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ORLANDO -- Survival improved and disease progression slowed in men with metastatic castration-resistant prostate cancer (CRPC) treated initially with abiraterone acetate, updated results of a randomized trial showed.

The time to radiographic progression doubled in men treated with abiraterone (Zytiga) and prednisone versus prednisone alone at 16.5 versus 8.3 months. Overall survival (OS) improved by 5 months in the abiraterone arm. More than twice as many patients had at least a 50% decline in PSA levels with abiraterone, reported Dana Rathkopf, MD, from Memorial Sloan-Kettering Cancer Center in New York City, and colleagues.

Results were consistent across all prespecified subgroups, she said at the Genitourinary Cancers Symposium.

"Treatment with abiraterone plus prednisone delays the time to opiate and [subsequent] chemotherapy use, improves quality-of-life measures, and remains safe and well tolerated with longer exposures," she explained.

The findings came from a new analysis of a randomized comparison of abiraterone-prednisone versus prednisone-placebo as first-line therapy for metastatic CRPC. An interim analysis demonstrated significant improvement in radiographic progression-free survival (rPFS) in the abiraterone arm and a trend toward improved OS after a median follow-up of 2 years, leading to early termination of the trial.

An inhibitor of androgen biosynthesis, abiraterone received FDA approval for treatment of metastatic CRPC that had progressed after first-line therapy with docetaxel. Rathkopf reported findings from a trial that examined abiraterone's potential as an option for first-line therapy.

The analysis included 1,088 men randomized and treated by investigators in 12 countries. The trial had coprimary endpoints of OS and rPFS. The previous analysis showed the median rPFS and median OS had yet to be reached in the abiraterone arm.

After a median follow-up of 27.1 months, the updated analysis demonstrated a 47% reduction in the progression hazard for abiraterone-prednisone versus prednisone-placebo (hazard ratio 0.53, 95% CI 0.45 to 0.62, P<0.0001).

The abiraterone group had a median OS of 35.3 months compared with 30.1 months for the placebo group, representing a 21% improvement, which did not meet the prespecified definition for statistical significance of P=0.0035 (HR 0.79, 95% CI 0.66 to 0.95, P=0.0151). Data analyses have been event driven, and a final analysis of OS will occur after 773 events, Rathkopf said.

Analysis of both coprimary endpoints showed a uniform response in analyses stratified for performance status, pain score, sites of metastasis, age, baseline laboratory values (PSA, lactate dehydrogenase, and alkaline phosphatase), and geographic region.

More than two-thirds of patients received subsequent therapy, most often docetaxel (about 60%). Other therapies included cabazitaxel (Jevtana), ketoconazole, sipuleucel-T (Provenge), and crossover from placebo to abiraterone.

Evaluation of secondary and exploratory endpoints showed significant advantages for abiraterone with respect to time to opiate use, time to subsequent chemotherapy, time to deterioration of performance status, time to PSA progression, time to pain progression, and time to deterioration in health-related quality of life (P=0.0052 to P<0.0001).

Rathkopf reported that 69% of patients treated with abiraterone had at least a 50% decline in PSA values compared with 29% of the control group.

In general, abiraterone was well tolerated, and no unexpected adverse events occurred. The most common adverse events (all grades) were fatigue (40%), fluid retention (29%), hypertension (22%), cardiac disorders (21%), hypokalemia (17%), and elevated liver enzymes (11% to 12%). Grade 3/4 adverse events were uncommon and did not exceed 7% for any type of event.

Invited discussant William Oh, MD, said abiraterone has demonstrated efficacy. The next step is to determine optimal timing for initiation of therapy.

"The improvement in rPFS appears meaningfully better in the prechemotherapy setting," said Oh, of Mount Sinai Medical Center in New York City. "There was an 8-month difference in the [prechemotherapy setting] and a 2-month difference in the [postchemotherapy setting]."

"Notably, the OS benefit is the same -- about 5 months -- irrespective of chemotherapy," he added. "It is likely that the maximal benefit of abiraterone is seen when used prior to chemotherapy."

The Genitourinary Cancers Symposium is cosponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and Society of Urologic Oncology.

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