Enzalutamide-vista

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ENZALUTAMID-VISTA (ENZALUTAMID-VISTA)

Composition:

Active substance: enzalutamide;

One film-coated tablet contains 40 mg or 80 mg of enzalutamide;

Excipients: methacrylic acid copolymer (type A), colloidal silicon dioxide anhydrous, microcrystalline cellulose, sodium croscarmellose, magnesium stearate;

Coating of the tablet: hypromellose, macrogol, titanium dioxide (E 171), yellow iron oxide (E 172), talc.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

• for the 40 mg dosage: film-coated, round-shaped, yellow tablets, with "40" embossed on one side;

• for the 80 mg dosage: film-coated, oval-shaped, yellow tablets, with "80" embossed on one side.

Pharmacotherapeutic group. Hormone antagonists and related agents, antiandrogens. ATC code L02BB04.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

The development of prostate cancer is dependent on the presence of androgens and responds to inhibition of androgen receptor activity in tumor cells. Despite low or very low levels of androgens in plasma that are undetectable, androgen receptor activity in tumor cells continues to promote disease progression. Stimulation of tumor cell growth via androgen receptors requires their translocation into the cell nucleus and binding to DNA. Enzalutamide is a potent inhibitor of androgen receptors that blocks multiple steps in the androgen receptor signaling pathway. Enzalutamide competitively inhibits binding of androgens to androgen receptors, suppresses nuclear translocation of activated receptors, and inhibits binding of activated androgen receptors to DNA, even under conditions of overexpression of androgen receptors and in tumor cells resistant to antiandrogens. Treatment with enzalutamide inhibits prostate tumor cell growth and may induce cell death and tumor regression. In preclinical studies, enzalutamide lacked androgen receptor agonist activity.

Pharmacodynamic properties

In a phase III clinical study (AFFIRM) involving patients after ineffective docetaxel chemotherapy, a ≥50% reduction in prostate-specific antigen (PSA) levels from baseline was observed in 54% of patients receiving enzalutamide compared to 1.5% of patients receiving placebo.

In another phase III clinical trial (PREVAIL) involving patients who had not previously received chemotherapy, patients receiving enzalutamide demonstrated a significantly higher rate of PSA decline (defined as ≥50% reduction from baseline) compared to patients receiving placebo: 78% vs. 3.5% (difference – 74.5%, p < 0.0001).

In a phase II clinical trial (TERRAIN) involving patients who had not previously received chemotherapy, patients receiving enzalutamide demonstrated a significantly higher rate of PSA decline (defined as ≥50% reduction from baseline) compared to patients receiving bicalutamide: 82.1% vs. 20.9% (difference – 61.2%, p < 0.0001).

In a single-cohort study of patients (9785-CL-0410) who had previously received abiraterone (plus prednisone) for at least 24 weeks, ≥50% reduction in PSA levels from baseline was observed in 22.4% of patients. According to prior chemotherapy history, the proportion of patients with PSA reduction ≥50% was 22.1% and 23.2% in the group without prior chemotherapy and the chemotherapy group, respectively. In the clinical trial MDV3100-09 (STRIVE) involving patients with non-metastatic and metastatic castration-resistant prostate cancer (CRPC), the enzalutamide group demonstrated a significantly higher confirmed response rate in overall PSA levels (defined as a reduction of ≥50% from baseline) compared to the bicalutamide group: 81.3% vs. 31.3%, respectively (difference = 50%, p < 0.0001).

In the clinical trial MDV3100-14 (PROSPER) involving patients with non-metastatic CRPC, the enzalutamide group demonstrated a significantly higher confirmed response rate in overall PSA levels (defined as a reduction of ≥50% from baseline) compared to the placebo group: 76.3% vs. 2.4%, respectively (difference – 73.9%, p < 0.0001).

Clinical efficacy and safety

The efficacy of enzalutamide was established in three randomized, placebo-controlled, multicenter phase III clinical trials [MDV3100-14 (PROSPER), CRPC2 (AFFIRM), MDV3100-03 (PREVAIL)] in patients with metastatic prostate cancer progressing despite androgen deprivation therapy (using a gonadotropin-releasing hormone (GnRH) analogue or after bilateral orchidectomy). The PREVAIL trial included patients who had not received chemotherapy; the AFFIRM trial included patients who had previously received docetaxel; the PROSPER trial included patients with non-metastatic CRPC. Additionally, efficacy in patients with metastatic hormone-sensitive prostate cancer (mHSPC) was also established in one randomized, placebo-controlled, multicenter phase 3 clinical trial [9785-CL-0335 (ARCHES)]. All patients received a GnRH analogue or had undergone bilateral orchidectomy. In the study group, enzalutamide was administered orally at a dose of 160 mg once daily. In five clinical trials (EMBARK, ARCHES, PROSPER, AFFIRM, and PREVAIL), patients in the control group received placebo; patients were also allowed, but not required, to receive prednisolone (maximum allowable daily dose of prednisolone 10 mg or equivalent dose).

Independent changes in PSA levels do not always determine clinical efficacy. Therefore, in four studies, patients were recommended to continue their assigned therapy until they developed symptoms meeting the criteria for study discontinuation, as specified below for each study.

Study MDV3100-13 (EMBARK) (patients with high-risk non-metastatic prostate cancer with BCR).

The EMBARK study included 1068 patients with high-risk non-metastatic prostate cancer with BCR, who were randomized in a 1:1:1 ratio to receive enzalutamide orally at a dose of 160 mg once daily in combination with ADT (N = 355), enzalutamide orally at a dose of 160 mg once daily as open-label monotherapy (N = 355), or placebo orally once daily in combination with ADT (N = 358) (ADT defined as leuprolide). All patients had previously undergone definitive therapy with radical prostatectomy or radiation therapy (including brachytherapy) or both with curative intent. Patients were required to have confirmed non-metastatic disease by blinded independent central review (BICR) and high-risk biochemical recurrence (defined as PSA doubling time ≤9 months). Patients were also required to have PSA ≥1 ng/mL if they had previously undergone radical prostatectomy (with or without radiation therapy) as primary treatment for prostate cancer, or PSA at least 2 ng/mL above nadir if they had previously undergone radiation therapy alone. Patients who had previously undergone prostatectomy and were eligible candidates for radiation therapy as determined by the investigator were excluded from the study.

Patients were stratified by screening PSA level (≤10 ng/mL vs. >10 ng/mL), PSA doubling time (≤3 months vs. >3 months to ≤9 months), and prior hormonal therapy (prior hormonal therapy vs. no prior hormonal therapy). For patients with undetectable PSA levels (<0.2 ng/mL) at week 36, treatment was suspended at week 37 and then resumed when PSA levels increased to ≥2.0 ng/mL for patients with prior prostatectomy or ≥5.0 ng/mL for patients without prior prostatectomy. For patients with detectable PSA levels at week 36 (≥0.2 ng/mL), treatment continued without interruption until meeting the criteria for final treatment discontinuation. Treatment was permanently discontinued when radiographic progression was confirmed by centralized review after initial local assessment.

Demographic and baseline characteristics were well balanced across the three treatment groups. The overall median age at randomization was 69 years (range: 49–93). The majority of patients in the overall population were of Caucasian race (83.2%), 7.3% were Asian, and 4.4% were Black. The median PSA doubling time was 4.9 months. 74% of patients had previously undergone definitive therapy with radical prostatectomy, 75% had previously undergone radiation therapy, and 49% had previously undergone therapy with both methods. 32% of patients had a Gleason score ≥8. The Eastern Cooperative Oncology Group performance status (ECOG PS) at study entry was 0 for 92% of patients and 1 for 8% of patients.

The primary endpoint was metastasis-free survival (MFS) in patients randomized to receive enzalutamide plus ADT compared to patients randomized to receive placebo plus ADT. Metastasis-free survival was defined as the time from randomization to radiographic progression or death during the study, whichever occurred first.

Secondary endpoints evaluated with multiplicity adjustment included time to PSA progression, time to first use of antineoplastic therapy, and overall survival. Another secondary endpoint evaluated with multiplicity adjustment was MFS in patients randomized to receive enzalutamide as monotherapy compared to patients randomized to receive placebo plus ADT. After initiation of ADT as enzalutamide plus ADT or placebo plus ADT, testosterone levels rapidly decreased to castrate levels and remained low until treatment interruption at 37 weeks. After interruption, testosterone levels gradually increased to nearly baseline levels. After resumption of treatment, levels again decreased to castrate levels. In the enzalutamide monotherapy group, testosterone levels increased after treatment initiation and returned to baseline levels after treatment interruption. They again increased after resumption of enzalutamide treatment.

Study 9785-CL-0335 (ARCHES) (patients with mHSPC)

The ARCHES study included 1150 patients with mHSPC, randomized 1:1 to receive enzalutamide plus ADT or placebo plus ADT (ADT defined as a GnRH analogue or bilateral orchidectomy). Patients received enzalutamide 160 mg once daily (N = 574) or placebo (N = 576).

Patients with metastatic prostate cancer confirmed by positive radiological findings (bone disease) or documented metastatic lesions established by CT or MRI (for soft tissues) met the inclusion criteria. Patients with disease limited to regional pelvic lymph nodes were not included in the study. Patients could receive up to 6 cycles of docetaxel therapy within 2 months from the first day of study drug administration without any signs of disease progression during or after completion of docetaxel therapy. Patients with known or suspected brain metastases or active leptomeningeal disease, or with a history of seizures or any conditions that may predispose to seizures, were excluded from the study.

Demographic and baseline characteristics of participants in the two treatment groups were well balanced. The median age at randomization was 70 years in both treatment groups. The majority of patients in the overall population were of Caucasian race (80.5%); 13.5% were Asian and 1.4% were Black. At study initiation, the Eastern Cooperative Oncology Group (ECOG PS) score was 0 for 78% and 1 for 22% of patients. Participants were stratified by low and high disease burden and prior docetaxel therapy for prostate cancer. 37% of patients had low disease burden, and 63% had high disease burden. 82% of patients had not received prior docetaxel therapy, 2% received 1–5 cycles, and 16% received 6 prior cycles. Concomitant docetaxel therapy was not allowed.

Radiographic progression-free survival (rPFS), based on independent central review, was the primary endpoint, defined as the time from randomization to the first objective evidence of radiographic disease progression or death (from any cause from the time of randomization to 24 weeks after discontinuation of study drug) whichever occurred first. Enzalutamide demonstrated a statistically significant 61% reduction in the risk of rPFS compared to placebo [HR = 0.39 (95% CI: 0.30, 0.50); p < 0.0001]. Consistent rPFS results were observed in patients with high or low disease burden and in patients with or without prior docetaxel therapy. The median time to rPFS was not reached in the enzalutamide group and was 19 months (95% CI: 16.6, 22.2) in the placebo group. Key secondary efficacy endpoints evaluated in the study included time to PSA progression, time to initiation of new antineoplastic therapy, proportion of undetectable PSA (decrease to <0.2 µg/L), and objective response rate (RECIST 1.1 based on independent review). Statistically significant improvement was demonstrated for all these secondary endpoints in patients receiving enzalutamide compared to those receiving placebo. Another key secondary efficacy endpoint evaluated in the study was overall survival. In a pre-specified interim analysis of overall survival conducted when 356 deaths were recorded, a statistically significant 34% reduction in the risk of death was demonstrated in the group of patients randomized to receive enzalutamide compared to the group randomized to receive placebo [HR = 0.66, (95% CI: 0.53; 0.81), p < 0.0001]. Median overall survival was not reached in either treatment group. The estimated median follow-up time for all patients was 44.6 months.

Study MDV3100-14 (PROSPER) (patients with non-metastatic CRPC)

The PROSPER study included 1401 patients with non-metastatic CRPC at high risk of progression with asymptomatic disease, who continued androgen deprivation therapy (ADT; use of a GnRH analogue or prior bilateral orchidectomy). Eligibility for the study required a PSA doubling time ≤10 months, PSA level ≥2 ng/mL, and confirmation of non-metastatic disease by centralized independent blinded assessment (CIBA).

Patients with mild to moderate heart failure (NYHA class I or II) and patients taking medications that may lower the seizure threshold were allowed to participate in the study. Patients with a history of seizures or conditions that may predispose to seizures, or those who had previously received certain medications for prostate cancer (i.e., chemotherapy, ketoconazole, abiraterone acetate, aminoglutethimide, and/or enzalutamide) were excluded from the study. Patients were randomized 2:1 to receive enzalutamide orally at a dose of 160 mg once daily (N = 933) or placebo (N = 468). Patients were stratified by prostate-specific antigen doubling time (PSADT) (<6 months or ≥6 months) and use of bone-modifying agents (yes or no). Demographic and baseline characteristics were well balanced in both groups. The median age at randomization was 74 years in the enzalutamide group and 73 years in the placebo group. The majority of patients (approximately 71%) in the study were of Caucasian race; 16% were Asian, 2% were Black. In 81% of patients, the Eastern Cooperative Oncology Group (ECOG) performance status score was 0, and in 19% of patients, it was 1.

Metastasis-free survival (MFS) was the primary endpoint, defined as the time from randomization to radiographic progression or death within 112 days after discontinuation of treatment without evidence of radiographic progression, whichever occurred first. Key secondary endpoints evaluated in the study included time to PSA progression, time to first use of new antineoplastic therapy (TFAT), overall survival (OS). Additional secondary endpoints included time to first use of cytotoxic chemotherapy and chemotherapy-free survival.

Enzalutamide demonstrated a statistically significant 71% reduction in the relative risk of radiographic progression or death compared to placebo [HR = 0.29 (95% CI: 0.24–0.35), p < 0.0001]. The median MFS was 36.6 months (95% CI: 33.1–NR) in the enzalutamide group and 14.7 months (95% CI: 14.2–15) in the placebo group.

Consistent MFS results were also observed in all pre-specified patient subgroups stratified by PSADT (<6 months or ≥6 months), demographic region (North America, Europe, other regions), age (<75 years or ≥75 years), prior use of bone-modifying agents (yes or no). The final analysis of overall survival, conducted after recording 466 deaths, showed a statistically significant improvement in overall survival in patients randomized to receive enzalutamide compared to patients randomized to receive placebo, with a 26.6% reduction in the risk of death [hazard ratio (HR) = 0.734, (95% CI: 0.608; 0.885), p = 0.0011]. Median follow-up time was 48.6 and 47.2 months for the enzalutamide and placebo groups, respectively. 33% of patients receiving enzalutamide and 65% of patients receiving placebo received at least one subsequent cycle of antineoplastic therapy, which may prolong overall survival.

Enzalutamide demonstrated a statistically significant 93% reduction in the relative risk of PSA progression compared to placebo [HR = 0.07 (95% CI: 0.05–0.08), p < 0.0001]. The median time to PSA progression was 37.2 months (95% CI: 33.1–NR) in the enzalutamide group and 3.9 months (95% CI: 3.8, 4) in the placebo group.

Enzalutamide demonstrated a statistically significant prolongation of time to first use of new antineoplastic therapy compared to placebo [HR = 0.21 (95% CI: 0.17–0.26), p < 0.0001]. The median time to first use of new antineoplastic therapy was 39.6 months (95% CI: 37.7–NR) in the enzalutamide group and 17.7 months (95% CI: 16.2–19.7) in the placebo group.

Study MDV3100-09 (STRIVE) (patients with non-metastatic/metastatic CRPC who had not received chemotherapy)

The STRIVE study included 396 patients with CRPC (non-metastatic or metastatic) who had confirmed (serologically or radiologically) disease progression despite primary androgen deprivation therapy; patients were randomized to receive either enzalutamide at a dose of 160 mg once daily (N = 198) or bicalutamide at a dose of 50 mg once daily (N = 198). PFS (progression-free survival) was established as the primary endpoint, defined as the time from randomization to the first objective evidence of radiographic progression, PSA progression, or death during the study.

The median PFS was 19.4 months (95% CI: 16.5, not reached) in the enzalutamide group compared to 5.7 months (95% CI: 5.6, 8.1) in the bicalutamide group [HR = 0.24 (95% CI: 0.18, 0.32), p < 0.0001].

A significant advantage of enzalutamide over bicalutamide and consistent improvement in PFS were observed in all pre-specified patient subgroups. In the subgroup of patients with non-metastatic CRPC (N = 139), PFS was recorded in 19 of 70 (27.1%) patients receiving enzalutamide and in 49 of 69 (71%) patients receiving bicalutamide (total 68 events). The hazard ratio was 0.24 (95% CI: 0.14, 0.42), and the median PFS period was not reached in the enzalutamide group versus 8.6 months in the bicalutamide group.

Study 9785-CL-0222 (TERRAIN) (patients with metastatic CRPC who had not received chemotherapy)

The TERRAIN study included 375 patients with metastatic CRPC who had not received chemotherapy or antiandrogen therapy. They were randomized to receive either enzalutamide at a dose of 160 mg once daily (N = 184) or bicalutamide at a dose of 50 mg once daily (N = 191). The median PFS was 15.7 months for patients receiving enzalutamide versus 5.8 months for patients receiving bicalutamide [HR = 0.44 (95% CI: 0.34, 0.57), p < 0.0001]. Progression-free survival was defined based on objective radiographic evidence of disease progression by independent central review of skeletal events, initiation of new antineoplastic therapy, or death from any cause, whichever occurred first. Consistent improvement in PFS was observed in all pre-specified patient subgroups.

Study MDV3100-03 (PREVAIL) (patients with CRPC who had not received chemotherapy). A total of 1717 asymptomatic or mildly symptomatic patients who had not received chemotherapy were randomized 1:1 to the enzalutamide group at a dose of 160 mg once daily (N = 872) or the placebo group once daily (N = 845). Patients with visceral disorders, with a history of mild to moderate heart failure [NYHA class I or II], and patients taking medications that may lower the seizure threshold were included in the study. Patients with a history of seizures or conditions that may predispose to seizures, and patients with moderate or severe pain caused by prostate cancer were excluded from the study. Treatment in the study continued until disease progression (presence of radiographic progression, bone complications, or clinical progression) and initiation of cytotoxic therapy or treatment with another investigational agent, or until development of intolerable toxicity.

Demographic characteristics of patients and baseline disease characteristics were balanced between treatment groups. The median age was 71 years (42–93 years), and the racial distribution was as follows: Caucasians constituted 77%, Asians – 10%, African Americans – 2%, and other or unspecified races – 11%. ECOG performance status score was 0 in 68% of patients and 1 in 32% of patients. Baseline pain score was 0–1 (absence of symptoms) in 67% of patients and 2–3 (moderate symptoms) in 32% of patients according to the Brief Pain Inventory (short form) (pain intensity over the past 24 hours on a scale from 0 to 10). Approximately 45% of patients had soft tissue disease at baseline, and 12% had visceral (lung and/or liver) metastases. Composite primary endpoints of efficacy were overall survival and radiographic progression-free survival (rPFS). In addition to primary endpoints, efficacy was evaluated by time to initiation of cytotoxic chemotherapy, best overall response in soft tissues, time to first skeletal complication, PSA response (reduction ≥50% from baseline), period of PSA progression, and period of worsening of the FACT-P total score.

Radiographic progression was assessed by sequential imaging using PCWG2 criteria (for bone lesions) and/or RECIST v1.1 (for soft tissue involvement). Centralized assessment of radiographic progression was used for evaluation of rPFS.

In an interim analysis of overall survival at 540 patient deaths, treatment with enzalutamide showed a statistically significant increase in overall survival compared to placebo with a 29.4% reduction in the risk of death [hazard ratio (HR) = 0.706 (95% CI: 0.60; 0.84), p < 0.0001]. An updated analysis was performed at 784 deaths.

Results of the updated survival analysis (median survival was 35.3 and 31.3 months, respectively [HR = 0.77 (95% CI: 0.67; 0.88), p < 0.0002]) were consistent with the interim analysis data (median survival was 32.4 and 30.2 months, respectively [HR = 0.71 (95% CI: 0.60; 0.84), p < 0.00041]).

In the updated analysis, 52% of patients receiving enzalutamide and 81% of patients receiving placebo received treatment for metastatic castration-resistant prostate cancer, which may prolong overall survival.

The final analysis of five-year data from the PREVAIL study showed that patients receiving enzalutamide maintained a statistically significant increase in overall survival (OS) compared to patients in the placebo group [HR = 0.835, (95% CI: 0.75, 0.93); p-value = 0.0008], despite 28% of patients in the placebo group switching to enzalutamide. The five-year OS rate was 26% in the enzalutamide group compared to 21% in the placebo group.

In the planned analysis of rPFS, a statistically significant improvement was observed in the treatment groups with an 81.4% reduction in the risk of radiographic progression or death in the enzalutamide group [HR = 0.19 (95% CI: 0.15; 0.23), p < 0.0001]. Progression occurred in 118 (14%) patients receiving enzalutamide and in 321 (40%) patients receiving placebo. The median rPFS was not reached (95% CI: 3.7; 5.4) in the placebo group. Consistent improvement in rPFS was observed in all previously defined patient subgroups (e.g., age, baseline ECOG status, baseline PSA and LDH levels, Gleason score at diagnosis, visceral organ involvement at screening). In the planned analysis of rPFS during follow-up, a statistically significant improvement was demonstrated in the treatment groups with a 69.3% reduction in the risk of radiographic progression or death in the enzalutamide group [HR = 0.31 (95% CI: 0.27; 0.35), p < 0.0001]. The median rPFS was 19.7 months in the enzalutamide group and 5.4 months in the placebo group.

In addition to composite primary efficacy endpoints, statistically significant improvement was observed in the following prospectively defined endpoints. The median time to initiation of cytotoxic chemotherapy was 28 months for patients receiving enzalutamide and 10.8 months for patients receiving placebo [HR = 0.35; (95% CI: 0.3; 0.4), p < 0.0001].

Patients in the enzalutamide group with defined disease at baseline and objective response in soft tissues constituted 58.8% (95% CI: 53.8; 63.7) compared to 5% (95% CI: 3; 7.7) of patients receiving placebo. The absolute difference in objective response in soft tissues between the enzalutamide and placebo groups was 53.9% [(95% CI: 48.5; 59.1), p < 0.0001]. Complete response was observed in 19.7% of patients receiving enzalutamide compared to 1% of patients receiving placebo, and partial response was observed in 39.1% of patients receiving enzalutamide versus 3.9% of patients receiving placebo.

Enzalutamide significantly reduced the risk of first skeletal complication by 28% [HR = 0.718 (95% CI: 0.61; 0.84), p < 0.0001]. Skeletal complications were defined as radiation therapy or surgery on bone tissue due to prostate cancer, pathological bone fracture, spinal cord compression, or change in antineoplastic therapy for treatment of bone pain. The analysis included 587 skeletal complications, of which 389 cases (66.3%) were due to radiation therapy, 79 cases (13.5%) were spinal cord compression, 70 cases (11.9%) were pathological bone fractures, 45 cases (7.6%) were change in antineoplastic therapy for treatment of bone pain, and 22 cases (3.7%) were surgery on bone tissue.

Patients receiving enzalutamide had a significantly higher PSA response (defined as reduction ≥50% from baseline) compared to patients receiving placebo: 78% vs. 3.5% (difference = 74.5%, p < 0.0001).

The median time to PSA progression according to PCWG2 criteria was 11.2 months in patients in the enzalutamide group and 2.8 months in patients in the placebo group [HR = 0.17 (95% CI: 0.15; 0.2), p < 0.0001].

Treatment with enzalutamide reduced the risk of worsening on the FACT-P scale by 37.5% compared to placebo (p < 0.001). The median time to worsening on the FACT-P scale was 11.3 months in the enzalutamide group and 5.6 months in the placebo group.

Study CRPC2 (AFFIRM) (patients with metastatic prostate cancer who had received chemotherapy)

The efficacy and safety of enzalutamide in patients with metastatic castration-resistant prostate cancer who had received docetaxel and undergone orchidectomy were evaluated in a randomized, placebo-controlled, multicenter phase III clinical trial. 1199 patients were randomized 2:1 to receive enzalutamide at a dose of 160 mg once daily (N = 800) or placebo once daily (N = 399). Patients could take prednisone, but it was not mandatory (maximum daily dose of prednisolone or equivalent dose was 10 mg). Patients randomized to each group continued treatment until disease progression (presence of radiographic progression or development of bone complications) and initiation of new systemic antineoplastic therapy or until development of intolerable toxicity or withdrawal.

Demographic characteristics of patients and baseline disease characteristics were balanced between treatment groups. The median age was 69 years (41–92 years), and the racial distribution was as follows: 93% of patients were Caucasian, 4% were African American, 1% were Asian, and 2% were other races. ECOG performance status score was 0–1 in 91.5% of patients and 2 in 8.5% of patients; 28% of patients had a score ≥4 on the Brief Pain Inventory (short form) (patients reported increased pain over the past 24 hours, assessed over 7 days prior to randomization). Bone metastases were present in the majority of patients (91%), and visceral involvement of lungs and/or liver was present in 23%. At study entry, 41% of patients had progression only by PSA levels, while 59% had progression by radiographic data. At study entry, 51% of patients were receiving bisphosphonates.

Patients with medical conditions that could predispose to seizures (see section "Adverse Reactions") were excluded from the AFFIRM study, as were patients taking medications that may lower the seizure threshold, and patients with clinically significant cardiovascular diseases such as uncontrolled hypertension, myocardial infarction or unstable angina in the past, heart failure (NYHA class III or IV without ejection fraction ≥45%), clinically significant ventricular arrhythmia, or AV block without a permanent pacemaker. The protocol-specified interim analysis after 520 deaths showed a statistically significant advantage of enzalutamide use regarding overall survival. A statistically significant clinical advantage was observed in patients receiving enzalutamide compared to patients receiving placebo (median survival was 18.4 and 13.6 months, respectively) [HR = 0.63 (95% CI: 0.53; 0.75), p < 0.0001]. In addition to the observed improvement in overall survival, key secondary endpoints (PSA progression, radiographic progression-free survival, and time to first skeletal complication) also showed an advantage for enzalutamide, with statistically significant results demonstrated by repeated testing.

Radiographic progression-free survival (investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, for soft tissues or appearance of 2 or more bone lesions on bone scan) was 8.3 months in patients receiving enzalutamide and 2.9 months in patients receiving placebo [HR = 0.40 (95% CI: 0.35; 0.47), p < 0.0001]. The analysis included 216 cases of death without documented disease progression and 645 cases of documented progression, of which 303 (47%) were related to soft tissues, 268 (42%) were due to progression of bone metastases, and 74 (11%) were related to involvement of both soft and bone tissues.

Confirmed PSA reduction by 50% or 90% was observed in 54% and 24.8% of patients receiving enzalutamide, respectively, and in 1.5% and 0.9% of patients receiving placebo, respectively (p < 0.0001). The median time to PSA progression was 8.3 months in patients receiving enzalutamide and 3 months in patients receiving placebo [HR = 0.25 (95% CI: 0.20; 0.30), p < 0.0001].

The median time to first skeletal complication was 16.7 months in patients receiving enzalutamide and 13.3 months in patients receiving placebo [HR = 0.69 (95% CI: 0.57; 0.84), p < 0.0001].

Skeletal complications were defined as radiation therapy or surgical intervention on bone tissue, presence of pathological bone fracture, spinal cord compression, or change in antineoplastic therapy for treatment of bone pain. The analysis included 448 skeletal complications, of which 277 (62%) were bone radiation therapy, 95 (21%) were spinal cord compression, 47 (10%) were pathological bone fractures, 36 (8%) were change in antineoplastic therapy for treatment of bone pain, and 7 (2%) were surgical intervention on bone.

Study 9785-CL-0410 (enzalutamide after abiraterone in patients with metastatic CRPC)

The study included 214 patients with progressive metastatic prostate cancer who received enzalutamide (160 mg once daily) after completing a course of treatment lasting at least 24 weeks with abiraterone acetate plus prednisolone. The median radiographic progression-free survival (primary endpoint of the study) was 8.1 months (95% CI: 6.1; 8.3). Median OS was not reached. PSA response (defined as ≥50% reduction from baseline) was observed in 22.4% of patients (95% CI: 17; 28.6). For 69 patients who had previously received chemotherapy, the median radiographic progression-free survival was 7.9 months (95% CI: 5.5; 10.8). PSA response was observed in 23.2% of patients (95% CI: 13.9; 34.9). For 145 patients who had not previously received chemotherapy, the median radiographic progression-free survival was 8.1 months (95% CI: 5.7; 8.3). PSA response was observed in 22.1% of patients (95% CI: 15.6; 29.7). Limited response to enzalutamide treatment after abiraterone was observed in some patients, although the reason for this is currently unknown. The study design did not allow identification of patients who may benefit from treatment or the optimal sequence in which enzalutamide and abiraterone should be sequentially administered to achieve optimal outcomes.

Elderly patients

Of the 4403 patients who received enzalutamide in phase III studies, 3451 patients (78%) were aged 65 years or older, including 1540 patients (35%) aged over 75 years. No differences in safety and efficacy of enzalutamide use were observed between elderly and younger patients.

Pharmacokinetics

Enzalutamide has poor water solubility. The solubility of the drug substance is enhanced by the use of caprylocaproyl macrogolglycerides and an emulsifier/surfactant. In preclinical studies, absorption of enzalutamide was increased when dissolved in caprylocaproyl macroglycerides.

The pharmacokinetics of enzalutamide were studied in patients with prostate cancer and in healthy volunteers. The mean half-life (T1/2) of enzalutamide in patients after a single oral dose is 5.8 days (range 2.8 to 10.2 days), and steady-state concentration is reached approximately after one month. With daily oral administration, enzalutamide accumulates approximately 8.3 times faster than with a single dose. Daily fluctuations in plasma concentration are insignificant (peak-to-trough ratio 1.25). Elimination of enzalutamide is primarily via hepatic metabolism, forming an active metabolite that is as active as enzalutamide and circulates in plasma at approximately the same concentration as enzalutamide.

Absorption

Maximum plasma concentration (Cmax) of enzalutamide in patients was observed within 1–2 hours after administration. Based on mass balance studies in humans, oral absorption of enzalutamide was estimated to be at least 84.2%. Enzalutamide is not a substrate of efflux transporters P-glycoprotein or breast cancer resistance protein (BCRP). Steady-state, mean (Cmax) of enzalutamide and its active metabolite is 16.6 µg/mL (coefficient of variation (CV) 23%) and 12.7 µg/mL (CV 30%), respectively.

Food intake does not significantly affect the extent of enzalutamide absorption. In clinical trials, enzalutamide was administered independently of food intake.

Distribution

The mean volume of distribution (V/F) of enzalutamide in patients after a single oral dose is 110 L (29% CV). The volume of distribution of enzalutamide is greater than the total body fluid volume, indicating active distribution into peripheral tissues. Animal studies (rodents) showed that enzalutamide and its active metabolite can cross the blood-brain barrier.

Enzalutamide is 97–98% bound to plasma proteins, primarily to albumin. The active metabolite is 95% bound to plasma proteins. In vitro studies showed no displacement of protein binding between enzalutamide and other highly protein-bound drugs (warfarin, ibuprofen, and salicylic acid).

Metabolism

Enzalutamide is actively metabolized. Two major metabolites are present in human plasma: N-desmethylenzalutamide (active) and a carboxylic acid derivative (inactive). Enzalutamide is metabolized by CYP2C8 enzymes and to a lesser extent by CYP3A4/5, which play an important role in the formation of the active metabolite (see section "Interaction with other medicinal products and other types of interactions"). In vitro studies showed that N-desmethylenzalutamide is metabolized to the carboxylic acid metabolite by carboxylesterase 1, which also plays a minor role in the metabolism of enzalutamide to the carboxylic acid metabolite. N-desmethylenzalutamide was not metabolized by CYP enzymes in vitro. In clinical use, enzalutamide is a strong inducer of CYP3A4 enzyme, a moderate inducer of CYP2C9 and CYP2C19 enzymes, and has no clinically significant effect on CYP2C8 enzyme (see section "Interaction with other medicinal products and other types of interactions").

Elimination

The mean apparent clearance of enzalutamide in patients is 0.520 to 0.564 L/h. After oral administration of radiolabeled 14C-enzalutamide, 84.6% of the radioactive dose was excreted by day 77: 71% via kidneys (primarily as inactive metabolite with insignificant amounts of enzalutamide and active metabolite) and 13.6% via the intestine (0.39% of the dose of enzalutamide unchanged). In vitro laboratory data show that enzalutamide is not a substrate for OATP1B1, OATP1B3, or OST1, and N-desmethylenzalutamide is not a substrate for P-glycoprotein or BCRP.

In vitro laboratory studies show that enzalutamide and its major metabolites do not inhibit the following transporters at clinically relevant concentrations: OATP1B1, OATP1B3, OST2, or OAT1.

Linearity

In the dose range from 40 to 160 mg, no serious deviations from dose proportionality were observed. Steady-state Cmin values of enzalutamide and its active metabolite in individual patients remained unchanged for more than 1 year of continuous therapy, demonstrating time-linear pharmacokinetics after reaching steady-state.

Renal impairment

Studies on the use of enzalutamide in patients with renal impairment have not been conducted. Patients with serum creatinine levels >177 µmol/L (2 mg/dL) were excluded from clinical trials. According to population pharmacokinetic analysis, dose adjustment is not required for patients with creatinine clearance >30 mL/min (by Cockcroft-Gault formula). The efficacy of enzalutamide has not been studied in patients with severe renal impairment (creatinine clearance <30 mL/min) or end-stage renal disease; therefore, caution should be exercised when treating such patients. It is unlikely that enzalutamide will be significantly eliminated by intermittent hemodialysis or continuous ambulatory peritoneal dialysis.

Hepatic impairment

Hepatic impairment does not significantly affect the concentration of enzalutamide or its active metabolite. However, the elimination half-life of the drug was twice as long in patients with severe hepatic impairment compared to healthy volunteers (10.4 days vs. 4.7 days), possibly due to increased tissue distribution. The pharmacokinetics of enzalutamide were studied in patients with mild hepatic impairment (N = 6), moderate hepatic impairment (N = 8), or severe hepatic impairment (N = 8) (Child-Pugh classes A, B, and C, respectively) and in 22 patients in the control group with normal liver function. After a single oral dose of enzalutamide 160 mg, AUC and Cmax values of enzalutamide in patients with mild hepatic impairment increased by 5% and 24%, respectively, AUC and Cmax values of enzalutamide in patients with moderate impairment increased by 29% and decreased by 11%, respectively, and AUC and Cmax values of enzalutamide in patients with severe hepatic impairment increased by 5% and decreased by 41%, respectively, compared to the control group. AUC and Cmax of unbound enzalutamide and unbound active metabolites in patients with mild hepatic impairment increased by 14% and 19%, respectively, AUC and Cmax in patients with moderate hepatic impairment increased by 14% and decreased by 17%, respectively, and AUC and Cmax in patients with severe hepatic impairment increased by 34% and decreased by 27%, respectively, compared to the control group.

Race

The majority of patients participating in controlled clinical trials (>75%) were Caucasian. According to pharmacokinetic studies in patients with prostate cancer in Japan and China, no clinically significant differences were observed between populations. Data for assessing potential pharmacokinetic differences of enzalutamide depending on patient race are insufficient.

Elderly patients

No clinically significant effect of age on the pharmacokinetics of enzalutamide was observed.

Clinical characteristics

Indications

• Metastatic hormone-sensitive prostate cancer (mHSPC) in adult men as monotherapy or in combination with androgen deprivation therapy;
• Non-metastatic castration-resistant prostate cancer in adult men with a high risk of disease progression;
• Metastatic castration-resistant prostate cancer in adult men who are asymptomatic or have mild symptoms following prior androgen deprivation therapy, in the absence of clinical indications for chemotherapy;
• Metastatic castration-resistant prostate cancer in adult men whose disease has progressed during or after chemotherapy including docetaxel.

Contraindications

Hypersensitivity to the active substance or to any of the excipients. Contraindicated in pregnant women and women who may become pregnant (see section "Use in pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction

Medicinal products that may affect enzalutamide levels

Inhibitors of CYP2C8

The enzyme CYP2C8 plays an important role in the elimination of enzalutamide and in the formation of its active metabolite. Following oral administration of gemfibrozil, a potent inhibitor of CYP2C8 (600 mg twice daily), in healthy male volunteers, the AUC of enzalutamide increased by 326%, and the Cmax of enzalutamide decreased by 18%. The AUC of unbound enzalutamide and unbound active metabolite increased by 77%, while Cmax decreased by 19%. Concomitant use of enzalutamide with potent CYP2C8 inhibitors (e.g., gemfibrozil) should be avoided or used with caution. If a patient requires concomitant administration of a potent CYP2C8 inhibitor, the dose of enzalutamide should be reduced to 80 mg once daily (see section "Dosage and administration").

Inhibitors of CYP3A4

The enzyme CYP3A4 plays a minor role in enzalutamide metabolism. Following oral administration of itraconazole, a potent CYP3A4 inhibitor (200 mg once daily), in healthy male volunteers, the AUC of enzalutamide increased by 41%, while Cmax remained unchanged. The AUC of unbound enzalutamide and unbound active metabolite increased by 27%, while Cmax remained unchanged. Dose adjustment is not required when enzalutamide is co-administered with CYP3A4 inhibitors.

Inducers of CYP2C8 and CYP3A4

Following oral administration of rifampicin, a moderate inducer of CYP2C8 and a strong inducer of CYP3A4 (600 mg once daily), in healthy men, the AUC of enzalutamide and its active metabolite decreased by 37%, while Cmax remained unchanged. Dose adjustment is not required when enzalutamide is co-administered with inducers of CYP2C8 or CYP3A4.

Potential of enzalutamide to affect exposure to other medicinal products

Enzyme inducers

Enzalutamide is a strong inducer of enzymes that increases the synthesis of multiple enzymes and transporters; therefore, interactions with numerous medicinal products that are substrates of these enzymes or transporters are expected. Decreased plasma concentrations may be significant and lead to loss or reduction of clinical effect. There is also a risk of increased formation of active metabolites. Enzymes whose expression may be induced include hepatic and intestinal CYP3A, CYP2B6, CYP2C9, CYP2C19, and uridine-5’-diphosphate glucuronosyltransferase (UGTs – glucuronide-conjugating enzymes). Some transporters may also be induced, such as multidrug resistance-associated protein 2 (MRP2) and organic anion-transporting polypeptide 1B1 (OATP1B1).

In vivo studies have shown that enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. Concomitant administration of enzalutamide (160 mg once daily) in patients with prostate cancer resulted in an 86% reduction in AUC of midazolam (a CYP3A4 substrate), a 56% reduction in AUC of S-warfarin (a CYP2C9 substrate), and a 70% reduction in AUC of omeprazole (a CYP2C19 substrate). Induction of UGT1A1 is also possible. In a clinical study in patients with metastatic castration-resistant prostate cancer, enzalutamide (160 mg once daily) had no clinically significant effect on the pharmacokinetics of intravenously administered docetaxel (75 mg/m² infusion every 3 weeks). AUC of docetaxel decreased by 12% [geometric mean ratio (GMR) = 0.882 (90% CI: 0.767, 1.02)], while Cmax decreased by 4% [GMR = 0.963 (90% CI: 0.834, 1.11)].

Interactions with the following medicinal products, which are eliminated via metabolism or active transport, are also expected. Concomitant use of these medicinal products should be avoided or used with caution, especially when the therapeutic effect of these agents is critical and dose adjustment based on monitoring efficacy or blood concentration levels is difficult. The risk of liver injury after acetaminophen (paracetamol) use is considered higher in patients receiving concomitant enzyme inducers.

Medicinal products that may interact with enzalutamide include the following groups:

• Analgesics (e.g., fentanyl, tramadol)
• Antibiotics (e.g., clarithromycin, doxycycline)
• Antineoplastic agents (e.g., cabazitaxel)
• Antiepileptic drugs (e.g., carbamazepine, clonazepam, phenytoin, primidone, valproic acid)
• Antipsychotic medicinal products (e.g., haloperidol)
• Antithrombotic agents (e.g., acenocoumarol, warfarin, clopidogrel)
• Beta-blockers (e.g., bisoprolol, propranolol)
• Calcium channel blockers (e.g., diltiazem, felodipine, nicardipine, nifedipine, verapamil)
• Cardiac glycosides (e.g., digoxin)
• Corticosteroids (e.g., dexamethasone, prednisolone)
• Antiviral medicinal products for HIV infection (e.g., indinavir, ritonavir)
• Sedatives (e.g., diazepam, midazolam, zolpidem)
• Immunosuppressants (e.g., tacrolimus)
• Proton pump inhibitors (e.g., omeprazole)
• Statins metabolized by CYP3A4 (e.g., atorvastatin, simvastatin)
• Thyroid agents (e.g., levothyroxine)

The full induction potential of enzalutamide may become apparent approximately one month after initiation of treatment, following achievement of stable plasma concentrations, although some induction effect may occur earlier. In patients taking medicinal products that are substrates of CYP2B6, CYP3A4, CYP2C9, CYP2C19, or UGT1A1, the potential reduction in pharmacological effect (or increased effect if active metabolites are formed) should be evaluated during the first month of enzalutamide treatment, and doses adjusted accordingly. Due to the long elimination half-life of enzalutamide (5.8 days, see section "Dosage and administration"), the effect on enzymes may persist for one month or longer after discontinuation of enzalutamide. Upon discontinuation of enzalutamide, dose reduction of concomitant medicinal products may be necessary.

Substrates of CYP1A2 and CYP2C8

Enzalutamide (160 mg once daily) does not cause clinically significant changes in AUC or Cmax of caffeine (a CYP1A2 substrate) or pioglitazone (a CYP2C8 substrate). The AUC of pioglitazone increased by 20%, while Cmax decreased by 18%. AUC and Cmax of caffeine decreased by 11% and 4%, respectively. Dose adjustment is not required when substrates of CYP1A2 or CYP2C8 are co-administered with enzalutamide.

Substrates of P-glycoprotein

In vitro data indicate that enzalutamide may be an inhibitor of the efflux transporter P-glycoprotein. A moderate inhibitory effect of enzalutamide at steady state on P-glycoprotein was observed in a study involving patients with prostate cancer who received a single oral dose of the probe P-glycoprotein substrate digoxin before and concurrently with enzalutamide (concomitant administration followed by 160 mg enzalutamide once daily for at least 55 days). AUC and Cmax of digoxin increased by 33% and 17%, respectively. Digoxin plasma levels were measured using a validated liquid chromatography-tandem mass spectrometry method.

Effect on laboratory tests

In patients receiving enzalutamide, falsely elevated plasma digoxin levels were detected using microparticle chemiluminescent immunoassay (CMIA), regardless of digoxin treatment. Therefore, digoxin plasma concentration results obtained by CMIA should be interpreted with caution and confirmed by another assay type before any dose adjustments are made. Caution should be exercised when co-administering enzalutamide with medicinal products having a narrow therapeutic index that are P-glycoprotein substrates (e.g., colchicine, dabigatran etexilate, digoxin), and dose adjustments may be required to maintain optimal plasma concentrations.

Substrates of breast cancer resistance protein (BCRP)

At steady state, enzalutamide did not cause a clinically significant change in exposure to rosuvastatin, a probe substrate of breast cancer resistance protein (BCRP), in patients with prostate cancer who received a single oral dose of rosuvastatin before and concurrently with enzalutamide (concomitant administration followed by 160 mg enzalutamide once daily for at least 55 days). AUC of rosuvastatin decreased by 14%, while Cmax increased by 6%. Dose adjustment is not required when BCRP substrates are used concomitantly with enzalutamide.

Substrates of multidrug resistance-associated proteins 2 (MRP2), human organic anion transporter 3 (OAT3), and human organic cation transporter 1 (OCT1)

Based on in vitro laboratory data, inhibition of MRP2 (in the intestine), as well as organic anion transporter 3 (OAT3) and organic cation transporter 1 (OCT1) (systemic) cannot be excluded. Theoretical induction of these transporters is possible; the overall impact is currently unknown.

Medicinal products that prolong QT interval

Since androgen deprivation therapy may prolong the QT interval, the risks of concomitant use of enzalutamide with QT-prolonging agents and medicinal products associated with risk of torsade de pointes arrhythmia, such as class IA antiarrhythmics (e.g., quinidine, disopyramide) or class III (e.g., amiodarone, sotalol, dofetilide, ibutilide), methadone, moxifloxacin, neuroleptics, etc., should be carefully evaluated (see section "Special precautions for use").

Effect of food on enzalutamide exposure

Food intake has no clinically significant effect on the extent of enzalutamide absorption.

Special Warnings and Precautions for Use

Seizure Risk

The use of enzalutamide has been associated with cases of seizure (see section "Adverse Reactions"). The decision regarding continuation of therapy following a seizure should be considered individually for each patient.

Posterior Reversible Encephalopathy Syndrome (PRES)

Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving the medicinal product (see section "Adverse Reactions"). PRES is a rare, reversible neurological disorder characterized by rapidly developing symptoms such as seizures, headache, confusion, blindness, and other visual and neurological disturbances, with or without hypertension. Diagnosis of PRES should be confirmed by brain imaging, preferably MRI. If diagnosis is confirmed, the medicinal product should be discontinued.

Other Primary Malignancies

In clinical trials, cases of other primary malignant neoplasms have been reported in patients receiving enzalutamide. In phase III clinical trials, the most frequently reported cases among patients receiving enzalutamide were bladder cancer (0.3%), colorectal adenocarcinoma (0.2%), transitional cell carcinoma (0.2%), and malignant melanoma (0.2%).

Patients should be advised to seek immediate medical attention if gastrointestinal bleeding, macroscopic hematuria, or other symptoms such as dysuria or urinary urgency occur during enzalutamide treatment.

Concomitant Use with Other Medicinal Products

Enzalutamide is a strong inducer of enzymes and may reduce the efficacy of many commonly used medicinal products (see section "Interaction with Other Medicinal Products and Other Forms of Interaction"). Therefore, a review of concomitantly administered medicinal products should be conducted prior to initiating enzalutamide therapy.

In general, concomitant use of enzalutamide with medicinal products that are sensitive substrates of key metabolizing enzymes or transporters should be avoided (see section "Interaction with Other Medicinal Products and Other Forms of Interaction"); if the therapeutic effect of these medicinal products is critical for the patient and dose adjustment based on monitoring of efficacy or plasma concentrations is difficult, their use should be avoided or administered with caution.

Concomitant use of enzalutamide with warfarin and coumarin-like anticoagulants should be avoided. When enzalutamide is used concomitantly with anticoagulants metabolized by CYP2C9 (such as warfarin or acenocoumarol), additional monitoring of the international normalized ratio (INR) is required (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Renal Impairment

Caution should be exercised when administering enzalutamide to patients with severe renal impairment, as enzalutamide has not been studied in such patients.

Severe Hepatic Impairment

In patients with severe hepatic impairment, an increased elimination half-life of the drug has been observed, possibly related to tissue distribution. The clinical significance of this observation is unknown. It may take longer to reach steady-state concentrations and maximum pharmacological effect, as well as longer time for enzyme induction to begin and diminish (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Recent Cardiovascular Disease

Phase III trials did not include patients who had recently experienced myocardial infarction (within the last 6 months) or patients with unstable angina (within the last 3 months), patients with NYHA Class III–IV heart failure, except those with left ventricular ejection fraction (LVEF) ≥45%, bradycardia, or uncontrolled hypertension. These data should be considered when prescribing the medicinal product to such patients.

Androgen Deprivation Therapy May Prolong the QT Interval

In patients with prolonged QT interval or risk factors for QT prolongation, and in patients receiving concomitant therapy with medicinal products that may prolong the QT interval (see section "Interaction with Other Medicinal Products and Other Forms of Interaction"), the physician should assess the benefit-risk ratio before prescribing the medicinal product, including the potential risk of developing torsades de pointes ventricular tachycardia.

Concomitant Use with Chemotherapy

The safety and efficacy of concomitant use of the medicinal product with cytotoxic chemotherapy have not been evaluated. Concomitant use of enzalutamide has no clinically significant effect on the pharmacokinetics of intravenously administered docetaxel (see section "Interaction with Other Medicinal Products and Other Forms of Interaction"), but an increased incidence of docetaxel-induced neutropenia cannot be excluded.

Severe Skin Reactions

Severe skin adverse reactions, including Stevens-Johnson syndrome, have been reported during treatment with enzalutamide, which may be life-threatening or fatal.

Patients should be informed about the signs and symptoms of such reactions and closely monitored for skin reactions during treatment.

If signs or symptoms suggestive of such a reaction occur, enzalutamide should be discontinued immediately and alternative treatment considered (if needed).

Hypersensitivity Reactions

Allergic reactions have been observed with enzalutamide, manifesting as symptoms including rash, facial swelling, tongue swelling, lip and throat swelling (see section "Adverse Reactions"). Serious skin adverse reactions have been reported with enzalutamide. Patients should be informed of these signs and symptoms and closely monitored for skin reactions during enzalutamide therapy.

Dosage Form-Related Dysphagia

Reports have been received of patients experiencing difficulty swallowing the medicinal product, including choking episodes. Difficulty swallowing and choking episodes were mostly observed with the capsule formulation, possibly related to capsule size. Patients should be advised to swallow capsules whole with sufficient water.

Patients who have difficulty swallowing large capsules or have a history of dysphagia are recommended to use enzalutamide tablet formulations.

Important Information on Excipients

This medicinal product contains 16.25 mg of sodium (40 mg tablets) and 32.5 mg of sodium (80 mg tablets). Caution is advised when administering to patients on a sodium-restricted diet.

Use During Pregnancy or Breastfeeding

Women of Reproductive Potential

There are no data on the use of enzalutamide in pregnant women, and this medicinal product is not intended for use in women of reproductive potential. The medicinal product may cause harm to the unborn child or potential pregnancy loss if used during pregnancy.

Contraception in Men and Women

It is unknown whether enzalutamide or its metabolites are present in semen. If a patient has sexual intercourse with a pregnant woman, condoms should be used during enzalutamide treatment and for 3 months after discontinuation of enzalutamide. If a patient has sexual contact with a woman of reproductive potential, condoms and other effective contraceptive methods should be used during treatment and for 3 months after stopping enzalutamide. Animal studies indicate reproductive toxicity.

Pregnancy and Lactation

Enzalutamide should not be used in women. Enzalutamide is contraindicated in pregnant women and women of reproductive potential (see section "Contraindications"). It is unknown whether enzalutamide is present in human breast milk. However, enzalutamide and/or its metabolites are present in the milk of rats.

Fertility

Animal studies have shown that enzalutamide affects the reproductive system in male rats and dogs.

Ability to Affect Reaction Time While Driving or Operating Machinery

No studies on the effects of enzalutamide on the ability to drive or operate machinery have been conducted. However, enzalutamide may have a moderate influence on the ability to drive and operate machinery, as psychiatric and neurological adverse reactions, including seizures, have been reported (see section "Adverse Reactions"). Patients should be informed about possible psychiatric or neurological adverse reactions that may occur while driving or operating machinery.

Method of Administration and Dosage

Enzalutamide treatment should be initiated and supervised by specialist physicians experienced in the medical management of prostate cancer.

Dosage

The recommended dose of enzalutamide is 160 mg (4 film-coated tablets of 40 mg or 2 film-coated tablets of 80 mg) orally once daily. Medical castration using a gonadotropin-releasing hormone (GnRH) agonist should be continued during treatment in patients who have not undergone surgical castration.

The medicinal product is intended for oral administration. Film-coated tablets must not be chewed, dissolved, or divided; they should be swallowed whole with water. Film-coated tablets may be taken with or without food. If a patient misses a dose at the usual time, the prescribed dose should be taken as soon as possible up to the usual time. If a patient misses a dose for the entire day, treatment should be resumed the next day with the usual daily dose. If a patient develops toxicity (grade III or higher) or life-threatening adverse reactions, administration of the drug should be discontinued for one week or until symptoms resolve (to grade II toxicity or lower), and then, if appropriate, treatment should be resumed at the same or a reduced dose (120 mg or 80 mg).

Patients at high risk of biochemical recurrence (BCR) with non-metastatic castration-sensitive prostate cancer (nmHSPC) may receive enzalutamide with or without a GnRH analogue. For patients receiving enzalutamide with or without a GnRH analogue, treatment may be interrupted if PSA is undetectable (<0.2 ng/mL) after 36 weeks of therapy. Treatment should be resumed when PSA increases to ≥2.0 ng/mL in patients who previously underwent radical prostatectomy, or to ≥5.0 ng/mL in patients who previously received primary radiation therapy. If PSA is detectable (≥0.2 ng/mL) after 36 weeks of therapy, treatment should be continued.

If a patient misses a dose of enzalutamide at the usual time, the prescribed dose should be taken as close as possible to the usual time. If a patient misses a dose for the entire day, treatment should be resumed the next day with the usual daily dose.

If a patient develops ≥grade 3 toxicity or intolerable adverse reactions, administration should be interrupted for one week or until symptoms improve to ≤grade 2, and then, if appropriate, resumed at the same or reduced dose (80 mg or 120 mg).

Concomitant use with strong CYP2C8 enzyme inhibitors

Concomitant use of strong CYP2C8 enzyme inhibitors should be avoided if possible. If a patient must take a strong CYP2C8 enzyme inhibitor concomitantly, the dose of enzalutamide should be reduced to 80 mg once daily. When discontinuation of the strong CYP2C8 enzyme inhibitor occurs, the enzalutamide dose should be returned to the dose used prior to initiating the strong CYP2C8 inhibitor (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Elderly Patients

No dose adjustment is necessary for elderly patients (see sections "Pharmacodynamics", "Pharmacokinetics").

Hepatic Impairment

No dose adjustment is required for patients with mild, moderate, or severe hepatic impairment (Child–Pugh classes A, B, and C, respectively), although prolonged elimination half-life of enzalutamide has been observed in patients with severe hepatic impairment (see sections "Special Warnings and Precautions for Use", "Pharmacokinetic Properties").

Renal Impairment

No dose adjustment is required for patients with mild or moderate renal impairment (see section "Pharmacokinetics"). Caution should be exercised in patients with severe renal impairment or end-stage renal disease (see section "Special Warnings and Precautions for Use").

Children

Enzalutamide is not indicated for use in children, as the therapeutic indications are intended for adult males with prostate cancer and mCRPC.

Route of Administration

The medicinal product is intended for oral use. Film-coated tablets must not be chewed, dissolved, or divided; they should be swallowed whole with water. Film-coated tablets may be taken with or without food.

Children

The medicinal product is not intended for use in children.

Overdose

Symptoms. In the event of overdose, patients may be at increased risk of seizures.

Treatment. There is no specific antidote for enzalutamide. Enzalutamide treatment should be discontinued in the event of overdose, and appropriate supportive measures should be implemented, taking into account the elimination half-life of 5.8 days.

Adverse reactions

The most commonly reported adverse reactions were asthenia/fatigue, hot flushes, hypertension, fractures, and falls. Other important adverse reactions included ischemic heart disease and seizures.

Seizures occurred in 0.6% of patients receiving enzalutamide, in 0.1% of patients receiving placebo, and in 0.3% of patients receiving bicalutamide.

Posterior reversible encephalopathy syndrome (PRES) has been reported rarely during treatment with enzalutamide (see section "Special precautions").

Stevens-Johnson syndrome has been reported during treatment with enzalutamide (see section "Special precautions").

The adverse reactions listed below are classified by frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); not known (cannot be estimated from the available data). Adverse reactions within each frequency category are listed in order of decreasing severity.

Adverse reactions observed during clinical trials or in post-marketing surveillance.

System organ class according to MedDRA classification	Frequency
Blood and lymphatic system disorders	Uncommon: leukopenia, neutropenia Unknown*: thrombocytopenia
Immune system disorders	Unknown*: facial swelling, tongue swelling, lip swelling, pharyngeal swelling
Psychiatric disorders	Common: anxiety Uncommon: visual hallucinations
Nervous system disorders	Common: headache, memory impairment, amnesia, attention disturbance, dysgeusia, restless legs syndrome Uncommon: cognitive disorders, convulsions1 Unknown*: posterior reversible encephalopathy syndrome
Cardiac disorders	Common: ischaemic heart disease2 Unknown*: QT interval prolongation (see sections "Special warnings and precautions for use", "Interaction with other medicinal products and other forms of interaction")
Vascular disorders	Very common: flushing, hypertension
Gastrointestinal disorders	Unknown*: nausea, vomiting, diarrhea, dysphagia
Hepatobiliary disorders	Uncommon: increased levels of liver enzymes
Skin and subcutaneous tissue disorders	Common: dry skin, pruritus Unknown*: erythema multiforme, rash, Stevens-Johnson syndrome.
Musculoskeletal and connective tissue disorders	Very common: fractures** Unknown*: myalgia, muscle spasms, muscle weakness, back pain
Reproductive system and breast disorders	Common: gynecomastia, nipple pain***, breast tenderness***.
General disorders and administration site conditions	Very common: asthenia / fatigue
Injury, poisoning and procedural complications	Very common: falls

* Spontaneous cases from post-marketing surveillance.

1Assessment using the narrow SMQ term "convulsions", including convulsions, grand mal convulsions, complex partial seizures, partial seizures, and epileptic status. Includes rare cases of convulsions with complications leading to fatal outcomes.

2Assessment using the narrow SMQ terms "Myocardial infarction" and "Other forms of ischemic heart disease", including such defined terms used to describe adverse reactions observed in at least two patients in randomized placebo-controlled Phase III studies: angina pectoris, ischemic heart disease, myocardial infarction, acute myocardial infarction, acute coronary syndrome, unstable angina, myocardial ischemia, and coronary arteriosclerosis.

**Includes all cases described as bone fractures.

***Cases during monotherapy with enzalutamide.

Description of selected adverse reactions

Convulsions

During controlled clinical trials, convulsions were reported in 31 (0.6%) of 4403 patients receiving 160 mg of enzalutamide daily, in 4 patients (0.1%) receiving placebo, and in one patient (0.3%) receiving bicalutamide. Dose is an important predictor of seizure risk, as indicated by preclinical data and dose-escalation studies. Patients with a history of seizures or risk factors for seizures were excluded from both studies.

The single-arm clinical trial 9785-CL-0403 (UPWARD) evaluated the occurrence of convulsions in patients with risk factors for seizures (1.6% had a history of seizures). Convulsions occurred in 8 (2.2%) of 366 patients receiving enzalutamide. The median duration of treatment was 9.3 months. The mechanism by which enzalutamide may lower the seizure threshold is unknown. In vitro data suggest that enzalutamide and its active metabolites bind to and may inhibit the activity of gamma-aminobutyric acid (GABA) chloride channels.

Ischemic heart disease

In randomized placebo-controlled clinical trials, ischemic heart disease was observed in 3.5% of patients receiving enzalutamide plus androgen deprivation therapy, compared to 2% of patients receiving placebo plus androgen deprivation therapy.

Ischemic heart disease with complications leading to fatal outcomes occurred in 15 (0.4%) patients receiving enzalutamide and in 3 (0.1%) patients receiving placebo.

In the EMBARK study, ischemic heart disease occurred in 5.4% of patients receiving enzalutamide plus leuprolide and in 9% of patients receiving enzalutamide as monotherapy. Ischemic heart disease leading to fatal outcomes did not occur in any patient receiving enzalutamide plus leuprolide and occurred in one (0.3%) patient receiving enzalutamide as monotherapy.

Gynecomastia

In the EMBARK study, gynecomastia (all grades) was observed in 29 of 353 patients (8.2%) receiving enzalutamide plus leuprolide and in 159 of 354 patients (44.9%) receiving enzalutamide as monotherapy. Grade 3 or higher gynecomastia was not observed in any patient receiving enzalutamide plus leuprolide and was observed in 3 patients (0.8%) receiving enzalutamide as monotherapy.

Nipple pain

In the EMBARK study, nipple pain (all grades) was reported in 11 of 353 patients (3.1%) receiving enzalutamide plus leuprolide and in 54 of 354 patients (15.3%) receiving enzalutamide as monotherapy. Grade 3 or higher nipple pain was not observed in any patient receiving enzalutamide plus leuprolide or enzalutamide monotherapy.

Chest pain

In the EMBARK study, breast tenderness (all grades) was observed in 5 of 353 patients (1.4%) receiving enzalutamide plus leuprolide and in 51 of 354 patients (14.4%) receiving enzalutamide as monotherapy. Grade 3 or higher chest pain was not observed in any patient receiving enzalutamide plus leuprolide or enzalutamide monotherapy.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. No special storage conditions required. Keep out of reach of children.

Packaging. 28 tablets in a blister, 4 blisters in a cardboard pack for the 40 mg dosage. 14 tablets in a blister, 4 blisters in a cardboard pack for the 80 mg dosage.

Prescription status. Prescription only.

Manufacturer

FAROS MT Limited.

Manufacturer's address and location of operations

Hf62x, Hal Far Industrial Estate, Hal Far, Birzebbuga, BBG 3000, Malta.