ZYTIGA(R) Plus Prednisone Demonstrates Statistically Significant Overall Survival After 49-Month Follow-Up Analysis in Chemotherapy-Naïve Men with Metastatic Castration-Resistant Prostate Cancer

ZYTIGA(R) Plus Prednisone Demonstrates Statistically Significant Overall Survival After 49-Month Follow-Up Analysis in Chemotherapy-Naïve Men with Metastatic Castration-Resistant Prostate Cancer

HORSHAM, PA, September 28, 2014 - A final analysis of the Phase 3 COU-AA-302 trial presented today at the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid, Spain showed that ZYTIGA® (abiraterone acetate) plus prednisone significantly prolonged overall survival (OS), compared to an active control of placebo plus prednisone, in men with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). The Janssen Research & Development, LLC ("Janssen")-sponsored registration study demonstrated a 19 percent reduction in risk of death in this study population (median OS, 34.7 vs 30.3 months, respectively; HR= 0.81 [95% CI, 0.70-0.93]; p = 0.0033), after a median follow-up of more than four years (49.2 months).

The final analysis presented today is the first to demonstrate a statistically significant improvement in OS in this study. "OS is particularly noteworthy in COU-AA-302, because 67 percent of men in the ZYTIGA plus prednisone arm and 80 percent in the control arm received subsequent therapy. This includes 44 percent of men in the control arm who subsequently received ZYTIGA plus prednisone," said Charles Ryan, M.D., Professor of Clinical Medicine, Urology at the University of California, San Francisco, and lead investigator of the COU-AA-302 study. "The use of subsequent therapies did not impact the statistical significance between the ZYTIGA and control arms - and makes these results all the more compelling after adjusting for the crossover effect."

The U.S. Food and Drug Administration based its approval of ZYTIGA plus prednisone for treating men with mCRPC prior to chemotherapy on a planned second interim analysis of COU-AA-302, which met the co-primary endpoint of radiographic progression-free survival (rPFS). Based on results from the final analysis, Janssen has initiated regulatory submissions to relevant health authorities for a revision to the ZYTIGA label.

"Since the first report of interim data, ZYTIGA has become a key part of the treatment arsenal that doctors use to treat mCRPC, because it significantly delayed the progression of the disease and prolonged overall survival," Dr. Ryan added. "This final analysis also demonstrates a consistent safety profile with long-term co-administration of prednisone."

In addition, the final analysis demonstrated a significant improvement in median time to opiate use for cancer-related pain compared to placebo plus prednisone (median 33.4 vs. 23.4 months, respectively; HR= 0.72 [95% CI, 0.61-0.85]; p = 0.0001). With two additional years (a total of four years) of follow up since the last clinical cutoff (median 49.2 months), the safety profile of ZYTIGA remained unchanged compared to previous reports.

COU-AA-302 is an international, randomized, double-blind, placebo controlled Phase 3 study that included 1,088 men with mCRPC who had not received prior chemotherapy, and were randomized to receive ZYTIGA® (abiraterone acetate) 1,000 milligrams (mg) administered orally once daily plus prednisone 5 mg administered twice daily or placebo plus prednisone 5 mg administered twice daily. The co-primary endpoints of the study were rPFS and OS. Key secondary endpoints included time to opiate use, time to initiation of chemotherapy, time to Eastern Cooperative Oncology Group (ECOG) performance status deterioration and time to prostate-specific antigen (PSA) progression.

"In the last few years, we've entered a new era in prostate cancer treatment, with non-chemotherapy based treatment regimens and medicines based on an increasingly sophisticated understanding of the mechanism of disease. At Janssen, we're proud to be leading on these new innovations," said Peter Lebowitz, M.D., Ph.D., Global Therapeutic Area Head, Oncology, Janssen.

Janssen also presented positive Phase 2 data on ARN-509, an investigational compound currently in Phase 3 development for the treatment of men with high-risk non-metastatic castration-resistant prostate cancer (M0-CRPC). As part of the company's continued focus on advanced prostate cancer, ARN-509 provides an investigational opportunity that may address the unmet needs of patients with advanced prostate cancer.

Contraindications - ZYTIGA® (abiraterone acetate) is not indicated for use in women. ZYTIGA® can cause fetal harm (Pregnancy Category X) when administered to a pregnant woman 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 blood pressure, hypokalemia, or 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 (in Study 1) or NYHA Class II to IV heart failure (in Study 2) because these patients were excluded from these randomized clinical trials. 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 was reported 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 - 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.

Increased ZYTIGA® Exposures with Food - ZYTIGA® must be taken on an empty stomach. 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-? (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 (? 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.

DRUG INTERACTIONS - Based on in vitro data, ZYTIGA® is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone.

ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate drug. In vitro, ZYTIGA® inhibits CYP2C8. There are no clinical data on the use of ZYTIGA® with drugs that are substrates of CYP2C8. Patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

Use in Specific Populations - Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C).

About Prostate Cancer
Prostate cancer occurs in men when cancerous cells form in the tissues of the prostate, a gland that is located around the urethra and produces part of the seminal fluid.1 During the course of the illness, it may progress to castration-resistant prostate cancer (CRPC), which is resistant to medical or surgical treatments that lower testosterone (e.g., androgen deprivation therapy). CRPC that spreads to other areas of the body is called metastatic castration-resistant prostate cancer or mCRPC.2 Research has shown that prostate cancer tumor cells are capable of producing androgen, which helps to fuel their survival, suggesting that reducing androgen production is key to helping men with mCRPC manage their illness.3

ZYTIGA® (abiraterone acetate) is indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC). ZYTIGA® blocks CYP17-mediated androgen production - which fuels prostate cancer growth - at three sources: in the testes, adrenals and the prostate tumor tissue - and has proven efficacy in patients with mCRPC who have progressed on androgen deprivation therapy.

Since its first approval in the U.S. in 2011, more than 60,000 men in the U.S. have been prescribed ZYTIGA® and more than 140,000 patients worldwide have received treatment with this important therapeutic option.

Janssen is committed to supporting access to ZYTIGA® for appropriate patients who are prescribed this medicine. ZytigaOne™ Support provides enhanced support to physician offices and personalized care coordination services to patients, including the ZytigaOne™ Instant Savings Program, which can help commercially insured patients with out-of-pocket co-pays and coinsurance. For more information on ZytigaOne™ Support, contact 1-855-ZYTIGA-1.

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

About Janssen Research & Development, LLC
At Janssen, we are dedicated to addressing and solving some of the most important unmet medical needs of our time in oncology, immunology, neuroscience, infectious diseases and vaccines, and cardiovascular and metabolic diseases. Driven by our commitment to patients, we develop innovative products, services and healthcare solutions to help people throughout the world. Janssen Research & Development is part of the Janssen Pharmaceutical Companies. Please visit www.janssenrnd.com for more information.

Janssen in Oncology
In oncology, our goal is to fundamentally alter the way cancer is understood, diagnosed, and managed, reinforcing our commitment to the patients who inspire us. In looking to find innovative ways to address the cancer challenge, our primary efforts focus on several treatment and prevention solutions. These include a focus on hematologic malignancies, prostate cancer and lung cancer; cancer interception with the goal of developing products that interrupt the carcinogenic process; biomarkers that may help guide targeted, individualized use of our therapies; as well as safe and effective identification and treatment of early changes in the tumor microenvironment.

1 National Cancer Institute. What you need to know about prostate cancer. http://www.cancer.gov/cancertopics/wyntk/prostate/prostate.pdf. Accessed April 2014.
2 American Cancer Society. Prostate Cancer. http://www.cancer.org/cancer/prostatecancer/detailedguide/prostate-cancer-treating-recurrence. Accessed April 2014.
3 Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res 2008;68:6407-15.

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