Xtandi (Page 5 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A two-year carcinogenicity study was conducted in male and female rats at oral enzalutamide doses of 10, 30, and 100 mg/kg/day. Enzalutamide increased the incidence of benign Leydig cell tumors in the testes at all dose levels tested (≥ 0.3 times the human exposure based on AUC) and combined incidence of urothelial papilloma and carcinoma in the urinary bladder in male rats at 100 mg/kg/day (1.4 times the human exposure based on AUC). The findings in the testes are considered to be related to the pharmacological activity of enzalutamide. Rats are regarded as more sensitive than humans to developing interstitial cell tumors in the testes. Administration of enzalutamide to male and female rasH2 transgenic mice by oral gavage daily for 26 weeks did not result in increased incidence of neoplasms at doses up to 20 mg/kg/day.

Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma thymidine kinase (Tk) gene mutation assay or the in vivo mouse micronucleus assay.

Based on nonclinical findings in repeat-dose toxicology studies, which were consistent with the pharmacological activity of enzalutamide, male fertility may be impaired by treatment with XTANDI. In a 26-week study in rats, atrophy of the prostate and seminal vesicles was observed at ≥ 30 mg/kg/day (equal to the human exposure based on AUC). In 4-, 13-, and 39-week studies in dogs, hypospermatogenesis and atrophy of the prostate and epididymides were observed at ≥ 4 mg/kg/day (0.3 times the human exposure based on AUC).

14 CLINICAL STUDIES

The efficacy of XTANDI in patients with CRPC (N = 4692) or mCSPC (N = 1150) was demonstrated in five randomized, multicenter clinical trials. All patients received concomitant GnRH therapy or had prior bilateral orchiectomy. Patients were allowed, but not required, to continue or initiate glucocorticoids.

AFFIRM (NCT00974311): XTANDI versus Placebo in Metastatic CRPC Following Chemotherapy

In AFFIRM, a total of 1199 patients who had received prior docetaxel-based chemotherapy were randomized 2:1 to receive either XTANDI orally at a dose of 160 mg once daily (N = 800) or placebo orally once daily (N = 399). Study treatment continued until disease progression (evidence of radiographic progression, a skeletal-related event, or clinical progression), initiation of new systemic antineoplastic treatment, unacceptable toxicity, or withdrawal. Patients with a previous history of seizure, taking medicines known to decrease the seizure threshold, or with other risk factors for seizure were not eligible [see Warnings and Precautions (5.1)].

The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 69 years (range 41-92) and the racial distribution was 92.7% Caucasian, 3.9% Black, 1.1% Asian, and 2.1% Other. Ninety-two percent of patients had an ECOG performance status score of 0-1 and 28% had a mean Brief Pain Inventory score of ≥ 4. Ninety-one percent of patients had metastases in bone and 23% had visceral involvement in the lung and/or liver. Fifty-nine percent of patients had radiographic evidence of disease progression and 41% had PSA-only progression on study entry. All patients had received prior docetaxel-based therapy and 24% had received two cytotoxic chemotherapy regimens. During the trial, 48% of patients on the XTANDI arm and 46% of patients on the placebo arm received glucocorticoids.

A statistically significant improvement in overall survival was demonstrated at the pre-specified interim analysis at the time of 520 deaths in patients on the XTANDI arm compared to patients on the placebo arm (Table 7 and Figure 3).

Table 7. Overall Survival of Patients Treated with Either XTANDI or Placebo in AFFIRM
NR = Not reached.
*
P-value is derived from a log-rank test stratified by baseline ECOG performance status score (0-1 vs. 2) and mean baseline pain score (BPI-SF score < 4 vs. ≥ 4).
Hazard Ratio is derived from a stratified proportional hazards model. Hazard Ratio < 1 favors XTANDI.

XTANDI

(N = 800)

Placebo

(N = 399)

Number of Deaths (%)

308 (38.5)

212 (53.1)

Median Survival, months (95% CI)

18.4 (17.3, NR)

13.6 (11.3, 15.8)

P-value *

p < 0.0001

Hazard Ratio (95% CI)

0.63 (0.53, 0.75)

Figure 3. Kaplan-Meier Curves of Overall Survival in AFFIRM
(click image for full-size original)

Figure 3. Kaplan-Meier Curves of Overall Survival in AFFIRM

PREVAIL (NCT01212991): XTANDI versus Placebo in Chemotherapy-naïve Metastatic CRPC

In PREVAIL, 1717 chemotherapy-naïve patients were randomized 1:1 to receive either XTANDI orally at a dose of 160 mg once daily (N = 872) or placebo orally once daily (N = 845). Patients with visceral metastases, patients with a history of mild to moderate heart failure (NYHA class I or II), and patients taking medications associated with lowering the seizure threshold were allowed. Patients with a previous history of seizure or a condition that might predispose to seizure and patients with moderate or severe pain from prostate cancer were excluded. Study treatment continued until disease progression (evidence of radiographic progression, a skeletal-related event, or clinical progression) and the initiation of a cytotoxic chemotherapy or an investigational agent, unacceptable toxicity, or withdrawal. Overall survival and radiographic progression-free survival (rPFS) were assessed. Radiographic progression was assessed with the use of sequential imaging and was defined by bone scan identification of 2 or more new bone lesions with confirmation (Prostate Cancer Clinical Trials Working Group 2 criteria) and/or Response Evaluation Criteria in Solid Tumors (RECIST v 1.1) criteria for progression of soft tissue lesions. The primary analysis of rPFS utilized centrally reviewed radiographic assessment of progression.

Patient demographics and baseline disease characteristics were balanced between the treatment arms at entry. The median age was 71 years (range 42-93) and the racial distribution was 77% Caucasian, 10% Asian, 2% Black and 11% Other. The ECOG performance status score was 0 for 68% of patients, and 1 for 32% of patients. Baseline pain assessment was 0-1 (asymptomatic) in 67% of patients, and 2-3 (mildly symptomatic) in 32% of patients as defined by the Brief Pain Inventory Short Form (worst pain over past 24 hours at study entry). Fifty-four percent of patients had radiographic evidence of disease progression and 43% had PSA-only progression. Twelve percent of patients had visceral (lung and/or liver) disease involvement. During the study, 27% of patients on the XTANDI arm and 30% of patients on the placebo arm received glucocorticoids for varying reasons.

A statistically significant improvement in overall survival was demonstrated at the pre-specified interim analysis, conducted after 540 deaths in patients treated with XTANDI compared to those treated with placebo (Table 8). Forty percent of XTANDI-treated and 70% of placebo-treated patients received subsequent therapies for metastatic CRPC that may prolong overall survival. An updated survival analysis was conducted when 784 deaths were observed. The median follow-up time was 31 months. Results from this analysis were consistent with those from the pre-specified interim analysis (Table 8, Figure 4). At the updated analysis, 52% of XTANDI-treated and 81% of placebo-treated patients had received subsequent therapies that may prolong overall survival in metastatic CRPC. XTANDI was used as a subsequent therapy in 2% of XTANDI-treated patients and 29% of placebo-treated patients.

Table 8. Overall Survival of Patients Treated with Either XTANDI or Placebo in PREVAIL
NR = Not reached.
*
The data cutoff date is 16 Sep 2013.
P-value is derived from an unstratified log-rank test.
Hazard Ratio is derived from an unstratified proportional hazards model. Hazard Ratio < 1 favors XTANDI.
§
The data cutoff date is 1 Jun 2014. The planned number of deaths for the final overall survival analysis was ≥ 765.

XTANDI

(N = 872)

Placebo

(N = 845)

Pre-specified Interim Analysis *

Number of Deaths (%)

241 (28)

299 (35)

Median Survival, months (95% CI)

32.4 (30.1, NR)

30.2 (28.0, NR)

P-value

p < 0.0001

Hazard Ratio (95% CI)

0.71 (0.60, 0.84)

Updated Survival Analysis §

Number of Deaths (%)

368 (42)

416 (49)

Median Survival, months (95% CI)

35.3 (32.2, NR)

31.3 (28.8, 34.2)

Hazard Ratio (95% CI)

0.77 (0.67, 0.88)

Figure 4. Kaplan-Meier Curves of Overall Survival in PREVAIL
(click image for full-size original)

Figure 4. Kaplan-Meier Curves of Overall Survival in PREVAIL

A statistically significant improvement in rPFS was demonstrated in patients treated with XTANDI compared to patients treated with placebo (Table 9, Figure 5).

Table 9. Radiographic Progression-free Survival of Patients Treated with Either XTANDI or Placebo in PREVAIL
NR = Not reached.Note: As of the cutoff date for the rPFS analysis, 1633 patients had been randomized.
*
P-value is derived from an unstratified log-rank test.
Hazard Ratio is derived from an unstratified proportional hazards model. Hazard Ratio < 1 favors XTANDI.

XTANDI

(N = 832)

Placebo

(N = 801)

Number of Progression or Deaths (%)

118 (14)

320 (40)

Median rPFS (months) (95% CI)

NR (13.8, NR)

3.7 (3.6, 4.6)

P-value *

p < 0.0001

Hazard Ratio (95% CI)

0.17 (0.14, 0.21)

Figure 5. Kaplan-Meier Curves of Radiographic Progression-free Survival in PREVAIL
(click image for full-size original)

Figure 5. Kaplan-Meier Curves of Radiographic Progression-free Survival in PREVAIL

Time to initiation of cytotoxic chemotherapy was prolonged after XTANDI treatment, with a median of 28.0 months for patients on the XTANDI arm versus a median of 10.8 months for patients on the placebo arm [HR = 0.35 (95% CI: 0.30, 0.40), p < 0.0001].

The median time to first skeletal‑related event was 31.1 months for patients on the XTANDI arm versus 31.3 months for patients on the placebo arm [HR = 0.72 (95% CI: 0.61, 0.84), p < 0.0001]. A skeletal‑related event was defined as radiation therapy or surgery to bone for prostate cancer, pathologic bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain.

TERRAIN (NCT01288911): XTANDI versus Bicalutamide in Chemotherapy-naïve Metastatic CRPC

TERRAIN was conducted in 375 chemotherapy-naïve patients who were randomized 1:1 to receive either XTANDI orally at a dose of 160 mg once daily (N = 184) or bicalutamide orally at a dose of 50 mg once daily (N = 191). Patients with a previous history of seizure or a condition that might predispose to seizure and patients with moderate to severe pain from prostate cancer were excluded. Patients could have received prior bicalutamide, but those whose disease had progressed on prior antiandrogen therapy (e.g., bicalutamide) were excluded. Study treatment continued until disease progression (evidence of radiographic progression, a skeletal-related event), the initiation of subsequent antineoplastic agent, unacceptable toxicity, or withdrawal. Radiographic disease progression was assessed by Independent Central Review (ICR) using the Prostate Cancer Clinical Trials Working Group 2 criteria and/or Response Evaluation Criteria in Solid Tumors (RECIST v 1.1) criteria for progression of soft tissue lesions. Radiographic progression-free survival (rPFS) was defined as the time from randomization to the first objective evidence of radiographic progression as assessed by ICR or death, whichever occurred first.

Patient demographics and baseline disease characteristics were balanced between the treatment arms at entry. The median age was 71 years (range 48-96) and the racial distribution was 93% Caucasian, 5% Black, 1% Asian and 1% Other. The ECOG performance status score was 0 for 74% of patients and 1 for 26% of patients. Baseline pain assessment was 0‑1 (asymptomatic) in 58% of patients, and 2‑3 (mildly symptomatic) in 36% of patients as defined by the Brief Pain Inventory Short Form Question 3 (worst pain over past 24 hours at study entry). Ninety-eight percent of patients had objective evidence of disease progression at study entry. Forty-six percent of patients had received prior treatment with bicalutamide while no patients received prior treatment with XTANDI.

An improvement in rPFS was demonstrated in patients treated with XTANDI compared to patients treated with bicalutamide (Table 10, Figure 6).

Table 10. Radiographic Progression-free Survival of Patients in TERRAIN
NR = Not reached.
*
Hazard Ratio is derived from an unstratified proportional hazards model. Hazard Ratio < 1 favors XTANDI

XTANDI (N = 184)

Bicalutamide (N = 191)

Number of Progression or Deaths (%)

72 (39)

74 (39)

Median rPFS (months) (95% CI)

19.5 (11.8, NR)

13.4 (8.2, 16.4)

Hazard Ratio (95% CI)*

0.60 (0.43, 0.83)

Figure 6. Kaplan-Meier Curves of Radiographic Progression-free Survival in TERRAIN
(click image for full-size original)

Figure 6. Kaplan-Meier Curves of Radiographic Progression-free Survival in TERRAIN

PROSPER (NCT02003924): XTANDI versus Placebo in Non-metastatic CRPC

PROSPER enrolled 1401 patients with non-metastatic CRPC who were randomized 2:1 to receive either XTANDI orally at a dose of 160 mg once daily (N = 933) or placebo orally once daily (N = 468). All patients in the PROSPER trial received a gonadotropin-releasing hormone (GnRH) analog or had a prior bilateral orchiectomy. Patients were stratified by Prostate Specific Antigen (PSA) Doubling Time (PSADT) and the use of bone-targeting agents. Patients were required to have a PSA doubling time ≤ 10 months, PSA ≥ 2 ng/mL, and confirmation of non-metastatic disease by blinded independent central review (BICR). PSA results were blinded and were not used for treatment discontinuation. Patients randomized to either arm discontinued treatment for radiographic disease progression confirmed by BICR, initiation of new treatment, unacceptable toxicity, or withdrawal.

The following patient demographics and baseline characteristics were balanced between the two treatment arms. The median age at randomization was 74 years (range 50-95) and 23% were 80 years of age or older. The racial distribution was 71% Caucasian, 16% Asian, and 2% Black. A majority of patients had a Gleason score of 7 or higher (77%). The median PSADT was 3.7 months. Fifty-four percent (54%) of patients received prior treatment for prostate cancer with either surgery or radiation. Sixty-three percent (63%) of patients received prior treatment with an anti-androgen; 56% of patients received bicalutamide and 11% of patients received flutamide. All patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 0 or 1 at study entry.

The major efficacy outcome of the study was metastasis-free survival (MFS), defined as the time from randomization to whichever of the following occurred first 1) loco-regional and/or distant radiographic progression per BICR or 2) death up to 112 days after treatment discontinuation without evidence of radiographic progression. A statistically significant improvement in MFS was demonstrated in patients randomized to receive XTANDI compared with patients randomized to receive placebo. Consistent MFS results were observed when considering only distant radiographic progression events or deaths regardless of the cut-off date. Consistent MFS results were also observed in pre-specified and stratified patient sub-groups of PSADT (< 6 months or ≥ 6 months) and use of a prior bone-targeting agent (yes or no). Overall survival (OS) data were not mature at the time of final MFS analysis (28% of the required number of events had been reported). The efficacy results for MFS from PROSPER are summarized in Table 11 and Figure 7.

Table 11. Summary of Efficacy Results in PROSPER (Intent-to-treat Population)
NR = Not reached.
*
Based on Kaplan-Meier estimates.
Hazard Ratio is based on a Cox regression model (with treatment as the only covariate) stratified by PSA doubling time and prior or concurrent use of a bone-targeting agent. The HR is relative to placebo with < 1 favoring XTANDI.
P-value is based on a stratified log-rank test by PSA doubling time (< 6 months, ≥ 6 months) and prior or concurrent use of a bone-targeting agent (yes, no).

XTANDI (N = 933)

Placebo (N = 468)

Metastasis-free survival

Number of Events (%)

219 (23.5)

228 (48.7)

Median, months (95% CI)*

36.6 (33.1, NR)

14.7 (14.2, 15.0)

Hazard Ratio (95% CI)

0.29 (0.24, 0.35)

P-value

p < 0.0001

Figure 7. Kaplan-Meier Curves of Metastasis-free Survival in PROSPER
(click image for full-size original)

Figure 7. Kaplan-Meier Curves of Metastasis-free Survival in PROSPER

The primary efficacy outcome was supported by a statistically significant delay in time to first use of new antineoplastic therapy (TTA) for patients in the XTANDI arm compared to those in the placebo arm. The median TTA was 39.6 months for patients on XTANDI and was 17.7 months for patients on placebo (HR = 0.21; 95% CI: [0.17, 0.26], p < 0.0001).

ARCHES (NCT02677896): XTANDI versus Placebo in Metastatic CSPC

ARCHES enrolled 1150 patients with mCSPC who were randomized 1:1 to receive XTANDI orally at a dose of 160 mg once daily (N=574) or placebo orally once daily (N=576). All patients in the trial received a GnRH analog or had a prior bilateral orchiectomy. Patients were stratified by volume of disease (low vs high) and prior docetaxel therapy for prostate cancer (no prior docetaxel, 1-5 cycles, or 6 prior cycles). High volume of disease is defined as metastases involving the viscera or, in the absence of visceral lesions, there must be 4 or more bone lesions, at least 1 of which must be in a bony structure beyond the vertebral column and pelvic bone. Treatment with concurrent docetaxel was not allowed. Patients continued treatment until radiographic disease progression, initiation of new treatment, unacceptable toxicity, or withdrawal.

The following patient demographics and baseline characteristics were balanced between the two treatment arms. The median age at randomization was 70 years (range: 42-92) and 30% were 75 years of age or older. The racial distribution was 81% Caucasian, 14% Asian, and 1% Black. Sixty-six percent (66%) of patients had a Gleason score of ≥ 8. Thirty-seven percent (37%) of patients had a low volume of disease and 63% of patients had a high volume of disease. Eighty-two percent (82%) of patients had no prior docetaxel treatment; 2% of patients had 1 to 5 cycles of docetaxel and 16% of patients had 6 prior cycles of docetaxel treatment. Twelve percent (12%) of patients received concomitant bone-targeted agents (bisphosphonates or RANKL inhibitors) which included both prostate and non-prostate cancer indications. The Eastern Cooperative Oncology Group Performance Status (ECOG PS) score was 0 for 78% of patients and 1 for 22% of patients at study entry.

The major efficacy outcome measure was radiographic progression-free survival (rPFS) based on blinded independent central review (BICR). Radiographic progression-free survival was defined as the time from randomization to radiographic disease progression at any time or death within 24 weeks after study drug discontinuation. Radiographic disease progression was defined by identification of 2 or more new bone lesions on a bone scan with confirmation (Prostate Cancer Working Group 2 criteria) and/or progression in soft tissue disease. Time to new antineoplastic therapy was an additional efficacy endpoint.

XTANDI demonstrated a statistically significant improvement in rPFS compared to placebo. Consistent rPFS results were observed in patients with high or low volume of disease and patients with and without prior docetaxel therapy. Overall survival (OS) data were not mature at the time of rPFS analysis (7.3% deaths in the ITT population had been reported). Efficacy results for rPFS from ARCHES are summarized in Table 12 and Figure 8.

Table 12. Efficacy Results in ARCHES based on BICR (Intent-to-Treat Analysis)
NR = Not reached
*
Based on Kaplan-Meier estimates.
Hazard Ratio is based on a Cox regression model stratified by volume of disease (low vs high) and prior docetaxel use (yes vs no).
P-value is based on a stratified log-rank test by volume of disease (low vs high) and prior docetaxel use (yes or no).

XTANDI (N = 574)

Placebo (N=576)

Radiographic Progression-free Survival

Number of events (%)

89 (15.5)

198 (34.4)

Radiographic disease progression

77 (13.4)

185 (32.1)

Death within 24 weeks after treatment discontinuation

12 (2.1)

13 (2.3)

Median, months (95% CI)*

NR

19.4 (16.6, NR)

Hazard ratio (95% CI)

0.39 (0.30, 0.50)

P-value

p < 0.0001

Figure 8. Kaplan-Meier Curves of rPFS in ARCHES (Intent-to-Treat Analysis)
(click image for full-size original)

Figure 8. Kaplan-Meier Curves of rPFS in ARCHES (Intent-to-Treat Analysis)

A statistically significant improvement was also reported on the XTANDI arm compared to placebo in time to initiation of a new antineoplastic therapy (HR = 0.28 [95% CI: 0.20, 0.40]; p < 0.0001).

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