Second agent shows significant benefit in mCRPC pre-chemo

Abiraterone acetate (ZYTIGA) as therapy for chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) improved overall survival by a statistically significant 19% compared with placebo in the final analysis of the phase III COU-AA-302 clinical trial.

The study data importantly address “the very important question of the timing of this agent” and the benefit of earlier treatment, according to one prostate cancer expert.

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The final analysis, presented at the European Society of Medical Oncology annual meeting in Madrid, Spain, consisted of data from 49.2 months of follow-up. A third interim analysis had already shown a doubling in the time to radiographic progression-free survival (rPFS), from 8.2 months in the placebo/prednisone arm to 16.5 months in the abiraterone/prednisone arm (p<.0001). The benefit on overall survival with abiraterone did not meet the required p-value for significance at the three interim analyses but did so at the time of the final analysis, reported lead investigator Charles J. Ryan, MD, of the University of California, San Francisco.

Abiraterone is the second agent for mCRPC to show a significant survival benefit in the pre-chemotherapy setting. The FDA approved enzalutamide (XTANDI) last month based primarily on phase III study data showing enzalutamide significantly reduced the risk of death by 29% compared with placebo (HR: 0.71; p<.0001).

In the COU-AA-302 trial investigating abiraterone, eligible patients were required to have mCRPC and to be free of disease-related symptoms that would lead to a requirement for opiate analgesic use. The study included 1,008 men with mCRPC who were randomized to receive abiraterone, 1,000 mg orally once daily, with concurrent prednisone, 5 mg twice daily, or placebo plus prednisone, 5 mg twice daily.

The study was unblinded upon the recommendation of the Independent Data Safety Monitoring Committee after the second interim analysis based on a significant difference in rPFS as well as an emerging trend for OS in favor of abiraterone. After unblinding, the study was not discontinued. A subsequent protocol amendment allowed patients in the placebo arm to receive abiraterone.

At the time of the final analysis, 92% of patients in the abiraterone arm and 100% in the placebo arm have discontinued therapy, most often for radiographic progression. Median OS was 34.7 months in the abiraterone arm and 30.3 months in the placebo arm, corresponding to a 19% relative reduction in the risk of death (p=.0033). The treatment effect of abiraterone was more pronounced when adjusting for the 44% of patients in the placebo group who subsequently received abiraterone (HR: 0.74).

More than one fourth of patients randomized into the abiraterone arm have survived for 48 months or longer, Dr. Ryan noted.

"OS is particularly noteworthy in COU-AA-302, because 67% of men in the ZYTIGA plus prednisone arm and 80% in the control arm received subsequent therapy. This includes 44% of men in the control arm who subsequently received ZYTIGA plus prednisone," Dr. Ryan said in a news release from Janssen Research & Development, LLC, which sponsored the 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."

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The final analysis also demonstrated a significant improvement in median time to opiate use for cancer-related pain for abiraterone compared with placebo (median of 33.4 vs. 23.4 months, respectively; p=.00001). No new safety signals emerged despite the longer duration of therapy and follow-up compared with prior analyses.

The trial was more of a comparison between early and late hormone treatment strategies rather than one testing the utility of abiraterone pre-chemotherapy, said Bertrand Tombal, MD, PhD, who was not involved in the study.

“When you look at the second treatment and you notice that nearly 50% received abiraterone, the design of the trial has become early abiraterone versus late abiraterone in 50% of the patients,” said Dr. Tombal, of Université Catholique de Louvain, Brussels, Belgium. “More than ever, it addresses the very important question of the timing of this agent and the benefit of an earlier timing on the patient. To me, that is the most important question.”

Although the p-value for overall survival benefit with abiraterone in COU-AA-302 became more robust over time, “the hazard ratio hasn’t improved,” he added.

Over the past 60 years, studies have demonstrated that earlier hormone therapy changes the dynamic of progression but does not result in a major improvement in overall survival, he said. To have the greatest impact on overall survival, hormone therapy needs to be combined with some form of local treatment.

Based on the results of the final analysis, Janssen said it has initiated regulatory submissions to relevant health authorities for a revision to the abiraterone label.

Dr. Ryan has received honoraria from Janssen. Three study co-authors are employees of the company.

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