BERKELEY, CA (UroToday.com) - June 21, 2012 - Translating the clinical results observed from pre-specified interim analyses of the randomized, placebo-controlled phase III study, COU-AA-302 demonstrated that patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate plus prednisone showed a statistically significant improvement in radiographic progression-free survival (rPFS), and all secondary endpoints, compared to patients treated with placebo plus prednisone.
Perspectives on the interim analysis results of COU-AA-302 were discussed with Charles J. Ryan, MD in this exclusive interview with UroToday.
UroToday: Can you provide perspective on the clinical relevance of the results observed from pre-specified interim analyses of the randomized, placebo-controlled phase III study where COU-AA-302, demonstrated that patients with metastatic castration-resistant prostate cancer (mCRPC), treated with abiraterone acetate plus prednisone, showed a statistically significant improvement in radiographic progression-free survival (rPFS) and all secondary endpoints compared to patients treated with placebo plus prednisone?
Dr. Ryan: The first point is that anybody treating prostate cancer realizes that the application of chemotherapy in this disease is somewhat limited either by patient or physician choice due to the toxicity of that treatment. So the development of abiraterone acetate, as well as other therapies, is moving along the lines of developing oral, well-tolerated treatments that can delay progression and improve survival and that can help maintain the general well being of patients who have metastatic castration resistant prostate cancer (mCRPC) - many of whom are free of symptoms of the disease for a long period of time.
In the context of oncology in general at this time, abiraterone acetate is emblematic of where we are going as oncologists in the big picture in terms of developing more targeted, better-tolerated oral therapies.
The second point is prostate cancer in general is getting very complicated from the standpoint of the wide variety of treatments that are becoming available and determining where to sequence them in the spectrum of the disease.
So it is important as we talk about these results to know exactly who the patients were who were treated and what the results showed.
The third point is this phase III trial utilized co-primary endpoints, which were utilized for the reason that many of these patients have a fairly long expected survival. Therefore, only measuring overall survival as an endpoint of the trial can be complicated or contaminated by many other treatments that these patients could receive.
In light of that we used radiographic progression-free survival (rPFS) and overall survival (OS) as co-primary endpoints.
The results of the study show that patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate plus prednisone, when compared to prednisone alone, led to a statistically significant and clinically meaningful delay in disease progression. By clinically meaningful, I mean it more than doubled the time until patient disease progressed compared for the patients in the abiraterone acetate plus prednisone arm to those receiving prednisone alone.
For the purposes of this study, a rising PSA did not constitute progression of the disease. What constituted disease progression was the development of new metastatic lesions. And it is important to note that in this study the average PSA was 45 and about 50% of the patients had >10 bone metastases at study enrollment.
This is the first randomized study to demonstrate a radiographic progression-free survival benefit and a strong trend for overall survival in this patient population.
The fourth point is that in addition to looking at rPFS and overall survival, we looked at a series of other clinically relevant endpoints:
- Median time to opiate use for cancer pain: the median time in the abiraterone acetate plus prednisone arm was not reached and was 23.7 months in the control arm (HR = 0.69; 95% CI: [0.57, 0.83]; p = 0.0001).
- Median time to initiation of cytotoxic chemotherapy for prostate cancer: 25.2 months for the abiraterone acetate plus prednisone arm vs. 16.8 months for the control arm (HR = 0.58 [95% CI: 0.49, 0.69]; p < 0.0001).
- Median time to decline in performance status: 12.3 months for the abiraterone acetate plus prednisone arm vs. 10.9 months for the control arm (HR = 0.82; 95% CI: [0.71, 0.94]; p = 0.0053) for an increase in the Eastern Cooperative Oncology Group (ECOG) performance score of one point or more. The ECOG performance score is a standard measure used to assess functional status of a patient and is often used to determine prognosis and appropriate treatment.
- Median time to PSA progression: 11.1 months for the abiraterone acetate plus prednisone arm vs. 5.6 months for the control arm (HR = 0.49; 95% CI: [0.42, 0.57], p < 0.0001), based on The Prostate Cancer Clinical Trials Working Group (PCWG2) criteria.
On every one of these secondary endpoints, patients receiving abiraterone acetate plus prednisone had a statistically significant prolongation on average until that event occurred.
So, in summary these results show that patients:
- can live longer without disease progression
- can live longer without symptoms
- can live longer until performance status deteriorates
- can live longer until receiving chemotherapy
- and probably live longer overall.
The overall survival results of this trial are continuing to mature. And at the time of this interim analysis, we saw a strong trend in favor of abiraterone acetate plus prednisone arm compared to the prednisone arm, (p = 0.0097).
This is an important study with all clinically relevant endpoints favoring treatment with abiraterone acetate plus prednisone, and is also the first to suggest that inhibiting androgen production significantly delays initiation of chemotherapy.
There will be subsequent analysis for survival before the true statistical difference between the arms is known.
UroToday: Can you clarify the results of overall survival in this study and what may be analyzed in the future?
Dr. Ryan: The study is unblinded and ongoing. These are planned interim analyses.
The reason you do interim analyses is you are looking for an imbalance that would tell you that it is unethical to continue treating patients with placebo. These trials are monitored by Independent Data Monitoring Committees (IDMC) who do not work for the sponsor and who are not investigators on the trial. These committees are truly independent.
When the Independent Data Monitoring Committee (IDMC) looked at the data, they looked at the survival trend; they looked at this long rPFS difference; they looked at all the secondary endpoints we just reviewed. Then, they said as a group, unanimously including their statisticians, that these data demonstrate compelling evidence for clinical benefit associated with abiraterone acetate, and therefore they recommended to the sponsor that the study be unblinded and the sponsor, Janssen Research & Development, LLC. unblinded the study.
The study was unblinded in February 2012. The next interim analysis will be happening relatively shortly. We do not know yet how many patients were unblinded and crossed over abiraterone acetate. We look forward to the next interim analysis in the near future.
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