BEERSE, Belgium, June 2, 2012 /PRNewswire/ --
Note: Data in this release correspond to ASCO Abstract LBA 4518.
Phase III Results Show Significant Improvement in Radiographic Progression-Free Survival and a Trend for Increased Overall Survival in Patients Receiving
ZYTIGA Plus Prednisone
Results observed from pre-specified interim analyses of the randomised, placebo-controlled Phase III study, COU-AA-302, demonstrated that patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (ZYTIGA(R)) plus prednisone showed a statistically significant improvement in radiographic progression-free survival (rPFS) and all secondary endpoints compared to patients treated with placebo plus prednisone. The results, announced today by Janssen, also showed a trend for increased median overall survival (OS), the co-primary endpoint, in patients receiving ZYTIGA plus prednisone. The study included 1,088 asymptomatic or mildly symptomatic patients with mCRPC who had not received chemotherapy.
This is the first randomised study to demonstrate a radiographic progression-free survival benefit and an overall survival trend in this patient population. The COU-AA-302 results are being presented at the 48th Annual Meeting of the American Society of Clinical Oncology (ASCO).
"Prostate cancer, the commonest cancer in men and the second commonest killer from cancer in men, is devastating for the men diagnosed with the disease and their loved ones," said Johann S. de Bono, M.D., F.R.C.P., M.Sc., Ph.D., The Institute for Cancer Research, The Royal Marsden NHS Foundation Trust, and a COU-AA-302 investigator. "These results are important since they show that metastatic castration-resistant prostate cancer patients who have not received prior chemotherapy may benefit from this agent."
The data demonstrate a statistically significant improvement in rPFS in the abiraterone acetate plus prednisone arm (ZYTIGA arm) of the study compared to the placebo plus prednisone (control) arm. The median rPFS in the control arm was 8.3 months but had not yet been reached in the ZYTIGA arm because progression events were occurring more slowly in the ZYTIGA arm compared to the control arm (N=150 vs. 251, respectively). The Hazard Ratio (HR) equaled 0.43, there was a 95% confidence interval (CI): [0.35, 0.52], and the p value was <0.0001.
Additionally, treatment with ZYTIGA plus prednisone resulted in an estimated 33 percent improvement in survival (median overall survival in the ZYTIGA arm was not reached and was 27.2 months in the control arm; HR=0.75; 95% CI: [0.61, 0.93], p=0.0097). At the time of these interim analyses, the pre-specified p-value of 0.0008 to achieve statistical significance was not reached.
Treatment with ZYTIGA plus prednisone also suggested significant improvements in secondary study endpoints compared to the control arm, specifically, longer time until:
- Median time to opiate use for cancer pain: the median time in the ZYTIGA arm was not reached and was 23.7 months in the control arm (HR=0.69; 95% CI: [0.57, 0.83]; p=0.0001). - Median time to initiation of cytotoxic chemotherapy for prostate cancer: 25.2 months for the ZYTIGA arm vs. 16.8 months for the control arm (HR=0.58 [95% CI: 0.49, 0.69]; p<0.0001). - Median time to deterioration in performance status: 12.3 months for the ZYTIGA arm vs. 10.9 months for the control arm (HR=0.82; 95% CI: [0.71, 0.94]; p=0.0053) for an increase in the Eastern Cooperative Oncology Group (ECOG) performance score of one point or more. The ECOG performance score is a standard measure used to assess functional status of a patient and is often used to determine prognosis and appropriate treatment. - Median time to PSA progression: 11.1 months for the ZYTIGA arm vs. 5.6 months for the control arm (HR=0.49; 95% CI: [0.42, 0.57], p<0.0001), based on The Prostate Cancer Clinical Trials Working Group (PCWG2) criteria.
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.
Based on these results, Janssen plans to submit marketing applications with regulatory authorities to extend the use of ZYTIGA in men with mCRPC who have not received chemotherapy, beginning in the second half of 2012.
"These results further suggest evidence of the important clinical benefit of ZYTIGA for men with metastatic castration-resistant prostate cancer," said William N. Hait, M.D., Ph.D., Global Head, Janssen Research & Development, LLC and Head, Oncology Therapeutic Area. "The COU-AA-302 study expands our understanding of the utility of treating this disease with ZYTIGA, and is central to our goal of developing extraordinary oncology therapeutic solutions that can have a positive effect on patients' lives."
Janssen Research & Development, LLC previously announced that an Independent Data Monitoring Committee (IDMC) unanimously recommended unblinding this Phase III study after planned interim analyses found a statistically significant difference in rPFS and a trend in the difference in OS. Based on these results, the IDMC also recommended that patients in the control arm be offered treatment with abiraterone acetate.
Study COU-AA-302 is an international, randomised, double-blind, placebo controlled Phase III study that included 1,088 men with mCRPC who had not received prior chemotherapy, who were randomised to receive abiraterone acetate (ZYTIGA) 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 are rPFS and OS.
Since its approval in 2011, ZYTIGA has been made available in more than 40 countries worldwide, many thousands of men have received treatment with it, and it is quickly becoming one of the cornerstones of our oncology offerings.
ZYTIGA(R) in combination with prednisone was approved by the European Medicines Agency (EMA) in September 2011, for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen.
ZYTIGA(R) in combination with prednisone was approved by the U.S. Food and Drug Administration (FDA) in April 2011 for the treatment of men with metastatic castration-resistant prostate cancer who have received prior chemotherapy containing docetaxel.
The Phase III study for this initial ZYTIGA(R) indication was unblinded in August 2010, and approvals were based on results from the planned interim analysis showing a statistically significant improvement in overall survival and an acceptable safety profile. A subsequent analysis with more mature data confirmed the survival benefit and safety profile.
Important Safety Information
Contraindications - ZYTIGA(R) (abiraterone acetate) is not for use in women. Abiraterone acetate is contraindicated in women who are or may potentially be 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(R) 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 randomised clinical trial. Control hypertension and correct hypokalemia before and during treatment.
Monitor blood pressure, serum potassium, and symptoms of fluid retention before treatment and at least monthly thereafter.
Adrenocortical Insufficiency (AI) - AI has been reported in clinical trials in patients receiving ZYTIGA(R) 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(R). 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 interruption, dose modification, and/or discontinuation of ZYTIGA(R). Monitor liver function and modify, withhold, or discontinue ZYTIGA(R) dosing as recommended (see Prescribing Information for further details). Measure serum transaminases prior to starting treatment with ZYTIGA(R), every two weeks for the first three months of treatment, and monthly thereafter. If clinical symptoms or signs suggestive of hepatotoxicity develop, serum transaminases, in particular serum ALT, should be measured immediately. If at any time the ALT rises above 5 times the upper limit of normal, treatment should be interrupted immediately and liver function closely monitored. Re-treatment may take place only after return of liver function tests to the patient's baseline and at a reduced dose level. If patients develop severe hepatotoxicity (ALT 20 times the upper limit of normal) anytime while on therapy, treatment should be discontinued and patients should not be re-treated.
The safety of ZYTIGA(R) in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA(R).
Food Effect - ZYTIGA(R) must be taken on an empty stomach. Exposure to abiraterone increases up to
10-fold when ZYTIGA(R) is taken with meals. No food should be eaten for at least two hours before the dose of ZYTIGA(R) is taken and for at least one hour after the dose of ZYTIGA(R) is taken. Abiraterone Cmax and AUC0-lemniscate(exposure) were increased up to 17- and 10-fold, respectively, when a single dose of ZYTIGA(R) was administered with a meal compared to a fasted state.
Adverse Reactions - The most common adverse reactions (greater than or equal to 1/10) are hypokalemia, peripheral oedema, urinary tract infection and hypertension.
Drug Interactions - ZYTIGA(R) is an inhibitor of the hepatic drug-metabolising enzyme CYP2D6. Caution is advised when ZYTIGA(R) is administered with medicinal products activated by or metabolised by CYP2D6, particularly with medicinal products that have a narrow therapeutic index. Dose reduction of medicinal products with a narrow therapeutic index that are metabolised by CYP2D6 should be considered. Examples of medicinal products metabolised by CYP2D6 include metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecanide, codeine, oxycodone and tramadol (the latter three products requiring CYP2D6 to form their active analgesic metabolites).
Based on in vitro data, ZYTIGA(R) is a substrate of CYP3A4. The use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital) should be avoided, or used with caution during treatment with ZYTIGA(R).
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(This press release contains "forward-looking statements" as defined in the Private Securities Litigation Reform Act of 1995. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or unknown risks or uncertainties materialize, actual results could vary materially from the expectations and projections of Janssen Research & Development, LLC and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to, general industry conditions and competition; economic factors, such as interest rate and currency exchange rate fluctuations; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approvals; challenges to patents; changes in behavior and spending patterns or financial distress of purchasers of health care products and services; changes to governmental laws and regulations and domestic and foreign health care reforms; trends toward health care cost containment; and increased scrutiny of the health care industry by government agencies. A further list and description of these risks, uncertainties and other factors can be found in Exhibit 99 of Johnson & Johnson's Annual Report on Form 10-K for the fiscal year ended January 1, 2012. Copies of this Form 10-K, as well as subsequent filings, are available online a http://www.sec.gov,http://www.jnj.comor on request from Johnson & Johnson. Neither Janssen Research & Development, LLC nor Johnson & Johnson undertake to update any forward-looking statements as a result of new information or future events or developments.)
The original language of this press release is English. Translations into French, German, Italian and Spanish are provided by PR Newswire as a courtesy.
1. ZYTIGA(R) summary of product characteristics 2011.
2. de Bono JS et al. Abiraterone and Increased Survival in Metastatic Prostate Cancer. N Engl J Med 2011; 364(21): 1995-2005.
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