CHICAGO – Abiraterone acetate plus prednisone significantly delays progression and initiation of chemotherapy in asymptomatic or mildly symptomatic, chemotherapy-naive, metastatic, castration-resistant prostate cancer, according to much-anticipated data from a pivotal clinical trial.

The second preplanned interim analysis of the COU-AA-302 trial also revealed a strong overall survival trend favoring abiraterone (Zytiga) over prednisone and placebo, leading to unblinding of the phase III trial in March 2012 and crossover treatment for the control arm.

Median overall survival was 27.2 months with prednisone and placebo, but had not been reached in the abiraterone arm at the time of the analysis, with 43% of total events reported. This corresponds to a hazard ratio of 0.75 and P value of .0097 that fell shy of the prespecified significance level of .0008.

No subgroup of patients is driving the overall survival benefit, nor is there a particular group of patients who experienced an unfavorable outcome from treatment with abiraterone relative to the control group, reported Dr. Charles J. Ryan, lead author of a late-breaking abstract presented at the annual meeting of the American Society of Clinical Oncology.

"These data merit consideration as providing a new standard approach in this highly prevalent patient population faced with an unmet medical need," said Dr. Ryan of the University of California, San Francisco.

This is the first trial to show progression and overall survival benefits in this setting. Janssen Research & Development announced it will seek a new indication for abiraterone in chemotherapy-naive, metastatic, castration-resistant prostate cancer (mCRPC) in the second half of 2012.

The combination of abiraterone plus prednisone has already demonstrated an overall survival benefit in patients with prior chemotherapy, leading to its approval in April 2011 for mCRPC that had previously been treated with docetaxel (Taxotere) chemotherapy.

Invited discussant Susan Halabi, Ph.D., a biostatistician at Duke University Medical Center in Durham, N.C., said the trial represents a paradigm shift, but faulted the investigators for stopping the trial before a statistically significant overall survival benefit was seen. Stopping a trial too early may fail to persuade some clinicians to change medical practice, she observed.

COU-AA-302 investigators at 151 sites in 12 countries, including the United States, randomized 546 men to abiraterone at the standard dosage of 1,000 mg daily plus prednisone 5 mg twice daily, and 542 men to the same prednisone dosage plus daily placebo.

At initial diagnosis, 54% of the abiraterone and 50% of the control patients had a Gleason score of 8 or greater. Median prostate-specific antigen (PSA) levels at baseline were 42 ng/mL and 37.7 ng/mL, respectively. The patients’ median age was about 70 years.

After a median follow-up of 22.3 months, the co–primary end point of radiographic progression by blinded central review was reached at a median of 8.3 months in the control arm, but had not been reached in the abiraterone arm (HR, 0.43; P less than .0001). A subset analysis revealed that the benefit of abiraterone on progression-free survival occurred across all subgroups tested, said Dr. Ryan, The investigators also looked at several secondary end points that are hallmarks of disease progression and clinically meaningful to patients over the prolonged natural history of progressive mCRPC, he said.

Abiraterone significantly delayed the time to chemotherapy initiation from 16.8 months with prednisone plus placebo to 25.2 months (HR, 0.58; P less than .0001), to ECOG performance status deterioration from 10.9 months to 12.3 months (HR, 0.82; P = .0053), and to PSA progression from 5.6 months to 11.1 months (HR, 0.49; P less than .0001). Time to opiate use for cancer-related pain was 23.7 months in the control arm, but had not been reached with abiraterone (HR, 0.69; P = .0001).

Subsequent therapy, which can influence both survival and the secondary end points, was reported in 60% of the control arm and 44% of the abiraterone arm, he said. Docetaxel was most commonly used at 53% and 38%, respectively, although abiraterone was subsequently used in 10% of control and 5% of abiraterone patients.

Patients received a median of 15 cycles of abiraterone (range, 1-33 cycles), which is longer than in other trials, but the extended treatment did not lead to any new safety signals, Dr. Ryan said. The abiraterone arm reported more grade 3 and 4 adverse events than did the control arm, notably cardiac events (6% vs. 3%), hypertension (4% vs. 3%) and elevations in alanine aminotransferase (5.4% vs. 0.8%) and aspartate aminotransferase (3% vs. 0.9%). In all, 7% of abiraterone patients discontinued therapy due to an adverse event, compared with 5% of those on prednisone plus placebo.

Ortho Biotech Oncology Research & Development sponsored the study. Dr. Ryan reported no disclosures; his coauthors reported financial relationships with several companies, including Janssen.

Abiraterone Blocks Chemo-Naive Prostate Cancer