Charles J. Ryan, MD
The overall survival (OS) benefit seen with abiraterone acetate became more pronounced after adjustment for crossover from placebo to active treatment in men with progressive metastatic castration-resistant prostate cancer (mCRPC) in the COU-AA-302 study, investigators led by Charles J. Ryan, MD, reported at the 2015 Genitourinary Cancers Symposium.
“Effectively, at this point, abiraterone is one of the standards if not the standard of care in the chemotherapy-naïve castration-resistant prostate cancer patient in multiple countries worldwide,” said Ryan, associate professor of medicine and urology, University of California, San Francisco. “It compares very favorable to enzalutamide, the other agent in the class. These more recent results merely add to our confidence in the data by suggesting that there was an impact of cross over on the survival.”
COU-AA-302 was a phase III, multinational, randomized, double-blind, placebo-controlled trial of more than 1,088 men with asymptomatic or mildly symptomatic mCRPC who had not received chemotherapy previously. Patients were randomized in a 1:1 ratio to abiraterone acetate, 1000 mg daily, plus prednisone or placebo plus prednisone.
The study was unblinded at the second interim analysis following the recommendation of the data and safety monitoring committee. After only 43% of the planned deaths had occurred, patients randomized to placebo were permitted to crossover to receive abiraterone acetate. At the time of unblinding, abiraterone acetate increased OS and the time to opiate use.
A planned sensitivity analysis was performed to adjust for the crossover effect using the iterative parameter estimate (IPE) method “that estimates the true treatment effect under an accelerated failure time model.” It is a statistical method that tries to “ascertain what the survival difference would have been if that crossover had not occurred,” said Ryan. “It basically eliminates the effect of the crossover.”
Baseline characteristics were similar between the two randomized groups, including median time from initial diagnosis to first dose (5.5 years in patients randomized to abiraterone acetate vs 5.1 years in patients randomized to placebo), median level of prostate-specific antigen (42.0 ng/mL vs 37.7 ng/mL), the percentage who had Gleason grade ≥8 disease at initial diagnosis (54% vs 50%), and the extent of disease including the percentage with bone metastases (83% vs 80%). About half in each group had ≥10 bone metastases.
At a median follow-up of 49.2 months, 741 deaths occurred (96% of the planned deaths). At this time, 92% of patients in the abiraterone acetate arm and 100% in the placebo arm discontinued therapy. The reason for discontinuation was disease progression in 68% of the abiraterone acetate arm and 69% in the placebo arm.
“If we look at the abiraterone arm, there were 30% who stopped because of radiographic only progression,” said A. Oliver Sartor, Medical Director at Tulane Cancer Center, New Orleans, who was not involved in the study. “I was a little bit surprised. That was lower than I was expecting. 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.”
Clinical only progression was defined as pain requiring opioids, the need for chemotherapy or palliative radiation therapy, a decline in Eastern Cooperative Oncology Group performance status, or surgical intervention, and 26% met at least one of these criteria. “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,” said Sartor.
After protocol, the rate of subsequent therapy with either cabazitaxel, docetaxel, and enzalutamide was similar in both groups. Some 44% of patients randomized to placebo crossed over to abiraterone acetate while 13% of those randomized to abiraterone acetate were retreated with abiraterone.
At the final analysis, the risk of death was reduced by 19% in the abiraterone acetate arm, with the median OS prolonged from 30.3 months in the placebo arm to 34.7 months in the abiraterone acetate arm (P
=.0033). Forty-four percent of patients randomized to placebo crossed over to abiraterone acetate. The IPE adjustment improved the reduction in the risk of death with abiraterone acetate to 26% (P
<.0001). When adjusting for baseline prognostic factors, abiraterone acetate led to a 21% reduction in the risk of death (P
“I think it really does help to underscore that abiraterone in the pre-docetaxel phase can prolong survival,” said Sartor.