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EFFICACY RESULTS IN CSPC

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Radiographic Progression-Free Survival Overall Survival ARCHES Endpoints ENZAMET Endpoints

ARCHES Trial

XTANDI + GnRH therapy* significantly extended radiographic progression-free survival^†1

ARCHES assessed the efficacy and safety of XTANDI + GnRH therapy* vs placebo + GnRH therapy* in patients with mCSPC.¹

Radiographic Progression-Free Survival Chart

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

See mCSPC (ARCHES) adverse reactions

*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

View Study Design

ARCHES assessed the efficacy and safety of XTANDI + GnRH therapy* vs placebo + GnRH therapy* in patients with mCSPC¹

*Or after bilateral orchiectomy.¹

^†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

^‡Radiographic disease progression was defined by identification of ≥ 2 new bone lesions on a bone scan with confirmation (PCWG2 criteria) and/or progression in soft-tissue disease.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

Close Study Design

XTANDI + GnRH therapy* significantly extended overall survival¹

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.*^† This was not a prespecified analysis and is not in the US Full Prescribing Information for XTANDI⁴

*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.⁴

OVERALL SURVIVAL SUBGROUP ANALYSIS

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.

*Or after bilateral orchiectomy.¹

5-YEAR POST-HOC OVERALL SURVIVAL FOLLOW-UP ANALYSIS

The information below is not included in the USPI for XTANDI. There was no assessment of statistical significance for this post-hoc analysis; it was not alpha-protected and should be understood as descriptive information.

A post-hoc analysis of overall survival in patients with mCSPC was performed at 5 years⁶

Number of events: 191 (33.3%) with XTANDI + GnRH therapy* and 223 (38.7%) with placebo + GnRH therapy*⁶
At 60 months, 66% of patients randomized to XTANDI + GnRH therapy* and 53% of patients randomized to placebo + GnRH therapy* were alive according to Kaplan-Meier calculations⁶

*Or after bilateral orchiectomy.¹

TIME TO START OF NEW ANTINEOPLASTIC THERAPY

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

Number of events: 46 (8.0%) with XTANDI + GnRH therapy* vs 133 (23.1%) with placebo + GnRH therapy*⁵

*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.⁶

An updated analysis of time to start of new antineoplastic therapy was performed at the time of final overall survival analysis⁴

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.

Updated Time to Start of New Antineoplastic Therapy Chart

Number of events: 131 (22.82%) with XTANDI + GnRH therapy^† and 236 (40.97%) with placebo + GnRH therapy^†6

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.⁶

*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.⁷

^†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.⁴

PSA PROGRESSION

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.

Number of events: 45 (7.84%) with XTANDI + GnRH therapy^† and 189 (32.81%) with placebo + GnRH therapy^†⁶

*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.³

^†Or after bilateral orchiectomy.¹

POST-HOC ANALYSIS OF PSA PROGRESSION

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 analysis^4,7

Number of events: 117 (20.4%) with XTANDI + GnRH therapy^† and 259 (45.0%) with placebo + GnRH therapy^†⁶

^†Or after bilateral orchiectomy.¹

PSA undetectable rate and time to deterioration of urinary symptoms were also evaluated in patients with mCSPC^1,6

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*†

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^† group⁶
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)^‡6

Key secondary endpoint from primary analysis: Time to deterioration of urinary symptoms^§6

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.⁶

^†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

TIME TO CASTRATION RESISTANCE

Time to castration resistance was also evaluated in patients with mCSPC⁵

The 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.

Number of events: 90 (15.68%) with XTANDI + GnRH therapy* and 257 (44.62%) with placebo + GnRH therapy*⁶

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.⁵

*Or after bilateral orchiectomy.¹

A post-hoc analysis of time to castration resistance was performed at the time of final overall survival analysis^4,7

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.

Post-Hoc Time to Castration Resistance Chart

Number of events: 202 (35.2%) with XTANDI + GnRH therapy* and 327 (56.8%) with placebo + GnRH 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.⁴

Review more data about
XTANDI in mCSPC
(ARCHES trial
publication)

Review more data about
XTANDI in mCSPC (ARCHES
trial publication)

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):2974-2986.

View the Publication

ENZAMET Trial

Overall survival: XTANDI + GnRH therapy* and NSAA^† + GnRH therapy* in patients with mCSPC⁹

ENZAMET results were not accepted by the FDA for inclusion in the US Full Prescribing Information for XTANDI. The overall patient population in ENZAMET included patients who received or did not receive concomitant docetaxel. The efficacy and safety of XTANDI in combination with docetaxel has not been established. ENZAMET was neither designed nor powered to analyze the results of overall survival in the individual subgroups. Therefore, an improvement in overall survival cannot be established in any subgroup, including mCSPC patients taking XTANDI + GnRH therapy* alone or with concomitant docetaxel. The updated analysis of the primary endpoint was prespecified but not alpha protected and should be considered descriptive information.

30% reduction in the risk of death with XTANDI + GnRH therapy* vs NSAA + GnRH therapy*⁹

Number of events: 208 (37%) with XTANDI + GnRH therapy* and 268 (48%) with NSAA + GnRH therapy*⁹

This planned analysis was triggered by reaching 470 deaths. At the time of the planned analysis, with a median follow-up of 68 months, there were not enough death events in either arm to estimate the median overall survival.^8,9

*Or after bilateral orchiectomy.¹⁰

^†Conventional NSAAs: bicalutamide 50 mg/day, nilutamide 150 mg/day, or flutamide 250 mg 3 times a day.¹⁰

Concomitant docetaxel subgroup analyses

*Or after bilateral orchiectomy.¹⁰

^†Conventional NSAAs: bicalutamide 50 mg/day, nilutamide 150 mg/day, or flutamide 250 mg 3 times a day.¹⁰

See mCSPC (ENZAMET) Adverse Reactions

View Study Design

XTANDI + GnRH therapy* in mCSPC was assessed in another large phase 3 study (ENZAMET)⁸

ENZAMET was an open-label study assessing XTANDI + GnRH therapy* and NSAA^† + GnRH therapy* in patients with mCSPC⁸

ENZAMET results were not accepted by the FDA for inclusion in the US Full Prescribing Information for XTANDI. The overall patient population in ENZAMET included those who received or did not receive concomitant docetaxel, and the efficacy and safety of XTANDI in combination with docetaxel is not established.

The primary endpoint of overall survival was measured as the interval from randomization to death from any cause or to the date of last known follow-up.⁹

*Or after bilateral orchiectomy.¹⁰

^†Conventional NSAAs: bicalutamide 50 mg/day, nilutamide 150 mg/day, or flutamide 250 mg 3 times a day.¹⁰

^‡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.⁸

Close Study Design

OVERALL SURVIVAL SUBGROUP ANALYSIS

Overall survival: prespecified subgroup analysis in patients with mCSPC⁹

ENZAMET results were not accepted by the FDA for inclusion 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.

*Or after bilateral orchiectomy.¹⁰

^†Conventional NSAAs: bicalutamide 50 mg/day, nilutamide 150 mg/day, or flutamide 250 mg 3 times a day.¹⁰

PSA PROGRESSION-FREE SURVIVAL (SECONDARY ENDPOINT)

PSA progression-free survival: XTANDI + GnRH therapy* and NSAA^† + GnRH therapy* in patients with mCSPC⁹

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.

An update to the analysis of time to PSA progression was performed at the time of the updated overall survival analysis. There was no assessment of statistical significance, and it should be understood as descriptive information.

*Or after bilateral orchiectomy.¹⁰

^†Conventional NSAAs: bicalutamide 50 mg/day, nilutamide 150 mg/day, or flutamide 250 mg 3 times a day.¹⁰

^‡PSA progression-free survival was defined as time from randomization to the earliest PSA progression according to the PCWG2 criteria, clinical progression, or death from any cause, whichever occurred first, or the last known date of follow-up without PSA progression.⁹

CLINICAL PROGRESSION-FREE SURVIVAL (SECONDARY ENDPOINT)

Clinical progression-free survival: XTANDI + GnRH therapy* and NSAA^† + GnRH therapy* in patients with mCSPC⁹

An update to the analysis of clinical progression was performed at the time of the updated overall survival analysis. There was no assessment of statistical significance, and it should be understood as descriptive information.

Clinical Progression-Free Survival Chart

Clinical progression-free survival was defined as the earliest sign of radiographic progression using PCWG2 for bone lesions and RECIST 1.1 for soft-tissue lesions, symptoms attributable to cancer progression, or initiation of another anticancer treatment for prostate cancer.⁹

*Or after bilateral orchiectomy.¹⁰

^†Conventional NSAAs: bicalutamide 50 mg/day, nilutamide 150 mg/day, or flutamide 250 mg 3 times a day.¹⁰

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MFS XTANDI + GnRH Therapy MFS XTANDI (Single Agent) Other Endpoints

EMBARK Trial

XTANDI + GnRH therapy* significantly improved metastasis-free survival vs placebo + GnRH therapy*¹

EMBARK was a randomized phase 3 trial that assessed the efficacy and safety of XTANDI + GnRH therapy* vs placebo + GnRH therapy* in 1068 patients with nmCSPC with high-risk BCR.^1,2

Number of events: 45 (12.7%) with XTANDI + GnRH therapy* vs 92 (25.7%) with placebo + GnRH therapy*¹
Median metastasis-free survival was not reached in either the XTANDI + GnRH therapy* arm or the placebo + GnRH therapy* arm¹
The 5-year metastasis-free survival was 87% in the XTANDI + GnRH therapy* arm and 71% in the placebo + GnRH therapy* arm. This time point was not prespecified and is not in the US Full Prescribing Information for XTANDI^1,2

Overall survival data were not mature at the time of metastasis-free survival analysis (12.2% deaths across the overall population of 1068 patients had been reported).¹

See nmCSPC with high-risk BCR (EMBARK) adverse reactions

*Leuprolide.¹

View Study Design

The EMBARK trial assessed the efficacy and safety of XTANDI with or without GnRH therapy* vs placebo + GnRH therapy* in patients with nmCSPC with high-risk BCR¹

In the EMBARK trial, patients were required to have nonmetastatic disease by BICR, high-risk BCR (defined by a PSA doubling time ≤ 9 months), and PSA values ≥ 1 ng/mL if they had prior RP (with or without RT) as the primary treatment for prostate cancer or PSA values ≥ 2 ng/mL above the nadir if they had prior RT only.¹

*Leuprolide.¹

^†All treatment arms were eligible for treatment suspension. In the XTANDI + GnRH therapy* and placebo + GnRH therapy* arms, GnRH therapy* was also suspended.¹

^‡Study treatment was suspended once at Week 37 if PSA was < 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.¹

Patient demographics and baseline characteristics were balanced between the 3 treatment arms²

Percentages may not total 100 because of rounding.

*Leuprolide.¹

^†Race or ethnic group was reported by the patients. The "Other" category includes patients who identified as multiple races or ethnic groups.²

^‡ECOG Performance Status scores range from 0 to 5, with higher scores indicating greater disability.²

^§PSA doubling time at baseline was calculated on the basis of a sequence of PSA values tested over time during the enrollment period. Some baseline PSA doubling time values exceeded the enrollment threshold of less than 9 months owing to discrepancies in the PSA values captured in the case-report forms as compared with the values used for the enrollment calculation.²

Close Study Design

XTANDI (single agent) significantly improved metastasis-free survival vs placebo + GnRH therapy*¹

Number of events: 63 (17.7%) with XTANDI (single agent) vs 92 (25.7%) with placebo + GnRH therapy*¹
Median metastasis-free survival was not reached in either the XTANDI (single agent) arm or the placebo + GnRH therapy* arm¹
The 5-year metastasis-free survival was 80% in the XTANDI (single agent) arm and 71% in the placebo + GnRH therapy* arm. This endpoint was not prespecified and is not in the US Full Prescribing Information for XTANDI^1,2

*Leuprolide.¹

TIME TO START OF NEW ANTINEOPLASTIC THERAPY

Time to start of new antineoplastic therapy was also assessed with XTANDI + GnRH therapy* and placebo + GnRH therapy*^2,4

This endpoint was a prespecified, alpha-protected, key secondary endpoint. There is overlap of events between time to start of new antineoplastic therapy and metastasis-free survival, because patients with new metastases are generally started on a new antineoplastic drug. Hormonal therapy was the most frequent subsequent therapy received and accounted for approximately a quarter of patients who received any subsequent therapy. Less frequent subsequent therapies included cytotoxic therapies, prostate cancer vaccines, or systemic radiopharmaceuticals. This information should be considered when evaluating the clinical importance of this analysis. This information is not included in the US Full Prescribing Information for XTANDI.

Time to Start Antineoplastic Therapy Chart

Number of events: 58 (16%) with XTANDI + GnRH therapy* and 140 (39%) with placebo + GnRH therapy*²
Median time to start of new antineoplastic therapy was not reached in the XTANDI + GnRH therapy* arm and was 76.2 months in the placebo + GnRH therapy* arm⁴

Time to start of new antineoplastic therapy was defined as the time from randomization to first use of a new antineoplastic therapy for prostate cancer. Subsequent prostate cancer therapies included hormonal therapies, cytotoxic therapies, prostate cancer vaccines, or systemic radiopharmaceuticals for prostate cancer.⁵

*Leuprolide.¹

TREATMENT SUSPENSION

Treatment* was suspended if PSA dropped to undetectable at 36 weeks¹

For patients whose PSA was undetectable (< 0.2 ng/mL) at Week 36, treatment* was suspended at Week 37 and then reinitiated when PSA increased to ≥ 2.0 ng/mL for patients with prior prostatectomy or ≥ 5.0 ng/mL for patients without prior prostatectomy.¹

Approximately 91% of patients in the XTANDI + GnRH therapy^† arm reached undetectable PSA levels (< 0.2 ng/mL) at 9 months¹

Median treatment suspension duration in the XTANDI + GnRH therapy^† arm due to undetectable PSA (< 0.2 ng/mL) at 36 weeks was 18 months¹

*All treatment arms were eligible for treatment suspension. In the XTANDI + GnRH therapy^† and placebo + GnRH therapy^† arms, GnRH therapy^† was also suspended.¹

^†Leuprolide.¹

Review more data about XTANDI in nmCSPC with high-risk BCR (EMBARK trial publication)

Review more data about
XTANDI in nmCSPC with
high-risk BCR (EMBARK
trial publication)

Freedland SJ, de Almeida Luz M, De Giorgi U, et al. Improved outcomes with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med. 2023;389(16):1453-1465.

View The Publication

BCR, biochemical recurrence; BICR, blinded independent central review; CI, confidence interval; CSPC, castration-sensitive prostate cancer; ECOG, Eastern Cooperative Oncology Group; GnRH, gonadotropin-releasing hormone; HR, hazard ratio; mCSPC, metastatic castration-sensitive prostate cancer; MFS, metastasis-free survival; nmCSPC, nonmetastatic castration-sensitive prostate cancer; NR, not reached; PSA, prostate-specific antigen; RP, radical prostatectomy; RT, radiotherapy.

References: 1. XTANDI. Package insert. Northbrook, IL: Astellas Pharma US, Inc; 2025. 2. Freedland SJ, de Almeida Luz M, De Giorgi U, et al. Improved outcomes with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med. 2023;389(16):1453-1465. 3. Freedland SJ, De Giorgi U, Gleave M, et al. A phase 3 randomised study of enzalutamide plus leuprolide and enzalutamide monotherapy in high-risk non-metastatic hormone-sensitive prostate cancer with rising PSA after local therapy: EMBARK study design [published online August 12, 2021]. BMJ Open. 2021. Accessed February 5, 2025. https://bmjopen.bmj.com/content/bmjopen/11/8/e046588.full.pdf. 4. Astellas. XTANDI. Data on File. 5. Supplement to: Freedland SJ, de Almeida Luz M, De Giorgi U, et al. Improved outcomes with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med. 2023;389(16):1453-1465.

ACE, adult comorbidity evaluation; CI, confidence interval; CT, computed tomography; ECOG, Eastern Cooperative Oncology Group; FDA, U.S. Food and Drug Administration; GnRH, gonadotropin-releasing hormone; HR, hazard ratio; ITT, intent to treat; mCSPC, metastatic castration-sensitive prostate cancer; NE, not evaluable; nmCSPC, nonmetastatic castration-sensitive prostate cancer; NR, not reached; NSAA, nonsteroidal anti-androgen; PCWG2, Prostate Cancer Working Group 2; PSA, prostate-specific antigen; RANKL, receptor activator of nuclear factor; RECIST 1.1, Response Evaluation Criteria in Solid Tumors version 1.1.

References: 1. XTANDI. Package insert. Northbrook, IL: Astellas Pharma US, Inc; 2025. 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):2974-2986. 3. Protocol for: 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):2974-2986. 4. 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):1616-1622. 5. 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):2974-2986. 6. Astellas. XTANDI. Data on File. 7. 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):1616-1622. 8. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381(2):121-131. 9. Sweeney CJ, Martin AJ, Stockler MR, et al. Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial. Lancet Oncol. 2023;24(4):323-334. 10. Protocol for: Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381(2):121-131.

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Indications

XTANDI 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), or castration-resistant prostate cancer (CRPC).¹

Important Safety Information

Important Safety Information and Indications

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.

Dysphagia or Choking Severe dysphagia or choking, including events that could be life-threatening requiring medical intervention or fatal, can occur due to XTANDI product size. Advise patients to take each capsule or tablet whole with a sufficient amount of water to ensure that all medication is successfully swallowed. Consider use of a smaller tablet size of XTANDI in patients who have difficulty swallowing. Discontinue XTANDI for patients who cannot swallow capsules or tablets.

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, hypophosphatemia, 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)

Reference: 1. XTANDI. Package insert. Northbrook, IL: Astellas Pharma US, Inc; 2025.

ECOG, Eastern Cooperative Oncology Group; GnRH, gonadotropin-releasing hormone; mCRPC, metastatic castration-resistant prostate cancer; PSA, prostate-specific antigen.

*Or after bilateral orchiectomy.¹

†92% of study participants had an ECOG Performance Status score of 0 or 1. ECOG Performance Status scores range from 0 to 5, with 0 indicating full activity and 1 indicating a restriction in strenuous activity but the ability to be ambulatory and do light work.^1,2

EFFICACY RESULTS IN CSPC

XTANDI + GnRH therapy* significantly extended radiographic progression-free survival†1

ARCHES assessed the efficacy and safety of XTANDI + GnRH therapy* vs placebo + GnRH therapy* in patients with mCSPC1

XTANDI + GnRH therapy* significantly extended overall survival1

A post-hoc analysis of overall survival in patients with mCSPC was performed at 5 years6

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

An updated analysis of time to start of new antineoplastic therapy was performed at the time of final overall survival analysis4

Time to PSA progression was also evaluated in patients with mCSPC2

A post-hoc analysis of time to PSA progression was performed at the time of final overall survival analysis4,7

PSA undetectable rate and time to deterioration of urinary symptoms were also evaluated in patients with mCSPC1,6

Key secondary endpoint from primary analysis: Time to deterioration of urinary symptoms§6

Time to castration resistance was also evaluated in patients with mCSPC5

A post-hoc analysis of time to castration resistance was performed at the time of final overall survival analysis4,7

Overall survival: XTANDI + GnRH therapy* and NSAA† + GnRH therapy* in patients with mCSPC9

Concomitant docetaxel subgroup analyses

XTANDI + GnRH therapy* in mCSPC was assessed in another large phase 3 study (ENZAMET)8

ENZAMET was an open-label study assessing XTANDI + GnRH therapy* and NSAA† + GnRH therapy* in patients with mCSPC8

Overall survival: prespecified subgroup analysis in patients with mCSPC9

PSA progression-free survival: XTANDI + GnRH therapy* and NSAA† + GnRH therapy* in patients with mCSPC9

Clinical progression-free survival: XTANDI + GnRH therapy* and NSAA† + GnRH therapy* in patients with mCSPC9

XTANDI + GnRH therapy* significantly improved metastasis-free survival vs placebo + GnRH therapy*1

The EMBARK trial assessed the efficacy and safety of XTANDI with or without GnRH therapy* vs placebo + GnRH therapy* in patients with nmCSPC with high-risk BCR1

Patient demographics and baseline characteristics were balanced between the 3 treatment arms2

XTANDI (single agent) significantly improved metastasis-free survival vs placebo + GnRH therapy*1

Time to start of new antineoplastic therapy was also assessed with XTANDI + GnRH therapy* and placebo + GnRH therapy*2,4

Treatment* was suspended if PSA dropped to undetectable at 36 weeks1

For patients on GnRH therapy* who have progressed to mCRPC1

XTANDI + GnRH therapy* significantly extended radiographic progression-free survival^†1

ARCHES assessed the efficacy and safety of XTANDI + GnRH therapy* vs placebo + GnRH therapy* in patients with mCSPC¹

XTANDI + GnRH therapy* significantly extended overall survival¹

A post-hoc analysis of overall survival in patients with mCSPC was performed at 5 years⁶

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

An updated analysis of time to start of new antineoplastic therapy was performed at the time of final overall survival analysis⁴

Time to PSA progression was also evaluated in patients with mCSPC²

A post-hoc analysis of time to PSA progression was performed at the time of final overall survival analysis^4,7

PSA undetectable rate and time to deterioration of urinary symptoms were also evaluated in patients with mCSPC^1,6

Key secondary endpoint from primary analysis: Time to deterioration of urinary symptoms^§6

Time to castration resistance was also evaluated in patients with mCSPC⁵

A post-hoc analysis of time to castration resistance was performed at the time of final overall survival analysis^4,7

Overall survival: XTANDI + GnRH therapy* and NSAA^† + GnRH therapy* in patients with mCSPC⁹

XTANDI + GnRH therapy* in mCSPC was assessed in another large phase 3 study (ENZAMET)⁸

ENZAMET was an open-label study assessing XTANDI + GnRH therapy* and NSAA^† + GnRH therapy* in patients with mCSPC⁸

Overall survival: prespecified subgroup analysis in patients with mCSPC⁹

PSA progression-free survival: XTANDI + GnRH therapy* and NSAA^† + GnRH therapy* in patients with mCSPC⁹

Clinical progression-free survival: XTANDI + GnRH therapy* and NSAA^† + GnRH therapy* in patients with mCSPC⁹

XTANDI + GnRH therapy* significantly improved metastasis-free survival vs placebo + GnRH therapy*¹

The EMBARK trial assessed the efficacy and safety of XTANDI with or without GnRH therapy* vs placebo + GnRH therapy* in patients with nmCSPC with high-risk BCR¹

Patient demographics and baseline characteristics were balanced between the 3 treatment arms²

XTANDI (single agent) significantly improved metastasis-free survival vs placebo + GnRH therapy*¹

Time to start of new antineoplastic therapy was also assessed with XTANDI + GnRH therapy* and placebo + GnRH therapy*^2,4

Treatment* was suspended if PSA dropped to undetectable at 36 weeks¹

For patients on GnRH therapy* who have progressed to mCRPC¹