Efficacy
& Safety

Significant efficacy after a median 4 years (49 months) of follow-up

In the final analysis of overall survival (OS) from the pivotal Phase 3 study,* ZYTIGA® + prednisone achieved:

MEDIAN OVERALL SURVIVAL

for ZYTIGA® + prednisone vs 30.3 months with placebo + prednisone (active compound).

IMPROVEMENT IN MEDIAN OVERALL SURVIVAL

compared with placebo + prednisone.

Duo2

Co-primary end point—OS: hazard ratio (HR)=0.81; 95% CI: 0.70, 0.93; P=0.0033.

Co-primary end point—rPFS: at the prespecified radiographic progression-free survival (rPFS) analysis, median not reached for ZYTIGA® + prednisone vs a median of 8.28 months for placebo + prednisone; HR=0.425; 95% CI: 0.347, 0.522; P<0.0001.

35% of patients in the ZYTIGA® + prednisone arm were still alive vs 29% in the placebo + prednisone arm after a median follow-up of 49 months

*COU-AA-302 Study - Phase 3 Study conducted in patients with mCRPC who had not received prior chemotherapy.
At a prespecified final analysis for OS, 65% (354/546) of patients treated with ZYTIGA® plus prednisone compared with 71% (387/542) of patients treated with placebo plus prednisone had died.
Prednisone, as a single agent, is not approved for the treatment of prostate cancer.

Study Design

Phase 3, randomized, double-blind, placebo-controlled, multicenter study (Study 2) in patients with mCRPC who had not received prior chemotherapy (N=1,088)

Patients continued treatment until:

  • Protocol-Defined Radiographic Progression
  • OR
  • Clinical Progression defined as:
    • Initiation of cytotoxic chemotherapy
    • Radiation or surgical treatment for cancer
    • Pain requiring chronic opioids
    • Eastern Cooperative Oncology Group (ECOG)
      performance status decline to 3 or more
  • OR
  • Unacceptable Toxicity or Withdrawal
    Note:
    • If the patient had radiographic progression but no unequivocal clinical progression and alternate treatment was not initiated, the patient was allowed to continue on study treatment, at the investigator’s discretion.
    • If the patient had unequivocal clinical progression without radiographic progression, the current standard of care was indicated. Study treatment was to be stopped and patients advised regarding available treatment options.
    • Study treatment was to be continued in patients who had increased prostate-specific antigen (PSA) values in the absence of radiographic or unequivocal clinical progression.1

References: 1. Protocol for: Ryan CJ, Smith MR, de Bono JS, et al; COU-AA-302 Investigators. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138-148. http://www.nejm.org/doi/suppl/10.1056/NEJMoa1209096/suppl_file/nejmoa120....
Accessed May 5, 2016.

PATIENT POPULATION

Patients with metastatic castration-resistant prostate cancer (mCRPC) who had not received prior cytotoxic chemotherapy were included. Patients were using a gonadotropin-releasing hormone agonist or were previously treated with orchiectomy and had serum testosterone levels <50 ng/dL.

Select baseline patient demographics and disease characteristics:

  • Median age=70 years1
  • ECOG performance score of 0=76%; score of 1=24%
  • Baseline pain assessment: 0-1 (asymptomatic)=66%; 2-3 (mildly symptomatic)=26% as defined by the Brief Pain Inventory-Short Form (worst pain over the last 24 hours)

ECOG=Eastern Cooperative Oncology Group.

*Androgen Deprivation Therapy

Selected exclusion criteria included prior ketoconazole treatment for prostate cancer and a history of cardiovascular disease: LVEF<50% or NYHA Class II to IV heart failure. Previous therapy with an antiandrogen was required and patients with moderate or severe pain, opiate use for cancer pain, or visceral organ metastases were excluded. Patients were ineligible if AST and/or ALT ≥2.5X ULN and patients were excluded if they had liver metastases. Concurrent use of spironolactone was not allowed during the study period. 1, 2

References: 1. Ryan CJ, Smith MR, de Bono JS, et al; for the COU-AA-302 Investigators. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138-148. 2. ZYTIGA® (abiraterone acetate) Prescribing Information. Horsham, PA: Janssen Biotech, Inc.

CLINICAL STUDY RESULTS

Overall Survival

Co-primary endpoint
49 months
represents one of the longest median follow-up periodsamong studies of patients with mCRPC.2

In the final analysis of overall survival from the pivotal Phase 3 study, ZYTIGA® + prednisone significantly achieved:

MEDIAN OVERALL SURIVAL*

for ZYTIGA® + prednisone vs 30.3 months with placebo + prednisone (active compound).

IMPROVEMENT IN MEDIAN OVERALL SURVIVAL

compared with placebo + prednisone.

Hazard ratio (HR)=0.81; 95% CI: 0.70, 0.93; P=0.0033.

35% of patients in the ZYTIGA® + prednisone arm were still alive vs 29% in the placebo + prednisone arm after a median follow-up of 49 months

*At a prespecified final analysis for OS, 65% (354/546) of patients treated with ZYTIGA® + prednisone compared with 71% (387/542) of patients treated with placebo plus prednisone had died.

Prednisone, as a single agent, is not approved for the treatment of prostate cancer.

rPFS

Co-primary endpoint

At the pre-specified rPFS analysis, ZYTIGA® + prednisone achieved a 57% reduction in the risk of radiographic progression or death vs placebo + prednisone (active compound).*

Median radiographic progression-free survival (rPFS) for ZYTIGA® + prednisone not reached vs 8.28 months for placebo + prednisone.

HR=0.425; 95% CI: 0.347, 0.522; P<0.0001.

*Prednisone, as a single agent, is not approved for the treatment of prostate cancer.

Radiographically confirmed.

P value is derived from a log-rank test stratified by Eastern Cooperative Oncology Group (ECOG) performance status score (0 vs 1). Hazard ratio (HR) is derived from a stratified proportional hazards model. Hazard ratio <1 favors ZYTIGA®.

Radiographic progression-free survival (rPFS) 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.


At the prespecified rPFS analysis, 150 (28%) patients treated with ZYTIGA® and 251 (46%) patients treated with placebo had radiographic progression.

 

Adverse Reactions—The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection, and contusion.

The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.

Time to Chemotherapy

Secondary endpoint

ZYTIGA® + prednisone significantly delayed median time to initiation of chemotherapy.

>8 MONTHS DELAY IN MEDIAN TIME TO INITIATION OF CHEMOTHERAPY

Median 25.2 months vs 16.8 months with placebo + prednisone (active compound).*

 HR=0.580; 95% CI: 0.487, 0.691; P<0.0001; prospectively defined secondary end point

bar chart1

HR=0.580; 95% CI: 0.487, 0.691; P<0.0001; prospectively defined secondary end point
*Prednisone, as a single agent, is not approved for the treatment of prostate cancer.

Time to Opiate Use

Secondary endpoint

ZYTIGA® + prednisone significantly delayed median time to opiate use for prostate cancer-related pain.

NOT REACHED vs 23.7 MONTHS WITH PLACEBO + PREDNISONE (ACTIVE COMPOUND)*

HR=0.686; 95% CI: 0.566, 0.833; P=0.0001; prospectively defined secondary end point

bar chart2

*Prednisone, as a single agent, is not approved for the treatment of prostate cancer.

SAFETY PROFILE

Mineralocorticoid excess: Use ZYTIGA® with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA® in patients with LVEF < 50% or NYHA Class III or IV heart failure in Study 1 or LVEF < 50% or NYHA Class II to IV heart failure in Study 2 was not established. Control hypertension and correct hypokalemia before treatment. Monitor blood pressure, serum potassium and symptoms of fluid retention at least monthly.

Adrenocortical insufficiency: Monitor for symptoms and signs of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations.

Hepatotoxicity: Can be severe and fatal. Monitor liver function and modify, interrupt, or discontinue ZYTIGA® dosing as recommended.

Please see full Important Safety Information below.

Adverse reactions in ≥5% of patients in the ZYTIGA® + prednisone arm in Study 2*

Adverse Reactions ZYTIGA® + prednisone
(n=542)
Placebo + prednisone
(n=540)
Fatigue 39.1% 34.3%
Edema 25.1% 20.7%
Pyrexia 8.7% 5.9%
Joint swelling/discomfort 30.3% 25.2%
Groin pain 6.6% 4.1%
Constipation 23.1% 19.1%
Diarrhea 21.6% 17.8%
Dyspepsia 11.1% 5.0%
Hot flush 22.3% 18.1%
Hypertension 21.6% 13.1%
Cough 17.3% 13.5%
Dyspnea 11.8% 9.6%
Insomnia 13.5% 11.3%
Contusion 13.3% 9.1%
Falls 5.9% 3.3%
Upper respiratory tract infection 12.7% 8.0%
Nasopharyngitis 10.7% 8.1%
Hematuria 10.3% 5.6%
Rash 8.1% 3.7%
Adverse Reactions ZYTIGA® + prednisone
(n=542)
Placebo + prednisone
(n=540)
Fatigue 2.2% 1.7%
Edema 0.4% 1.1%
Pyrexia 0.6% 0.2%
Joint swelling/discomfort 2.0% 2.0%
Groin pain 0.4% 0.7%
Constipation 0.4% 0.6%
Diarrhea 0.9% 0.9%
Dyspepsia 2.4% 0.9%
Hot flush 0.2% 0%
Hypertension 3.9% 3.0%
Cough 0% 0.2%
Dyspnea 0% 0.2%
Insomnia 0.2% 0%
Contusion 0% 0%
Falls 0% 0%
Upper respiratory tract infection 0% 0%
Nasopharyngitis 0% 0%
Hematuria 1.3% 0.6%
Rash 0% 0%

 

References: 1. Ryan CJ, Smith MR, de Bono JS, et al; for the COU-AA-302 Investigators. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138-148. 2. Ryan CJ, Smith MR, Fizazi K, et al; for the COU-AA-302 Investigators. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomized, double-blind, placebo-controlled Phase 3 study. Lancet Oncol. 2015;16(2):152-160. 

STUDY DESIGN

Phase 3, randomized, double-blind, placebo-controlled, multicenter study (Study 1) in patients with mCRPC who received prior docetaxel therapy (N=1,195)

In this Phase 3 clinical study, patients were to continue until disease progression, initiation of new treatment, unacceptable toxicity or withdrawal.

All of the following criteria were to be met prior to discontinuation due to progression:1

  • Increased PSA* as defined by the PSA Working Group (PSAWG) (25% increase over baseline, with a minimum PSA increase of 5 ng/mL)
  • Radiographic progression (progression on bone scans or soft-tissue disease progression)
  • Symptomatic or clinical progression defined by pain progression, development of skeletal-related events, increase in prednisone or prednisolone dose, or change in corticosteroid to treat prostate cancer–related signs and symptoms

*PSA=prostate-specific antigen.


References: 1. Protocol for: de Bono JS, Logothetis CJ, Molina A, et al; for the COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005. http://www.nejm.org/action/showSupplements?doi=10.1056%2FNEJMoa1014618&v....
Accessed March 29, 2016.

 

DURATION OF TREATMENT

At the updated analysis for overall survival, the median duration of treatment in patients with mCRPC who received prior docetaxel therapy was:1

ZYTIGA® + Prednisone
7.4 MONTHS

Placebo + Prednisone
3.6 MONTHS

PATIENT POPULATION

Patients were using a gonadotropin-releasing hormone analog or were previously treated with orchiectomy and had serum testosterone levels <50 ng/dL.

Select baseline patient demographics and disease characteristics:

  • Median age=69 years2
  • ECOG performance score of 0 to 1=89%
  • Brief Pain Inventory-Short Form score of ≥4 (patients reported worst pain over the previous 24 hours)=45%
  • Bone metastases=90%; visceral involvement=30%
    - The most common sites of visceral disease were the lungs (42%) and liver (33%). Other sites included prostate mass, bladder, and adrenal glands3
  • Prior cytotoxic chemotherapy: 1 regimen=70%; 2 regimens=30%
  • Radiographic evidence of disease progression=70%; PSA-only progression=30%

ECOG=Eastern Cooperative Oncology Group.
PSA=prostate-specific antigen.

Patients were using a gonadotropin-releasing hormone agonist or were previously treated with orchiectomy and had serum testosterone levels <50 ng/dL. Selected exclusion criteria included prior ketoconazole treatment for prostate cancer and a history of cardiovascular disease: LVEF<50% or New York Heart Association (NYHA) Class III or IV heart failure. Patients were not eligible if AST and/or ALT ≥2.5X ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN. Concurrent use of spironolactone was not allowed during the study period.1


References: 1. de Bono JS, Logothetis CJ, Molina A, et al; for the COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005.

Clinical Study Results

 

Median Overall Survival

The primary survival analysis showed a 3.9-month difference in median OS for ZYTIGA® + prednisone compared with placebo + prednisone* (14.8 months vs 10.9 months, respectively) (HR=0.646; 95% CI: 0.543, 0.768; P<0.0001).

4.6 MONTHS IMPROVEMENT IN MEDIAN OVERALL SURVIVAL OVERALL SURVIVAL (OS) AT THE UPDATED ANALYSIS

Median OS: 15.8 months with ZYTIGA® plus prednisone vs 11.2 months with placebo plus prednisone 1 (active compound)*

HR=0.740; 95% CI: 0.638, 0.859; P<0.0001.4

*Prednisone, as a single agent, is not approved for the treatment of prostate cancer.

 

Kaplan-Meier Survival Curve

Kaplan-Meier curves of patients treated with either ZYTIGA® + prednisone or placebo + prednisone (primary survival, intent-to-treat-analysis).

HR=0.646; 95% CI: 0.543, 0.768; P<0.0001

ADT rFPS Endpoint Curve

SAFETY PROFILE

Mineralocorticoid excess: Use ZYTIGA® with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA® in patients with LVEF < 50% or NYHA Class III or IV heart failure in Study 1 or LVEF < 50% or NYHA Class II to IV heart failure in Study 2 was not established. Control hypertension and correct hypokalemia before treatment. Monitor blood pressure, serum potassium and symptoms of fluid retention at least monthly.

Adrenocortical insufficiency: Monitor for symptoms and signs of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations.

Hepatotoxicity: Can be severe and fatal. Monitor liver function and modify, interrupt, or discontinue ZYTIGA® dosing as recommended.

Please see full Important Safety Information below.

 

Adverse reactions in patients in the ZYTIGA® + prednisone arm in Study 1*

Adverse Reactions

ZYTIGA® + prednisone

(n=791)

Placebo + prednisone

(n=394)

Joint swelling/discomfort

29.5%

23.4%

Muscle discomfort

26.2%

23.1%

Edema§

26.7%

18.3%

Hot flush

19.0%

16.8%

Hypertension

8.5%

6.9%

Diarrhea

17.6%

13.5%

Dyspepsia

6.1%

3.3%

Urinary tract infection

11.5%

7.1%

Upper respiratory tract infection

5.4%

2.5%

Cough

10.6%

7.6%

Urinary frequency

7.2%

5.1%

Nocturia

6.2%

4.1%

FracturesII

5.9%

2.3%

Arrhythmia

7.2%

4.6%

Chest pain or chest discomfort#

3.8%

2.8%

Cardiac failure**

2.3%

1.0%

Adverse reactions

ZYTIGA® + prednisone

(n=791)

Placebo + prednisone

(n=394)

Joint swelling/discomfort

4.2%

4.1%

Muscle discomfort

3.0%

2.3%

Edema§

1.9%

0.8%

Hot flush

0.3%

0.3%

Hypertension

1.3%

0.3%

Diarrhea

0.6%

1.3%

Dyspepsia

0%

0%

Urinary tract infection

2.1%

0.5%

Upper respiratory tract infection

0%

0%

Cough

0%

0%

Urinary frequency

0.3%

0.3%

Nocturia

0%

0%

FracturesII

1.4%

0%

Arrhythmia

1.1%

1.0%

Chest pain or chest discomfort#

0.5%

0%

Cardiac failure**

1.9%

0.3%

References: 1. Fizazi K, Scher HI, Molina A, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomized, double-blind, placebo-controlled Phase 3 study. Lancet Oncol. 2012;13(10):983-992. 2. de Bono JS, Logothetis CJ, Molina A, et al; for the COU-AA-301 Investigators. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995-2005. 3. Goodman OB, Flaig TW, Mulders PFA, et al. Exploratory analysis of the visceral disease subgroup in a Phase 3 study of abiraterone acetate in metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. 2014;17:34-39. 4. Fizazi K, Scher HI, Molina A, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomized, double-blind, placebo-controlled Phase 3 study. Lancet Oncol. 2012;13(10):983-992.