Charles J. Ryan, MD, recently presented the final analysis of the COU-AA-302 study of abiraterone acetate (ZYTIGA) versus placebo.
Orlando, FL-An improvement in overall survival (OS) with abiraterone acetate (ZYTIGA) compared with placebo in men with progressive metastatic castration-resistant prostate cancer (mCRPC) is statistically significant after a median follow-up of more than 4 years in the COU-AA-302 study.
The final analysis, presented at the Genitourinary Cancers Symposium in Orlando, FL, showed that with the occurrence of 96% of the planned deaths (median follow-up: 49.2 months), abiraterone plus prednisone reduced the risk of death by 19% (p=.0033) compared with placebo and prednisone in this study of 1,088 men with asymptomatic or mildly symptomatic mCRPC.
Dr. RyanAfter adjustment for crossover from placebo to abiraterone, the treatment effect was even more pronounced, with a 26% decrease (p<.0001) in the adjusted risk of death in the abiraterone group, said first author Charles J. Ryan, MD, professor of medicine in the division of hematology/oncology the University of California, San Francisco. This adjustment to the analysis was prespecified.
The adjustment method was an iterative parameter estimate that tries to “ascertain what the survival difference would have been if that crossover had not occurred,” said Dr. Ryan. “It basically eliminates the effect of the crossover.”
COU-AA-302 was a phase III, multinational, randomized, double-blind, placebo-controlled trial of 1,088 men with asymptomatic or mildly symptomatic mCRPC who had not received chemotherapy previously. Patients were randomized to abiraterone, 1,000 mg daily, plus prednisone; or placebo plus prednisone.
Previous analyses of OS benefit with abiraterone in COU-AA-302 had failed to achieve significance because of the number of interim analyses, said Dr. Ryan. The study was unblinded at the second interim analysis on the recommendation of the data and safety monitoring committee, when 43% of the planned deaths had occurred.
“The key factor is that we expected a fair amount of subsequent therapy. We really didn’t know how much crossover there would be when the study was planned, and as it turned out, 44% of those enrolled on the placebo arm subsequently received abiraterone at some point in the course of the study,” Dr. Ryan said.
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At the final analysis, 92% of patients in the abiraterone arm and 100% in the placebo arm discontinued therapy. Subsequent therapy was used in 67% of the abiraterone arm and in 80% of the placebo arm, with doectaxel (Taxotere) being the most common subsequent therapy. Subsequent therapy in the abiraterone and placebo arms was as follows: docetaxel (57% and 61%, respectively), abiraterone (13% and 44%), cabazitaxel (Jevtana, 18% and 19%), enzalutamide (XTANDI, 16% and 10%), ketoconazole (8% and 13%), sipuleucel-T (Provenge, 8% and 6%), and radium-223 (Xofigo, 4% and 1%).
Of note, the reason for discontinuation was disease progression in 68% of the abiraterone arm and 69% in the placebo arm, and 30% in the abiraterone arm discontinued because of radiographic-only progression.
Dr. Sartor“I was a little bit surprised. That was lower than I was expecting,” said A. Oliver Sartor, MD, medical director of Tulane Cancer Center, New Orleans, who was not involved in the study. “On the other hand, clinical progression, either clinical progression only or in combination with radiographic progression, was 39% of the patients, and this was clinically significant. This tells me that a lot of patients will clinically deteriorate without having radiographic progression, and that’s important if you’re treating these patients.”
In a multivariate analysis, treatment with abiraterone emerged as a significant (p=.0013) predictor of survival as well. Other baseline prognostic factors that were significant for OS were PSA (p<.0001), lactate dehydrogenase (p<.0001), hemoglobin (p<.0001), alkaline phosphatase (p<.0001), bone metastases (p=.001), and age (p=.0069).
“Effectively, at this point, abiraterone is one of the standards if not the standard of care in chemotherapy-naïve castration-resistant prostate cancer patient in multiple countries worldwide,” said Dr. Ryan.
Dr. Ryan has received honoraria and travel, accommodations, and expenses remuneration from Janssen Pharmaceuticals, Inc. For a full list of disclosures, click here.
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