Charles J. Ryan, MD, discusses the final survival data for pre-chemotherapy use of abiraterone from the COUGAR-AA-302 study, which demonstrated a median of 35 months for men with castration resistant prostate cancer.
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 < .0001).
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 = .0013).
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.
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.”
While some clinicians may discontinue abiraterone therapy based on a rise in PSA level, Ryan advises against this approach because continuing therapy may still help slow down the progression of disease. However, he says, for patients who are developing progressive disease with new lesions on bone scans or new visceral metastases, discontinuation of abiraterone is clinically prudent.
When to discontinue abiraterone during the patient’s regimen is difficult to answer. According to the COUGAR study, patients did not discontinue abiraterone because of a rising prostate-specific antigen. “In fact, there was a fairly lengthy time interval between when PSAs began to rise and when radiographic progression occurred. In many cases, it’s 6 or 7 months, and, in some cases, I’ve had patients who continue to take abiraterone for well over a year or even longer without requiring discontinuation.” Discontinuing abiraterone because of a simple rise in PSA may actually be doing patients a disservice. “Continuing the therapy may continue to slow down the progression of the disease, and some of the data we have from the 302 study bear that out.”
“If a patient is developing progressive disease with progressive symptoms and objective progression, new lesions on bone scan or new visceral metastases, it’s clinically prudent to discontinue the abiraterone.”
Ryan cautioned that “there are patients who will progress and may exhibit symptomatic progression. These patients can be treated with radiation therapy. I’d urge clinicians to evaluate progression as its own event and look at it and ask the question, ‘Is it global progression?’ ‘Does it involve multiple sites and general decline?’ Or is it an isolated progression? If it’s an isolated progression, consider either a focal radiation therapy or something along those lines.”
Demonstrating Overall Survival in Metastatic Prostate Cancer
There are several challenges in demonstrating an improvement in overall survival in metastatic prostate cancer, said Ryan.
There are multiple agents available for patients, and “so if we want to test something in metastatic castration resistant prostate cancer (mCRPC), we’re going to require or allow that patients would receive subsequent therapy.” He said there are numerous chemotherapies available. The challenge is that “once you begin lining up a series of therapies, all of which have survival benefits, it becomes statistically quite difficult to demonstrate survival benefits.” That makes subsequent therapy a major challenge.
He said that the other major challenge in the design of phase III trials of mCRPC is the fact that this is a chronic disease and patients live a long time. “That’s a clinically good thing but it’s a challenge in terms of designing a phase III trial. So, when one considers initiating a trial in the current era with all these available therapies, and we now have data to show that the median survival for patients with mCRPC is about three years, you’re talking about a five- or six-year endeavor in order to design, run, and read out phase III trials.”
When non-metastatic castration resistant prostate cancer is considered, it is even more challenging because the patients are in an even earlier clinical state. “So the trials that are taking place in that area of non-metastatic CRPC or the early asymptomatic CRPC state, are generally getting larger, accruing 1400 or 1700 patients, and are taking longer. That becomes a pretty significant resource impediment.”
Castration Resistance With no Metastasis
With the advent of a number of therapies for metastatic castration resistant prostate cancer, researchers are now looking at patients who are castration resistant but exhibit no disease spread.
One group of patients exist because of early use of androgen deprivation therapy (ADT) for patients with a serologic relapse, sometimes referred to as the “PSA-only patient,” said Ryan. The other group is less common and are characterized by metastases in the lymph nodes, for example, who start on ADT, and then ultimately progress by having a prostate-specific antigen (PSA) rise. However, imaging scans reveal no evidence of metastatic disease.
“These patients don’t really fit into the standard of care guidelines that govern metastatic disease,” said Ryan.
During this year’s American Urologic Association meeting, Ryan presented results from a Phase II study involving 125 patients who were treated with abiraterone and low-dose prednisone. The study was designed to measure PSA changes.
Ryan reported that “87% of patients who received abiraterone had a 50% decline in their PSA. That’s a higher percentage of patients having a PSA decline than we saw with metastatic disease.” This group has not met the median progression free survival.
“This study is ongoing and it will provide some very important insight into the efficacy of abiraterone in that setting.”
Impact of crossover and baseline prognostic factors on overall survival (OS) with abiraterone acetate (AA) in the COU-AA-302 final analysis. Presented at: 2015 Genitourinary Cancers Symposium; February 26-28, 2015; Orlando, FL. Abstract 142.