Brand Name
Xtandi
Generic Name
Enzalutamide
View Brand Information FDA approval date: August 31, 2012
Classification: Androgen Receptor Inhibitor
Form: Tablet, Capsule
What is Xtandi (Enzalutamide)?
XTANDI ® is indicated for the treatment of patients with: castration-resistant prostate cancer , metastatic castration-sensitive prostate cancer , non‑metastatic castration‑sensitive prostate cancer with biochemical recurrence at high risk for metastasis XTANDI is an androgen receptor inhibitor indicated for the treatment of patients with:, castration-resistant prostate cancer. , metastatic castration-sensitive prostate cancer. , non‑metastatic castration‑sensitive prostate cancer with biochemical recurrence at high risk for metastasis.
Approved To Treat
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Related Latest Advances
Brand Information
Xtandi (enzalutamide)
1INDICATIONS AND USAGE
XTANDI
- castration-resistant prostate cancer (CRPC)
- metastatic castration-sensitive prostate cancer (mCSPC)
- non‑metastatic castration‑sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk for metastasis (high-risk BCR)
2DOSAGE FORMS AND STRENGTHS
XTANDI 40 mg capsules are white to off-white oblong soft gelatin capsules imprinted in black ink with ENZ.
XTANDI 40 mg tablets are yellow, round, film-coated and debossed with E 40.
XTANDI 80 mg tablets are yellow, oval, film-coated and debossed with E 80.
3CONTRAINDICATIONS
None.
4ADVERSE REACTIONS
The following is discussed in more detail in other sections of the labeling:
- Seizure
- Posterior Reversible Encephalopathy Syndrome (PRES)
- Hypersensitivity
- Ischemic Heart Disease
- Falls and Fractures
- Dysphagia or Choking
4.1Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data in WARNINGS and PRECAUTIONS reflect eight randomized, controlled trials [AFFIRM, PREVAIL, TERRAIN, PROSPER, ARCHES, EMBARK, Asian PREVAIL (NCT02294461), and STRIVE (NCT01664923)] that were pooled to conduct safety analyses in patients with CRPC (N = 3651), mCSPC (N = 752), or nmCSPC with high‑risk BCR (N = 707) treated with XTANDI. Patients received XTANDI 160 mg (N = 5110) or placebo orally once daily (N = 2829) or bicalutamide 50 mg orally once daily (N = 387). In these eight trials, the median duration of treatment was 22.1 months (range: < 0.1 to 95.0) in patients that received XTANDI.
In five placebo-controlled trials (AFFIRM, PROSPER, PREVAIL, ARCHES, and EMBARK), the median duration of treatment was 19.4 months (range: < 0.1 to 90.4) in the XTANDI group
AFFIRM: XTANDI versus Placebo in Metastatic CRPC Following Chemotherapy
AFFIRM enrolled 1199 patients with metastatic CRPC who had previously received docetaxel. The median duration of treatment was 8.3 months with XTANDI and 3.0 months with placebo. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids.
Grade 3 and higher adverse reactions were reported among 47% of XTANDI-treated patients. Discontinuations due to adverse reactions were reported for 16% of XTANDI-treated patients. The most common adverse reaction leading to treatment discontinuation was seizure, which occurred in 0.9% of the XTANDI-treated patients compared to none (0%) of the placebo-treated patients.
PREVAIL: XTANDI versus Placebo in Chemotherapy-naïve Metastatic CRPC
PREVAIL enrolled 1717 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 1715 received at least one dose of study drug. The median duration of treatment was 17.5 months with XTANDI and 4.6 months with placebo. Grade 3-4 adverse reactions were reported in 44% of XTANDI-treated patients and 37% of placebo-treated patients. Discontinuations due to adverse reactions were reported for 6% of XTANDI-treated patients. The most common adverse reaction leading to treatment discontinuation was fatigue/asthenia, which occurred in 1% of patients on each treatment arm.
TERRAIN: XTANDI versus Bicalutamide in Chemotherapy-naïve Metastatic CRPC
TERRAIN enrolled 375 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy, of whom 372 received at least one dose of study drug. The median duration of treatment was 11.6 months with XTANDI and 5.8 months with bicalutamide. Discontinuations with an adverse reaction as the primary reason were reported for 8% of XTANDI-treated patients and 6% of bicalutamide-treated patients. The most common adverse reactions leading to treatment discontinuation were back pain and pathological fracture, which occurred in 3.8% of XTANDI-treated patients for each event and in 2.1% and 1.6% of bicalutamide-treated patients, respectively.
PROSPER: XTANDI versus Placebo in Non-metastatic CRPC Patients
PROSPER enrolled 1401 patients with non-metastatic CRPC, of whom 1395 received at least one dose of study drug. Patients were randomized 2:1 and received either XTANDI at a dose of 160 mg once daily (N = 930) or placebo (N = 465). The median duration of treatment at the time of analysis was 18.4 months (range: 0.0 to 42 months) with XTANDI and 11.1 months (range: 0.0 to 43 months) with placebo.
Overall, 32 patients (3.4%) receiving XTANDI died from adverse reactions. The reasons for death with ≥ 2 patients included coronary artery disorders (n = 7), sudden death (n = 2), cardiac arrhythmias (n = 2), general physical health deterioration (n = 2), stroke (n = 2), and secondary malignancy (n = 5; one each of acute myeloid leukemia, brain neoplasm, mesothelioma, small cell lung cancer, and malignant neoplasm of unknown primary site). Three patients (0.6%) receiving placebo died from adverse reactions of cardiac arrest (n = 1), left ventricular failure (n = 1), and pancreatic carcinoma (n = 1). Grade 3 or higher adverse reactions were reported among 31% of XTANDI-treated patients and 23% of placebo‑treated patients. Discontinuations with an adverse reaction as the primary reason were reported for 9% of XTANDI-treated patients and 6% of placebo-treated patients. Of these, the most common adverse reaction leading to treatment discontinuation was fatigue, which occurred in 1.6% of the XTANDI-treated patients compared to none of the placebo-treated patients.
ARCHES: XTANDI versus Placebo in Metastatic CSPC Patients
ARCHES randomized 1150 patients with mCSPC, of whom 1146 received at least one dose of study drug. All patients received either a gonadotropin-releasing hormone (GnRH) analog concurrently or had bilateral orchiectomy. Patients received either XTANDI at a dose of 160 mg once daily (N = 572) or placebo (N = 574). The median duration of treatment was 12.8 months (range: 0.2 to 26.6 months) with XTANDI and 11.6 months (range: 0.2 to 24.6 months) with placebo.
Overall, 10 patients (1.7%) receiving XTANDI died from adverse reactions. The reasons for death in ≥ 2 patients included heart disease (n = 3), sepsis (n = 2) and pulmonary embolism (n = 2). Eight patients (1.4%) receiving placebo died from adverse reactions. The reasons for death in ≥ 2 patients included heart disease (n = 2) and sudden death (n = 2). Grade 3 or higher adverse reactions were reported in 24% of patients treated with XTANDI. Permanent discontinuation due to adverse reactions as the primary reason was reported in 4.9% of XTANDI-treated patients and 3.7% of placebo-treated patients. The most common adverse reactions resulting in permanent discontinuation in XTANDI-treated patients were alanine aminotransferase increased, aspartate aminotransferase elevation, and seizure, each in 0.3%. The most common adverse reactions leading to permanent discontinuation in placebo-treated patients were arthralgia, and fatigue, each in 0.3%.
Dose reductions due to an adverse reaction occurred in 4.4% of patients who received XTANDI. Fatigue/asthenia was the most frequent adverse reaction requiring dose reduction in 2.1% of XTANDI-treated patients and 0.7% of placebo-treated patients.
Table 5 shows adverse reactions reported in ARCHES that occurred at a ≥ 2% higher frequency in the XTANDI arm than in the placebo arm.
EMBARK: XTANDI versus Placebo in Non-metastatic CSPC Patients with High-Risk BCR
EMBARK enrolled 1068 patients with high-risk BCR, of whom 1061 patients received at least one dose of study drug. Patients received XTANDI at a dose of 160 mg once daily concurrently with leuprolide (N = 353), XTANDI at a dose of 160 mg once daily as open‑label monotherapy (N = 354), or placebo concurrently with leuprolide (N = 354). At week 37, treatment was suspended for patients whose PSA values were undetectable (<0.2 ng/mL) at week 36. Treatment was reinitiated when PSA values increased to ≥2.0 ng/mL for patients with prior prostatectomy or ≥5.0 ng/mL for patients without prior prostatectomy. For patients whose PSA values were detectable (≥0.2 ng/mL) at week 36, treatment continued without suspension until permanent treatment discontinuation criteria were met.
Table 6 shows the total duration of treatment for the three treatment arms.
Overall, deaths from adverse reactions during the total duration of treatment occurred in 6 patients (1.7%) receiving XTANDI plus leuprolide, 8 patients (2.3%) receiving XTANDI as a single agent, and 3 patients (0.8%) receiving placebo plus leuprolide. The reason for death in ≥ 2 patients receiving XTANDI plus leuprolide was infection (n = 2), and the reason for death in ≥ 2 patients receiving XTANDI as a single agent was arterial thromboembolism (n=2).
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 most common adverse reactions resulting in permanent discontinuation included fatigue (3.4% of patients treated with XTANDI plus leuprolide, 3.7% of patients receiving XTANDI as a single agent, and 1.4% of patients receiving placebo plus leuprolide), hot flush (2% of patients treated with XTANDI plus leuprolide, 0% of patients receiving XTANDI as a single agent, and 1.1% of patients receiving placebo plus leuprolide), nausea (1.1% of patients treated with XTANDI plus leuprolide, 0.6% of patients receiving XTANDI as a single agent, and 0.3% of patients receiving placebo plus leuprolide), and cognitive disorder (1.1% of patients treated with XTANDI plus leuprolide, 1.4% of patients receiving XTANDI as a single agent, and 0.8% of patients receiving placebo plus leuprolide).
Dose reductions due to an adverse reaction occurred in 7% of patients who received XTANDI plus leuprolide, 16% of patients who received XTANDI as a single agent, and 4.5% of patients who received placebo plus leuprolide. Fatigue was the most frequent adverse reaction requiring dose reduction in 3.1% of patients treated with XTANDI plus leuprolide, 10% of patients receiving XTANDI as a single agent, and 1.7% of patients receiving placebo plus leuprolide.
Table 7 shows adverse reactions reported in EMBARK that occurred at a ≥ 5% (Grade 1-4) or ≥ 2% (Grade 3-4) higher frequency in either of the XTANDI arms than in the placebo arm.
Clinically relevant adverse reactions that did not meet criteria for inclusion in Table 7 include hypertension (XTANDI plus leuprolide, 25%; XTANDI as a single agent, 21%), angioedema (XTANDI plus leuprolide, 2.5%; XTANDI as a single agent, 2%), and seizure (XTANDI plus leuprolide, 1.1%; XTANDI as a single agent, 0.8%).
Laboratory Abnormalities
Table 8 shows laboratory 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.
Hypertension
In the combined data from five randomized placebo-controlled clinical trials, hypertension was reported in 14% of patients receiving XTANDI and 7% of patients receiving placebo. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm.
4.2Post-Marketing Experience
The following additional adverse reactions have been identified during post-approval use of XTANDI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Gastrointestinal Disorders: vomiting, dysphagia (including choking related to XTANDI product size)
Immune System Disorders: hypersensitivity (edema of the face, tongue, lip, or pharynx)
Neurological Disorders: posterior reversible encephalopathy syndrome (PRES), dysgeusia
Skin and Subcutaneous Tissue Disorders: rash, severe cutaneous adverse reactions (including Stevens-Johnson syndrome (SJS), erythema multiforme, toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP))
5OVERDOSAGE
In the event of an overdosage, stop treatment with XTANDI and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at
6DESCRIPTION
Enzalutamide is an androgen receptor inhibitor. The chemical name is 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-
The molecular weight is 464.44 and molecular formula is C
Enzalutamide is a white crystalline non-hygroscopic solid. It is practically insoluble in water.
XTANDI is available as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides. The inactive ingredients are caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, and black iron oxide.
XTANDI is also available as film-coated tablets for oral administration. Each tablet contains 40 mg or 80 mg of enzalutamide. The inactive ingredients are hypromellose acetate succinate, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate. The tablet film-coat contains hypromellose, talc, polyethylene glycol, titanium dioxide, and ferric oxide.
7CLINICAL STUDIES
The efficacy of XTANDI in patients with CRPC (N = 4692), mCSPC (N = 1150), or nmCSPC with high‑risk BCR (N = 1068) was demonstrated in six randomized, multicenter clinical trials. Patients received concomitant GnRH therapy or had prior bilateral orchiectomy, unless otherwise indicated.
AFFIRM (NCT00974311): XTANDI versus Placebo in Metastatic CRPC Following Chemotherapy
In AFFIRM, a total of 1199 patients who had received prior docetaxel-based chemotherapy were randomized 2:1 to receive either XTANDI orally at a dose of 160 mg once daily (N = 800) or placebo orally once daily (N = 399). Study treatment continued until disease progression (evidence of radiographic progression, a skeletal-related event, or clinical progression), initiation of new systemic antineoplastic treatment, unacceptable toxicity, or withdrawal. Patients with a previous history of seizure, taking medicines known to decrease the seizure threshold, or with other risk factors for seizure were not eligible
The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 69 years (range 41-92) and the racial distribution was 92.7% White, 3.9% Black, 1.1% Asian, and 2.1% Other. Ninety-two percent of patients had an ECOG performance status score of 0-1 and 28% had a mean Brief Pain Inventory score of ≥ 4. Ninety-one percent of patients had metastases in bone and 23% had visceral involvement in the lung and/or liver. Fifty-nine percent of patients had radiographic evidence of disease progression and 41% had PSA-only progression on study entry. All patients had received prior docetaxel-based therapy and 24% had received two cytotoxic chemotherapy regimens. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids.
A statistically significant improvement in overall survival was demonstrated at the pre-specified interim analysis at the time of 520 deaths in patients on the XTANDI arm compared to patients on the placebo arm (
PREVAIL (NCT01212991): XTANDI versus Placebo in Chemotherapy-naïve Metastatic CRPC
In PREVAIL, 1717 chemotherapy-naïve patients were randomized 1:1 to receive either XTANDI orally at a dose of 160 mg once daily (N = 872) or placebo orally once daily (N = 845). Patients with visceral metastases, patients with a history of mild to moderate heart failure (NYHA class I or II), and patients taking medications associated with lowering the seizure threshold were allowed. Patients with a previous history of seizure or a condition that might predispose to seizure and patients with moderate or severe pain from prostate cancer were excluded. Study treatment continued until disease progression (evidence of radiographic progression, a skeletal-related event, or clinical progression) and the initiation of a cytotoxic chemotherapy or an investigational agent, unacceptable toxicity, or withdrawal. Overall survival and radiographic progression-free survival (rPFS) were assessed. Radiographic progression was assessed with the use of sequential imaging and was defined by bone scan identification of 2 or more new bone lesions with confirmation (Prostate Cancer Clinical Trials Working Group 2 criteria) and/or Response Evaluation Criteria in Solid Tumors (RECIST v 1.1) criteria for progression of soft tissue lesions. The primary analysis of rPFS utilized centrally reviewed radiographic assessment of progression.
Patient demographics and baseline disease characteristics were balanced between the treatment arms at entry. The median age was 71 years (range 42-93) and the racial distribution was 77% White, 10% Asian, 2% Black and 11% Other. The ECOG performance status score was 0 for 68% of patients, and 1 for 32% of patients. Baseline pain assessment was 0-1 (asymptomatic) in 67% of patients, and 2-3 (mildly symptomatic) in 32% of patients as defined by the Brief Pain Inventory Short Form (worst pain over past 24 hours at study entry). Fifty-four percent of patients had radiographic evidence of disease progression and 43% had PSA-only progression. Twelve percent of patients had visceral (lung and/or liver) disease involvement. During the study, 27% of patients on the XTANDI arm and 30% of patients on the placebo arm received glucocorticoids for varying reasons.
A statistically significant improvement in overall survival was demonstrated at the pre-specified interim analysis, conducted after 540 deaths, in patients treated with XTANDI compared to those treated with placebo (
A statistically significant improvement in rPFS was demonstrated in patients treated with XTANDI compared to patients treated with placebo (
Time to initiation of cytotoxic chemotherapy was prolonged after XTANDI treatment, with a median of 28.0 months for patients on the XTANDI arm versus a median of 10.8 months for patients on the placebo arm [HR = 0.35 (95% CI: 0.30, 0.40), p < 0.0001].
The median time to first skeletal‑related event was 31.1 months for patients on the XTANDI arm versus 31.3 months for patients on the placebo arm [HR = 0.72 (95% CI: 0.61, 0.84), p < 0.0001]. A skeletal‑related event was defined as radiation therapy or surgery to bone for prostate cancer, pathologic bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain.
TERRAIN (NCT01288911): XTANDI versus Bicalutamide in Chemotherapy-naïve Metastatic CRPC
TERRAIN was conducted in 375 chemotherapy-naïve patients who were randomized 1:1 to receive either XTANDI orally at a dose of 160 mg once daily (N = 184) or bicalutamide orally at a dose of 50 mg once daily (N = 191). Patients with a previous history of seizure or a condition that might predispose to seizure and patients with moderate to severe pain from prostate cancer were excluded. Patients could have received prior bicalutamide, but those whose disease had progressed on prior antiandrogen therapy (e.g., bicalutamide) were excluded. Study treatment continued until disease progression (evidence of radiographic progression, a skeletal-related event), the initiation of subsequent antineoplastic agent, unacceptable toxicity, or withdrawal. Radiographic disease progression was assessed by Independent Central Review (ICR) using the Prostate Cancer Clinical Trials Working Group 2 criteria and/or Response Evaluation Criteria in Solid Tumors (RECIST v 1.1) criteria for progression of soft tissue lesions. Radiographic progression-free survival (rPFS) was defined as the time from randomization to the first objective evidence of radiographic progression as assessed by ICR or death, whichever occurred first.
Patient demographics and baseline disease characteristics were balanced between the treatment arms at entry. The median age was 71 years (range 48-96) and the racial distribution was 93% White, 5% Black, 1% Asian and 1% Other. The ECOG performance status score was 0 for 74% of patients and 1 for 26% of patients. Baseline pain assessment was 0‑1 (asymptomatic) in 58% of patients, and 2‑3 (mildly symptomatic) in 36% of patients as defined by the Brief Pain Inventory Short Form Question 3 (worst pain over past 24 hours at study entry). Ninety-eight percent of patients had objective evidence of disease progression at study entry. Forty-six percent of patients had received prior treatment with bicalutamide while no patients received prior treatment with XTANDI.
An improvement in rPFS was demonstrated in patients treated with XTANDI compared to patients treated with bicalutamide (
PROSPER (NCT02003924): XTANDI versus Placebo in Non-metastatic CRPC
PROSPER enrolled 1401 patients with non-metastatic CRPC who were randomized 2:1 to receive either XTANDI orally at a dose of 160 mg once daily (N = 933) or placebo orally once daily (N = 468). All patients in the PROSPER trial received a gonadotropin-releasing hormone (GnRH) analog or had a prior bilateral orchiectomy. Patients were stratified by Prostate Specific Antigen (PSA) Doubling Time (PSADT) and the use of bone-targeting agents. Patients were required to have a PSA doubling time ≤ 10 months, PSA ≥ 2 ng/mL, and confirmation of non-metastatic disease by blinded independent central review (BICR). PSA results were blinded and were not used for treatment discontinuation. Patients randomized to either arm discontinued treatment for radiographic disease progression confirmed by BICR, initiation of new treatment, unacceptable toxicity, or withdrawal.
The following patient demographics and baseline characteristics were balanced between the two treatment arms. The median age at randomization was 74 years (range 50-95) and 23% were 80 years of age or older. The racial distribution was 71% White, 16% Asian, and 2% Black. A majority of patients had a Gleason score of 7 or higher (77%). The median PSADT was 3.7 months. Fifty-four percent (54%) of patients received prior treatment for prostate cancer with either surgery or radiation. Sixty-three percent (63%) of patients received prior treatment with an anti-androgen; 56% of patients received bicalutamide and 11% of patients received flutamide. All patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 at study entry.
The major efficacy outcome of the study was metastasis-free survival (MFS), defined as the time from randomization to whichever of the following occurred first 1) loco-regional and/or distant radiographic progression per BICR or 2) death up to 112 days after treatment discontinuation without evidence of radiographic progression. A statistically significant improvement in MFS and OS was demonstrated in patients randomized to receive XTANDI compared with patients randomized to receive placebo. Consistent MFS results were observed when considering only distant radiographic progression events or deaths regardless of the cut-off date. Consistent MFS results were also observed 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). The efficacy results from PROSPER are summarized in
The primary efficacy outcome was also supported by a statistically significant delay in time to first use of new antineoplastic therapy (TTA) for patients in the XTANDI arm compared to those in the placebo arm. The median TTA was 39.6 months for patients on XTANDI and was 17.7 months for patients on placebo (HR = 0.21; 95% CI: [0.17, 0.26], p < 0.0001).
ARCHES (NCT02677896): XTANDI versus Placebo in Metastatic CSPC
ARCHES enrolled 1150 patients with mCSPC who were randomized 1:1 to receive XTANDI orally at a dose of 160 mg once daily (N = 574) or placebo orally once daily (N = 576). All patients in the trial received a GnRH analog or had a prior bilateral orchiectomy. Patients were stratified by volume of disease (low vs high) and prior docetaxel therapy for prostate cancer (no prior docetaxel, 1-5 cycles, or 6 prior cycles). High volume of disease is defined as metastases involving the viscera or, in the absence of visceral lesions, there must be 4 or more bone lesions, at least 1 of which must be in a bony structure beyond the vertebral column and pelvic bone. Treatment with concurrent docetaxel was not allowed. Patients continued treatment until radiographic disease progression, initiation of new treatment, unacceptable toxicity, or withdrawal.
The following patient demographics and baseline characteristics were balanced between the two treatment arms. The median age at randomization was 70 years (range: 42-92) and 30% were 75 years of age or older. The racial distribution was 81% White, 14% Asian, and 1% Black. Sixty-six percent (66%) of patients had a Gleason score of ≥ 8. Thirty-seven percent (37%) of patients had a low volume of disease and 63% of patients had a high volume of disease. Eighty-two percent (82%) of patients had no prior docetaxel treatment; 2% of patients had 1 to 5 cycles of docetaxel and 16% of patients had 6 prior cycles of docetaxel treatment. Twelve percent (12%) of patients received concomitant bone-targeted agents (bisphosphonates or RANKL inhibitors) which included both prostate and non-prostate cancer indications. The Eastern Cooperative Oncology Group Performance Status (ECOG PS) score was 0 for 78% of patients and 1 for 22% of patients at study entry.
The major efficacy outcome measure was radiographic progression-free survival (rPFS) based on blinded independent central review (BICR). 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. Radiographic disease progression was defined by identification of 2 or more new bone lesions on a bone scan with confirmation (Prostate Cancer Working Group 2 criteria) and/or progression in soft tissue disease. Time to new antineoplastic therapy and OS were additional efficacy endpoints.
XTANDI demonstrated a statistically significant improvement in rPFS and OS compared to placebo. Consistent rPFS results were observed in patients with high or low volume of disease and patients with and without prior docetaxel therapy. Efficacy results for rPFS and OS from ARCHES are summarized in
A statistically significant improvement was also reported on the XTANDI arm compared to placebo in time to initiation of a new antineoplastic therapy (HR = 0.28 [95% CI: 0.20, 0.40]; p < 0.0001).
EMBARK (NCT02319837): XTANDI versus Placebo in Non-metastatic CSPC with High-Risk BCR
EMBARK enrolled 1068 patients with nmCSPC with high-risk BCR who were randomized 1:1:1 to receive XTANDI orally at a dose of 160 mg once daily concurrently with leuprolide (N = 355), XTANDI orally at a dose of 160 mg once daily as open‑label as a single agent (N = 355), or placebo orally once daily concurrently with leuprolide (N = 358). All patients had prior definitive therapy with radical prostatectomy or radiotherapy (including brachytherapy) with curative intent, or both. Patients were not candidates for salvage radiotherapy at the time of enrollment. Patients were required to have confirmation of non-metastatic disease by BICR, high‑risk BCR (defined by a PSA doubling time ≤ 9 months), and PSA values ≥1 ng/mL if they had prior radical prostatectomy (with or without radiotherapy) as the primary treatment for prostate cancer or PSA values at least 2 ng/mL above the nadir if they had prior radiotherapy only.
Patients were stratified by screening PSA (≤10 ng/mL vs. >10 ng/mL), PSA doubling time (≤3 months versus >3 months to ≤ 9 months), and prior hormonal therapy. For patients whose PSA values were undetectable (<0.2 ng/mL) at week 36, treatment was suspended at week 37 and then reinitiated when PSA values increased to ≥2.0 ng/mL for patients with prior prostatectomy or ≥5.0 ng/mL for patients without prior prostatectomy. For patients whose PSA values were detectable (≥0.2 ng/mL) at week 36, treatment continued without suspension until permanent treatment discontinuation criteria were met. For all patients, treatment was permanently discontinued upon radiographic disease progression confirmed by BICR, initiation of new treatment, unacceptable toxicity, or withdrawal.
The median age at randomization was 69 years (range: 49-93) and 23% were 75 years of age or older. The racial distribution was 83% White, 7% Asian, 4% Black, 2.3% Others, and 2.7% not reported; 5.5% of patients were Hispanic or Latino. The median PSADT was 4.9 months. Seventy-four percent (74%) of patients had prior definitive therapy with radical prostatectomy, 34% of patients had prior primary radiotherapy (including brachytherapy), and 49% of patients had prior therapy with both surgery and radiotherapy (including adjuvant and salvage radiotherapy). Thirty-two percent (32%) of patients had a Gleason score of ≥ 8. The ECOG PS score was 0 for 92% of patients and 1 for 8% of patients at study entry.
The major efficacy outcome measure was metastasis-free survival (MFS) in patients randomized to receive XTANDI plus leuprolide compared to patients randomized to receive placebo plus leuprolide. MFS was defined as the time from randomization to whichever of the following occurred first 1) radiographic progression per BICR or 2) death. MFS in patients randomized to receive XTANDI as a single agent compared to patients randomized to receive placebo plus leuprolide and overall survival (OS) were additional efficacy outcome measures.
A statistically significant improvement in MFS was demonstrated in patients randomized to receive XTANDI plus leuprolide compared with patients randomized to receive placebo plus leuprolide. A statistically significant improvement in MFS was also demonstrated in patients randomized to receive XTANDI as a single agent compared with patients randomized to receive placebo plus leuprolide. The results are summarized in
OS data were not mature at the time of MFS analysis (12.2% deaths across the overall population of 1068 patients).
8HOW SUPPLIED/STORAGE AND HANDLING
XTANDI (enzalutamide) 40 mg capsules are supplied as white to off-white oblong soft gelatin capsules imprinted in black ink with ENZ and are available in the following package size:
- Bottles of 120 capsules with child resistant closures (NDC 0469-0125-99)
XTANDI (enzalutamide) 40 mg tablets are supplied as yellow, round, film-coated tablets debossed with E 40, and are available in the following package size:
- Bottles of 120 tablets with child resistant closures (NDC 0469-0625-99)
XTANDI (enzalutamide) 80 mg tablets are supplied as yellow, oval, film-coated tablets debossed with E 80, and are available in the following package size:
- Bottles of 60 tablets with child resistant closures (NDC 0469-0725-60)
Store XTANDI capsules and tablets at 20°C to 25°C (68°F to 77°F) in a dry place and keep the container tightly closed. Excursions permitted from 15°C to 30°C (59°F to 86°F).
9PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Seizure
- Inform patients that XTANDI has been associated with an increased risk of seizure. Discuss conditions that may predispose to seizures and medications that may lower the seizure threshold. Advise patients of the risk of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Inform patients to contact their healthcare provider right away if they have loss of consciousness or seizure
Posterior Reversible Encephalopathy Syndrome (PRES)
- Inform patients to contact their healthcare provider right away if they experience rapidly worsening symptoms possibly indicative of PRES such as seizure, headache, decreased alertness, confusion, reduced eyesight, or blurred vision
Hypersensitivity
- Inform patients that XTANDI may be associated with hypersensitivity reactions that include swelling of the face, lip, tongue, or throat
Ischemic Heart Disease
- Inform patients that XTANDI has been associated with an increased risk of ischemic heart disease. Advise patients to seek immediate medical attention if any symptoms suggestive of a cardiovascular event occur
Falls and Fractures
- Inform patients that XTANDI is associated with an increased incidence of dizziness/vertigo, falls, and fractures. Advise patients to report these adverse reactions to their healthcare provider
Dysphagia or Choking
- Inform patients that the size of XTANDI capsules and tablets has been associated with severe dysphagia or choking.
- Advise patients to take each capsule or tablet as instructed in Dosage and Administration.
- Advise patients to inform their healthcare provider if experiencing difficulty swallowing XTANDI
Hypertension
- Inform patients that XTANDI is associated with an increased incidence of hypertension
Dosage and Administration
- Inform patients who have not undergone bilateral orchiectomy and are receiving GnRH therapy that they need to maintain this treatment during the course of treatment with XTANDI.
- Instruct patients to take their dose at the same time each day (once daily). XTANDI can be taken with or without food. Advise patients to take each capsule or tablet whole with a sufficient amount of water to ensure that all medication is successfully swallowed. Do not chew, dissolve, or open the capsules. Do not cut, crush, or chew the tablets
- Inform patients that they should not interrupt, modify the dose, or stop XTANDI without first consulting their healthcare provider.
- Inform patients that if they miss a dose, then they should take it as soon as they remember. If they forget to take the dose for the whole day, then they should take their normal dose the next day. They should not take more than their prescribed dose per day
Embryo-Fetal Toxicity
- Inform patients that XTANDI can be harmful to a developing fetus and can cause loss of pregnancy.
- Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of XTANDI. Advise male patients to use a condom if having sex with a pregnant woman
Infertility
- Inform male patients that XTANDI may impair fertility
Manufactured for and Distributed by: Astellas Pharma US, Inc., Northbrook, IL 60062
Marketed by:
Astellas Pharma US, Inc., Northbrook, IL 60062 Pfizer Inc., New York, NY 10001
430539-XTA-USA
Astellas Pharma US, Inc., Northbrook, IL 60062 Pfizer Inc., New York, NY 10001
430539-XTA-USA
Rx Only
© 2025 Astellas Pharma Inc. or its affiliates
© 2025 Astellas Pharma Inc. or its affiliates
10PACKAGE/LABEL PRINCIPAL DISPLAY PANEL
NDC 0469-0125-99
Rx Only
Xtandi
(enzalutamide)
capsules
(enzalutamide)
capsules
40 mg
Swallow capsules whole with a sufficient
120 Capsules
Manufactured by
111607-04
415196-XTA-USA
4006396
11PACKAGE/LABEL PRINCIPAL DISPLAY PANEL
NDC 0469-0625-99
Rx Only
Xtandi
(enzalutamide)
tablets
(enzalutamide)
tablets
40 mg
Swallow tablets whole with a
120 Tablets
Distributed by
75104449
415196-XTA-USA
4006397
12PACKAGE/LABEL PRINCIPAL DISPLAY PANEL
NDC 0469-0725-60
Rx Only
Xtandi
(enzalutamide)
tablets
(enzalutamide)
tablets
80 mg
Swallow tablets whole with a
60 Tablets
Distributed by
75104452
415196-XTA-USA
4006399
13PACKAGE/LABEL PRINCIPAL DISPLAY PANEL
NDC 0469-1125-56
Rx Only
Xtandi
40 mg
56 Soft Capsules
SAMPLE
SAMPLE – NOT FOR SALE
14PACKAGE/LABEL PRINCIPAL DISPLAY PANEL
NDC 0469-1725-56
Rx Only
Xtandi
(enzalutamide)
tablets
(enzalutamide)
tablets
40 mg
Swallow tablets whole with a
56 Tablets
Sample – Not for Sale
Distributed by
75104450
415196-XTA-USA
4006398
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