Charles J. Ryan, MD
Final survival data for pre-chemotherapy use of abiraterone from the COUGAR-AA-302 study demonstrated a median of 35 months for men with castration resistant prostate cancer. The findings compared favorably with the median survival of 30 months in patients treated with prednisone and placebo, initially, said Charles J. Ryan, MD, professor of medicine and urology at the Hellen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, during an interview with OncLive
From April 2009 to June 2010, 1088 patients were randomized to receive abiraterone with prednisone or prednisone with placebo. Initial outcomes data for progression-free survival (PFS) were released in 2012, but mature survival data were not achieved until mid-2015, said Ryan. During the time of this study, abiraterone was approved and became available in most countries participating in the clinical trial.
“As a result, 44% of the patients who were initially enrolled in the placebo arm went on to receive abiraterone,” said Ryan. There was also a significant amount of subsequent therapy with docetaxel, cabazitaxel, and enzalutamide in both arms of the study, explained Ryan. This resulted in survival curves that required a relatively long period of time to fully mature, which explains why the 2012 data did not demonstrate statistically significant endpoints while the 2015 follow-up analyses confirmed significance.
“But when one sees the evolution of the curves, one sees that when we did that initial presentation and publication, the curves were really just beginning to separate,” said Ryan. “And by the time we get to the median follow-up that we have now, we see a significant and persistent separation of the survival curves.”
At the final 49.2-month analysis of the COU-AA-302 study, the median overall survival (OS) was 34.7 months with abiraterone versus 30.3 months with placebo (HR = 0.81; P
= .0033). The median radiographic professional-free survival (rPFS) with abiraterone acetate was 16.5 months compared with 8.3 months for prednisone (HR = 0.53; P
Clinical progression, either clinical progression only or in combination with radiographic progression, was seen in 39% of the patients, which 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.
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 re-treated 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 iterative parameter estimate (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
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.Secondary Endpoint
A secondary endpoint in COU-AA-302 was time to first opiate use. COU-AA-302 enrolled patients who had very little to no pain that was associated with their disease, and, in fact, patients were required to not be taking opiates at the time of enrollment. Patients receiving abiraterone went 1 year longer than patients in the placebo arm without requiring opiate analgesics. “The development of pain is a major landmark in metastatic prostate cancer,” said Ryan.
“That’s quite a significant time when you think about it, one year less of opiate requirement, and so that’s a very critical, I think, clinical useful and very meaningful endpoint that clinicians and patients can relate to. Interestingly, it took a long time for the majority of patients on the study to require opiates, and so this was one of the later endpoints that matured.”Halting Abiraterone