Abiraterone Acetate: Package Insert and Label Information (Page 6 of 8)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

A two-year carcinogenicity study was conducted in rats at oral abiraterone acetate doses of 5, 15, and 50 mg/kg/day for males and 15, 50, and 150 mg/kg/day for females. Abiraterone acetate increased the combined incidence of interstitial cell adenomas and carcinomas in the testes at all dose levels tested. This finding is considered to be related to the pharmacological activity of abiraterone. Rats are regarded as more sensitive than humans to developing interstitial cell tumors in the testes. Abiraterone acetate was not carcinogenic in female rats at exposure levels up to 0.8 times the human clinical exposure based on AUC. Abiraterone acetate was not carcinogenic in a 6-month study in the transgenic (Tg.rasH2) mouse.

Abiraterone acetate and abiraterone was not mutagenic in an in vitro microbial mutagenesis (Ames) assay or clastogenic in an in vitro cytogenetic assay using primary human lymphocytes or an in vivo rat micronucleus assay.

In repeat-dose toxicity studies in male rats (13- and 26-weeks) and monkeys (39-weeks), atrophy, aspermia/hypospermia, and hyperplasia in the reproductive system were observed at ≥ 50 mg/kg/day in rats and ≥ 250 mg/kg/day in monkeys and were consistent with the antiandrogenic pharmacological activity of abiraterone. These effects were observed in rats at systemic exposures similar to humans and in monkeys at exposures approximately 0.6 times the AUC in humans.

In a fertility study in male rats, reduced organ weights of the reproductive system, sperm counts, sperm motility, altered sperm morphology and decreased fertility were observed in animals dosed for 4 weeks at ≥ 30 mg/kg/day orally. Mating of untreated females with males that received 30 mg/kg/day oral abiraterone acetate resulted in a reduced number of corpora lutea, implantations and live embryos and an increased incidence of pre-implantation loss. Effects on male rats were reversible after 16 weeks from the last abiraterone acetate administration.

In a fertility study in female rats, animals dosed orally for 2 weeks until day 7 of pregnancy at ≥ 30 mg/kg/day had an increased incidence of irregular or extended estrous cycles and pre-implantation loss (300 mg/kg/day). There were no differences in mating, fertility, and litter parameters in female rats that received abiraterone acetate. Effects on female rats were reversible after 4 weeks from the last abiraterone acetate administration.

The dose of 30 mg/kg/day in rats is approximately 0.3 times the recommended dose of 1,000 mg/day based on body surface area.

In 13- and 26-week studies in rats and 13- and 39-week studies in monkeys, a reduction in circulating testosterone levels occurred with abiraterone acetate at approximately one half the human clinical exposure based on AUC. As a result, decreases in organ weights and toxicities were observed in the male and female reproductive system, adrenal glands, liver, pituitary (rats only), and male mammary glands. The changes in the reproductive organs are consistent with the antiandrogenic pharmacological activity of abiraterone acetate.

13.2 Animal Toxicology and/or Pharmacology

A dose-dependent increase in cataracts was observed in rats after daily oral abiraterone acetate administration for 26 weeks starting at ≥ 50 mg/kg/day (similar to the human clinical exposure based on AUC). In a 39-week monkey study with daily oral abiraterone acetate administration, no cataracts were observed at higher doses (2 times greater than the clinical exposure based on AUC).

14 CLINICAL STUDIES

The efficacy and safety of abiraterone acetate tablets with prednisone was established in three randomized placebo-controlled international clinical studies. All patients in these studies received a GnRH analog or had prior bilateral orchiectomy. Patients with prior ketoconazole treatment for prostate cancer and a history of adrenal gland or pituitary disorders were excluded from these trials. Concurrent use of spironolactone was not allowed during the study period.

COU-AA-301: Patients with Metastatic CRPC who had Received Prior Docetaxel Chemotherapy: In COU-AA-301 (NCT00638690), a total of 1195 patients were randomized 2:1 to receive either abiraterone acetate tablets orally at a dose of 1,000 mg once daily in combination with prednisone 5 mg orally twice daily (N = 797) or placebo once daily plus prednisone 5 mg orally twice daily (N = 398). Patients randomized to either arm were to continue treatment until disease progression (defined as a 25% increase in PSA over the patient’s baseline/nadir together with protocol-defined radiographic progression and symptomatic or clinical progression), initiation of new treatment, unacceptable toxicity or withdrawal.

The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 69 years (range 39-95) and the racial distribution was 93% Caucasian, 3.6% Black, 1.7% Asian, and 1.6% Other. Eighty-nine percent of patients enrolled had an ECOG performance status score of 0-1 and 45% had a Brief Pain Inventory-Short Form score of ≥ 4 (patient’s reported worst pain over the previous 24 hours). Ninety percent of patients had metastases in bone and 30% had visceral involvement. Seventy percent of patients had radiographic evidence of disease progression and 30% had PSA-only progression. Seventy percent of patients had previously received one cytotoxic chemotherapy regimen and 30% received two regimens.

The protocol pre-specified interim analysis was conducted after 552 deaths and showed a statistically significant improvement in overall survival (OS) in patients treated with abiraterone acetate tablets with prednisone compared to patients in the placebo with prednisone arm (Table 9 and Figure 1). An updated survival analysis was conducted when 775 deaths (97% of the planned number of deaths for final analysis) were observed. Results from this analysis were consistent with those from the interim analysis (Table 7).

Table 7: Overall Survival of Patients Treated with Either Abiraterone Acetate Tablets or Placebo in Combination with Prednisone in COU-AA-301 (Intent-to-Treat Analysis)
*
p-value is derived from a log-rank test stratified by ECOG performance status score (0-1 vs. 2), pain score (absent vs. present), number of prior chemotherapy regimens (1 vs. 2), and type of disease progression (PSA only vs. radiographic).
Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio < 1 favors abiraterone acetate tablets with prednisone.

Abiraterone Acetate Tablets with Prednisone(N = 797)

Placebo with Prednisone

(N = 398)

Primary Survival Analysis

Deaths (%)

333 (42%)

219 (55%)

Median survival (months) (95% CI)

14.8 (14.1, 15.4)

10.9 (10.2, 12.0)

p-value *

< 0.0001

Hazard ratio (95% CI)

0.646 (0.543, 0.768)

Updated Survival Analysis

Deaths (%)

501 (63%)

274 (69%)

Median survival (months) (95% CI)

15.8 (14.8, 17.0)

11.2 (10.4, 13.1)

Hazard ratio (95% CI)

0.740 (0.638, 0.859)

Figure 1: Kaplan-Meier Overall Survival Curves in COU-AA-301 (Intent-to-Treat Analysis)
(click image for full-size original)

Figure 1: Kaplan-Meier Overall Survival Curves in COU-AA-301 (Intent-to-Treat Analysis)

COU-AA-302: Patients with Metastatic CRPC who had not Received Prior Cytotoxic Chemotherapy: In COU-AA-302 (NCT00887198), 1088 patients were randomized 1:1 to receive either abiraterone acetate tablets orally at a dose of 1,000 mg once daily (N = 546) or Placebo orally once daily (N = 542). Both arms were given concomitant prednisone 5 mg twice daily. Patients continued treatment until radiographic or clinical (cytotoxic chemotherapy, radiation or surgical treatment for cancer, pain requiring chronic opioids, or ECOG performance status decline to 3 or more) disease progression, unacceptable toxicity or withdrawal. Patients with moderate or severe pain, opiate use for cancer pain, or visceral organ metastases were excluded.

Patient demographics were balanced between the treatment arms. The median age was 70 years. The racial distribution of patients treated with abiraterone acetate tablets was 95% Caucasian, 2.8% Black, 0.7% Asian and 1.1% Other. The ECOG performance status was 0 for 76% of patients, and 1 for 24% of patients. Co-primary efficacy endpoints were overall survival and radiographic progression-free survival (rPFS). Baseline pain assessment was 0-1 (asymptomatic) in 66% of patients and 2-3 (mildly symptomatic) in 26% of patients as defined by the Brief Pain Inventory-Short Form (worst pain over the last 24 hours).

Radiographic progression-free survival was assessed with the use of sequential imaging studies and was defined by bone scan identification of 2 or more new bone lesions with confirmation (Prostate Cancer Working Group 2 criteria) and/or modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria for progression of soft tissue lesions. Analysis of rPFS utilized centrally-reviewed radiographic assessment of progression.

The planned final analysis for OS, conducted after 741 deaths (median follow up of 49 months) demonstrated a statistically significant OS improvement in patients treated with abiraterone acetate tablets with prednisone compared to those treated with placebo with prednisone (Table 8 and Figure 2). Sixty-five percent of patients on the abiraterone acetate tablets arm and 78% of patients on the placebo arm used subsequent therapies that may prolong OS in metastatic CRPC. Abiraterone acetate tablets were used as a subsequent therapy in 13% of patients on the abiraterone acetate tablets arm and 44% of patients on the placebo arm.

Table 8: Overall Survival of Patients Treated with Either Abiraterone Acetate Tablets or Placebo in Combination with Prednisone in COU-AA-302 (Intent-to-Treat Analysis)
*
p-value is derived from a log-rank test stratified by ECOG performance status score (0 vs. 1).
Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio < 1 favors abiraterone acetate tablets with prednisone.

Abiraterone Acetate Tablets with Prednisone(N = 546)

Placebo with Prednisone

(N = 542)

Overall Survival

Deaths

354 (65%)

387 (71%)

Median survival (months) (95% CI)

34.7 (32.7, 36.8)

30.3 (28.7, 33.3)

p-value *

0.0033

Hazard ratio (95% CI)

0.81 (0.70, 0.93)

Figure 2: Kaplan Meier Overall Survival Curves in COU-AA-302
(click image for full-size original)

Figure 2: Kaplan Meier Overall Survival Curves in COU-AA-302

At the pre-specified rPFS analysis, 150 (28%) patients treated with abiraterone acetate tablets with prednisone and 251 (46%) patients treated with placebo with prednisone had radiographic progression. A significant difference in rPFS between treatment groups was observed (Table 9 and Figure 3).

Table 9: Radiographic Progression-free Survival of Patients Treated with Either Abiraterone Acetate Tablets or Placebo in Combination with Prednisone in COU-AA-302 (Intent-to-Treat Analysis)
NR = Not reached.
*
p-value is derived from a log-rank test stratified by ECOG performance status score (0 vs. 1).
Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio < 1 favors abiraterone acetate tablets with prednisone.

Abiraterone Acetate Tablets with Prednisone(N = 546)

Placebo with Prednisone

(N = 542)

Radiographic Progression-free Survival

Progression or death

150 (28%)

251 (46%)

Median rPFS (months) (95% CI)

NR (11.66, NR)

8.28(8.12, 8.54)

p-value *

< 0.0001

Hazard ratio (95% CI)

0.425 (0.347, 0.522)

Figure 3: Kaplan Meier Curves of Radiographic Progression-free Survival in COU-AA-302 (Intent-to-Treat Analysis)
(click image for full-size original)

Figure 3: Kaplan Meier Curves of Radiographic Progression-free Survival in COU-AA-302 (Intent-to-Treat Analysis)

The primary efficacy analyses are supported by the following prospectively defined endpoints. The median time to initiation of cytotoxic chemotherapy was 25.2 months for patients in the abiraterone acetate tablets arm and 16.8 months for patients in the placebo arm (HR = 0.580; 95% CI: [0.487, 0.691], p < 0.0001).

The median time to opiate use for prostate cancer pain was not reached for patients receiving abiraterone acetate tablets and was 23.7 months for patients receiving placebo (HR = 0.686; 95% CI: [0.566, 0.833], p = 0.0001). The time to opiate use result was supported by a delay in patient reported pain progression favoring the abiraterone acetate tablets arm.

LATITUDE: Patients with Metastatic High-Risk CSPC: In LATITUDE (NCT01715285), 1199 patients with metastatic high-risk CSPC were randomized 1:1 to receive either abiraterone acetate tablets orally at a dose of 1,000 mg once daily with prednisone 5 mg once daily (N = 597) or placebos orally once daily (N = 602). High-risk disease was defined as having at least two of three risk factors at baseline: a total Gleason score of ≥ 8, presence of ≥ 3 lesions on bone scan, and evidence of measurable visceral metastases. Patients with significant cardiac, adrenal, or hepatic dysfunction were excluded. Patients continued treatment until radiographic or clinical disease progression, unacceptable toxicity, withdrawal or death. Clinical progression was defined as the need for cytotoxic chemotherapy, radiation or surgical treatment for cancer, pain requiring chronic opioids, or ECOG performance status decline to ≥ 3.

Patient demographics were balanced between the treatment arms. The median age was 67 years among all randomized subjects. The racial distribution of patients treated with abiraterone acetate tablets was 69% Caucasian, 2.5% Black, 21% Asian, and 8.1% Other. The ECOG performance status was 0 for 55%, 1 for 42%, and 2 for 3.5% of patients. Baseline pain assessment was 0-1 (asymptomatic) in 50% of patients, 2-3 (mildly symptomatic) in 23% of patients, and ≥ 4 in 28% of patients as defined by the Brief Pain Inventory-Short Form (worst pain over the last 24 hours).

A major efficacy outcome was overall survival. The pre-specified interim analysis after 406 deaths showed a statistically significant improvement in OS in patients on abiraterone acetate tablets with prednisone compared to those on placebos. Twenty-one percent of patients on the abiraterone acetate tablets arm and 41% of patients on the placebos arm received subsequent therapies that may prolong OS in metastatic CRPC. An updated survival analysis was conducted when 618 deaths were observed. The median follow-up time was 52 months. Results from this analysis were consistent with those from the pre-specified interim analysis (Table 10 and Figure 4). At the updated analysis, 29% of patients on the abiraterone acetate tablets arm and 45% of patients on the placebos arm received subsequent therapies that may prolong OS in metastatic CRPC.

Table 10: Overall Survival of Patients Treated with Either Abiraterone Acetate Tablets or Placebos in LATITUDE (Intent-to-Treat Analysis)
NE = Not estimable
*
This is based on the pre-specified interim analysis
p value is from log-rank test stratified by ECOG PS score (0/1 or 2) and visceral (absent or present).
Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio < 1 favors abiraterone acetate tablets with prednisone.

Abiraterone Acetate Tablets with Prednisone

(N = 597)

Placebos

(N = 602)

Overall Survival *

Deaths (%)

169 (28%)

237 (39%)

Median survival (months)

NE (NE, NE)

34.7 (33.1, NE)

(95% CI)

p-value

< 0.0001

Hazard ratio (95% CI)

0.62 (0.51, 0.76)

Updated Overall Survival

Deaths (%)

275 (46%)

343 (57%)

Median survival (months)

53.3

36.5

(95% CI)

(48.2, NE)

(33.5, 40.0)

Hazard ratio (95% CI)

0.66 (0.56, 0.78)

Figure 4: Kaplan-Meier Plot of Overall Survival; Intent-To-Treat-Population in LATITUDE Updated Analysis
(click image for full-size original)

Figure 4: Kaplan-Meier Plot of Overall Survival; Intent-To-Treat-Population in LATITUDE Updated Analysis

The major efficacy outcome was supported by a statistically significant delay in time to initiation of chemotherapy for patients in the abiraterone acetate tablets arm compared to those in the placebos arm. The median time to initiation of chemotherapy was not reached for patients on abiraterone acetate tablets with prednisone and was 38.9 months for patients on placebos (HR = 0.44; 95% CI: [0.35, 0.56], p < 0.0001).

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