. If coadministration cannot be avoided, increase the dosage of XTANDI.

Effect of XTANDI on Other Drugs Avoid coadministration with certain CYP3A4, CYP2C9, and CYP2C19 substrates for which minimal decrease in concentration may lead to therapeutic failure of the substrate. If coadministration cannot be avoided, increase the dosage of these substrates in accordance with their Prescribing Information. In cases where active metabolites are formed, there may be increased exposure to the active metabolites.

Indications

XTANDI® (enzalutamide) is indicated for the treatment of patients with:

  • nonmetastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk for metastasis (high-risk BCR)
  • metastatic castration-sensitive prostate cancer (mCSPC)
  • castration-resistant prostate cancer (CRPC)

Please see Full Prescribing Information.