The therapeutic landscape for the treatment of castration-resistant prostate cancer has changed dramatically in the past 4 years, as five new agents affecting different aspects of the malignant process were proven to prolong life. The results are a great benefit to patients, but at the same time make it more difficult to prove a survival benefit for future drugs because effective treatment given after enrollment on a trial can blunt a survival outcome. Urgently need are validated biomarkers of clinical benefit that can be used as intermediate endpoints or that can serve as endpoints that are approvable in their own right.
Bone metastases are the most frequent form of prostate cancer spread and are responsible for some of the most feared complications of the disease, including pain, spinal cord compression, and deterioration in functional status and overall quality of life. Pain in itself is an adverse prognostic factor for survival.
Problems in assessing disease in bone have long been recognized due to the lack of standards for interpreting the imaging modalities used to detect and monitor the illness. Similarly, problems arise from the lack of validated and reliable biomarkers that reflect the adverse impact of the disease on the individual patient or a cohort of patients at baseline or following treatment.
Paradigm for Drug Development
In 2008, the Prostate Cancer Working Group (PCWG2) described a paradigm for drug development in castration-resistant prostate cancer focused on short-term “response” measures (reflecting the control, relief, or elimination of disease manifestations present at the time treatment is initiated) and “progression” measures (represented by the delay or prevention of future manifestations).1
To apply the approach in a clinical setting requires analytically valid “biomarkers” of the disease that, in turn, are validated clinically in prospective trials focused specifically on the context in which they will be used. Qualification of a biomarker to be used in a filing for regulatory approval requires evidence generated from multiple phase III trials, each addressing the same context of use (ie, the clinical setting for which the results of the test will be used to inform a medical decision) in accordance with PCWG2 recommendations and U.S. Food and Drug Administration (FDA) guidelines.
The process requires close collaboration among investigators, study sponsors, and regulatory agencies. “Prevent or delay” biomarkers such as pain progression must also undergo rigorous statistical analysis to assess their adequacy as surrogates. Several candidate biomarkers seek to fulfill the unmet need for validated indicators of treatment efficacy, of which changes in circulating tumor cell enumeration as a surrogate for survival is most mature.
In a study reported in The Lancet Oncology and reviewed in this issue of The ASCO Post, Basch and coworkers applied the PCWG2 principle of using validated measures to compare the effects of abiraterone (Zytiga) plus prednisone vs placebo plus prednisone on maintaining (controlling) quality of life and on preventing (delaying) deterioration of pain status and overall health of patients enrolled in the phase III COU-AA-302 trial.2,3 The coprimary endpoints of this registration trial were radiographic progression-free survival and overall survival.
The analyses reported here were prespecified secondary outcomes.2 Pain was assessed using an instrument validated according to standards defined by the FDA in its guidance for patient-reported outcomes, the Brief Pain Inventory Short Form coupled with World Health Organization analgesic use criteria. The measures were recorded at baseline, repeatedly at 4-week intervals during treatment, and at treatment discontinuation, and the definition of pain progression included a confirmatory measurement. Overall patient compliance was outstanding.
The results showed that the combination of abiraterone plus prednisone was superior to placebo plus prednisone for all of the quality-of-life measures reported and demonstrated the feasibility of measuring pain progression and deterioration in quality of life in a patient with minimal or no symptoms. The association of the benefit shown for abiraterone plus prednisone relative to placebo plus prednisone with the delay in time to radiographic progression-free survival events provided additional evidence in support of the clinical utility of the health-related quality-of-life endpoint used.
Importance of Biomarker Questions
The trial also illustrates the importance and value of investing time and resources to embed biomarker questions using validated instruments in large scale randomized trials so that the outcomes assessed with the biomarker can be associated with the clinical benefit outcome that the trial was designed to demonstrate. Validated intermediate endpoint biomarkers short of survival that can serve as surrogates for benefit, or that represent a benefit in their own right, would significantly shorten drug development time lines, enable the evaluation of more treatments, and make needed drugs available to patients more rapidly. ■
Dr. Scher is Chief, Genitourinary Oncology Service at the Sidney Kimmel Center for Urologic and Prostate Cancers at Memorial Sloan-Kettering Cancer Center, New York.
Disclosure: Dr. Scher reported no potential conflicts of interest.
1. Scher HI, Halabi S, Tannock I, et al: Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: Recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 26:1148-1159, 2008.
2. Basch E, Autio K, Ryan CJ, et al: Abiraterone acetate plus prednisone versus prednisone alone in chemotherapy-naive men with metastatic castration-resistant prostate cancer: Patient-reported outcome results of a randomised phase 3 trial. Lancet Oncology 14:1193-1199, 2013.
3. Ryan CJ, Smith MR, de Bono JS, et al: Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 368:138-148, 2013.
An interim analysis of the COU-AA-302 phase III trial in asymptomatic or mildly symptomatic chemotherapy-naive men with metastatic castration-resistant prostate cancer showed that the addition of abiraterone (Zytiga) to prednisone significantly delayed radiographic progression and improved overall...