New ZYTIGA® (abiraterone acetate) Data on Pain and Function Presented at the ESMO 2012 Congress (European Society for Medical Oncology)

VIENNA, Sept. 30, 2012 /PRNewswire/ -- Additional data from pre-specified interim analyses of COU-AA-302, a Phase 3, randomized, placebo-controlled study, suggested ZYTIGA^® (abiraterone acetate) plus prednisone, compared to placebo plus prednisone, delayed pain progression and functional decline in asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC) patients whose disease progressed after androgen deprivation therapy and anti-androgens.  Additional data from COU-AA-302 suggest that the assessment of radiographic progression-free survival (rPFS), adapted from Prostate Cancer Working Group 2 (PCWG2) consensus criteria, was highly consistent between investigators and independent blinded radiologists and was positively associated with overall survival (OS).  The results were presented today at the ESMO 2012 Congress (European Society for Medical Oncology).

Safety and efficacy findings from COU-AA-302 were the basis of recent filings with health authorities around the world to extend the use of ZYTIGA administered with prednisone to include the treatment of patients with mCRPC who are asymptomatic or mildly symptomatic and whose disease progressed after androgen deprivation therapy and anti-androgens.

"We understand that managing pain and maintaining function are of critical importance to prescribing physicians and patients, which is why we included and analyzed these endpoints," said Michael L. Meyers, M.D., Ph.D., Vice President, Compound Development Team Leader, ZYTIGA.  "These data, from a second pivotal Phase 3 study, add to the growing body of knowledge about ZYTIGA in this patient population where significant unmet medical needs remain."

Study COU-AA-302 is a Phase 3, randomized, double-blind, placebo-controlled, international study that included 1,088 men with mCRPC who had not received prior chemotherapy, and who were randomized to receive ZYTIGA 1,000 milligrams (mg) administered orally once daily plus prednisone 5 mg administered twice daily (n=546; ZYTIGA arm) or placebo plus prednisone 5 mg administered twice daily (n=542; control arm).  The co-primary endpoints of the study are rPFS and OS; these data were presented earlier in 2012.  Functional status and pain progression were secondary endpoints. 

The patients reported their pain and functional status at baseline and on the first day of pre-specified treatment cycles over 13.8 months and 8.3 months in the two arms, respectively, using standard, validated instruments: the Brief Pain Inventory – Short Form (BPI-SF) and the Functional Assessment of Cancer Therapy – Prostate Cancer (FACT-P).  Both the BPI-SF and FACT-P questionnaires are used to assess pain and health-related quality of life in men with prostate cancer. 

Patients in the ZYTIGA arm reported statistically significant delays in most measures of pain progression and functional decline compared to those in the control arm, and the median number of months to reach pre-defined degrees of worsening were greater (more delayed) in the ZYTIGA arm vs. the control arm, respectively:

Pain Progression

• Average pain progression: 26.7 vs. 18.4 months (HR=0.817; 95% CI: [0.668, 0.999]; p=0.049)
• Worst pain intensity progression: 14.8 vs. 12.0  months (HR=0.777; 95% CI: [0.607, 0.995]; p=0.045)
• Progression of pain interference with daily function: 10.3 vs. 7.4 months (HR=0.792; 95% CI: [0.674, 0.931]; p = 0.005)
• Median time to opiate use for cancer pain: not reached in ZYTIGA arm vs. 23.7 months (HR=0.817; 95% CI: [0.668, 0.999]; p=0.0001)

Functional Status Degradation

• FACT-G score (general function status): 16.6 vs. 11.1 (HR=0.76; 95% CI: [0.63, 0.91]; p=0.002)
• FACT-P total score: 12.7 vs. 8.3 months (HR=0.778; 95% CI: [0.659, 0.918]; p=0.003)
• Physical well-being: 14.8 vs. 11.1 months (HR=0.76; 95% CI: [0.64, 0.90]; p=0.002)
• Emotional well-being: 22.1 vs. 14.2 months (HR= 0.71; 95% CI: [0.59, 0.87]; p=0.001)
• Functional well-being: 13.3 vs. 8.4 months (HR=0.76; 95% CI: [0.64, 0.90]; p=0.001)
• Prostate cancer subscale score: 11.1 vs. 5.8 months (HR=0.70; 95% CI: [0.60, 0.83]; p<0.001)

Differences for the two treatment groups of worst pain intensity (26.7 vs. 19.4 months; HR=0.845; 95% CI: [0.688, 1.038]; p=0.109) and social/family well-being (18.4 vs. 16.6 months; HR=0.94; 95% CI: [0.78, 1.14]; p=0.528) were not statistically significant.

Additional data from COU-AA-302 allowed investigators to examine the correlation between rPFS and OS. The investigators found a positive association of rPFS with OS (correlation coefficient r = +0.71, possible range -1 to +1).  Furthermore, the findings suggested that the assessment of rPFS was highly consistent between investigators and independent blinded radiologists, suggesting that this novel endpoint adapted from PCWG2 criteria is reliable and reproducible.   

"The association between rPFS and OS provides preliminary support for use of radiographic progression-free survival as an intermediate marker of overall survival, and as a primary/co-primary endpoint in Phase 3 mCRPC studies," said Charles J. Ryan, M.D., lead investigator of the study and Associate Professor of Clinical Medicine at the UCSF Helen Diller Family Comprehensive Cancer Center.

Safety Findings
Previously reported safety findings showed that patients in the ZYTIGA arm of the study experienced more grade 3 and grade 4 adverse events than those in the control arm, including cardiac disorders (6% vs. 3%) and hypertension (4% vs. 3%), as well as increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (5.4% vs. 0.8% and 3.0% vs. 0.9%, respectively).  Fatigue was the most common adverse event observed in the study.

About ZYTIGA
Since its first approval in the U.S. in 2011, ZYTIGA has been approved in more than 50 countries.  More than 30,000 men worldwide have received treatment with it, and it is quickly becoming one of the cornerstones of treatments for mCRPC.

ZYTIGA in combination with prednisone was approved by the U.S. Food and Drug Administration (FDA) in April 2011 for the treatment of men with mCRPC who have received prior chemotherapy containing docetaxel.  The Phase 3 study for this initial ZYTIGA indication was also unblinded after review of a pre-specified interim analysis and recommendations from the IDMC, in August 2010, based on a statistically significant improvement in median OS and an acceptable safety profile.  A subsequent analysis with more mature data confirmed the survival benefit and safety profile. 

A supplemental New Drug Application for ZYTIGA administered in combination with prednisone for the treatment of patients with mCRPC who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy was granted Priority Review by the FDA.

More information about ZYTIGA can be found at www.zytiga.com.

Indication
ZYTIGA^® (abiraterone acetate) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel.

Important Safety Information

Contraindications - ZYTIGA^® (abiraterone acetate) may cause fetal harm (Pregnancy Category X) and is contraindicated in women who are or may become pregnant.

Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess - Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in hypertension, hypokalemia, and fluid retention. ZYTIGA^® may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Safety has not been established in patients with LVEF <50% or New York Heart Association (NYHA) Class III or IV heart failure because these patients were excluded from the randomized clinical trial. Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

Adrenocortical Insufficiency (AI) - AI has been reported in clinical trials in patients receiving ZYTIGA^® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA^®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations.

Hepatotoxicity - Increases in liver enzymes have led to drug interruption, dose modification, and/or discontinuation. Monitor liver function and modify, withhold, or discontinue ZYTIGA^® dosing as recommended (see Prescribing Information for more information). Measure serum transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] and bilirubin levels prior to starting treatment with ZYTIGA^®, every two weeks for the first three months of treatment, and monthly thereafter.  Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient's baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the upper limit of normal (ULN) or the bilirubin rises above three times the ULN, interrupt ZYTIGA^® treatment and closely monitor liver function.

Food Effect - ZYTIGA^® must be taken on an empty stomach. Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. No food should be eaten for at least two hours before the dose of ZYTIGA^® is taken and for at least one hour after the dose of ZYTIGA^® is taken.  Abiraterone Cmax and AUC0-infinity (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state.

Adverse Reactions - The most common adverse reactions (>5%) are joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, fractures and upper respiratory tract infection.

Drug Interactions - ZYTIGA^® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid coadministration with CYP2D6 substrates that have a narrow therapeutic index. If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. Additionally, abiraterone is a substrate of CYP3A4 in vitro. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution.

Use in Specific Populations - The safety of ZYTIGA^® in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA^®.

About Janssen Research & Development, LLC
Janssen Research & Development, LLC, is headquartered in Raritan, N.J. and has affiliated facilities in Europe, the United States and Asia. Janssen Research & Development is leveraging a combination of internal and external innovation to discover and develop novel medicines and solutions in five distinct therapeutic areas: Neuroscience, Oncology, Immunology, Infectious Diseases and Vaccines, and Cardiovascular and Metabolism. For more information about Janssen Research & Development, LLC visit www.janssenrnd.com.

Note: Data in this release correspond to ESMO Abstracts 8940 and 8950.

ABSTRACT 8940: Association of radiographic progression-free survival (rPFS) adapted from Prostate Cancer Working Group 2 (PCWG2) consensus criteria (APCWG2) with overall survival (OS) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Results from COU-AA-302. Presenter: Charles Ryan, San Francisco, CA, USA. Session: Proffered Papers, Genitourinary tumors, prostate II. Date / Time: Sunday, September 30, 2012 / 3:00 PM CEST. Room: Hall A

ABSTRACT 8950: The impact of abiraterone acetate (AA) therapy on patient-reported pain and functional status in chemotherapy-naïve patients with progressive, metastatic castration-resistant prostate cancer (mCRPC). Presenter: Ethan Basch, New York, NY, USA; Session: Proffered Papers, Genitourinary tumors, prostate I. Date / Time: Sunday, September 30, 2012 / 10:45 AM CEST. Room: Hall D

SOURCE Janssen Research & Development, LLC

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