The test may have clinical utility in the future as a surrogate biomarker for survival in clinical trials, potentially speeding the drug testing and approval process, a speaker said. More work will be needed, however, before it can be used in the management of individual patients, he added.
Howard I. Scher, MD, of Memorial Sloan- Kettering Cancer Center, said the evaluation of CTCs as an efficacy response biomarker of OS was part of a planned interim analysis of a phase III study assessing abiraterone acetate (AA) for the treatment of mCRPC (Abstract LBA4517). AA, a CYP17 inhibitor, was recently approved by the U.S. Food and Drug Administration based on an earlier interim analysis of the same phase III study, COUAA- 301, which showed a survival benefit for the drug.
Dr. Scher explained that the prognostic capability of CTC was included as an endpoint in the clinical trial as part of a formal effort to establish a qualified biomarker panel that can be used instead of a survival endpoint in the design of future clinical trials for mCRPC therapies. The study was not designed to assess the use of CTCs for individual patient management.
Baseline CTC and lactate dehydrogenase (LDH) were prognostic for survival, but prostate- specific antigen (PSA) was not, he said. Conversion of CTC from unfavorable (greater than 5 cells/7.5 mL) to favorable (less than 5 cells/7.5 mL) was also prognostic for survival.
Once developed, a prognostic biomarker panel, including CTC, LDH, and other factors, will be prospectively tested in future trials, Dr. Scher said. A number of sponsors have included some of these tests in current clinical trial designs, he noted.
“The initial biomarker panel was strongly associated with survival [in COU-AA-301], and after adjusting for the biomarker panel the treatment effect was no longer apparent,” Dr. Scher said. “The surrogacy question will be explored further in future trials.”
The trial included 1,195 patients with mCRPC who had been previously treated with docetaxel; they were randomly assigned to AA plus prednisone or to prednisone plus placebo. In the second preplanned analysis, with a median follow-up of approximately 20 months, AA increased OS by a median 4.6 months (15.8 months with AA vs. 11.2 months with placebo; hazard ratio: 0.74; 95% CI [0.638, 0.859]; p < 0.0001).
Discussant Daniel J. George, MD, of the Duke Cancer Institute, called the clinical utility of CTC conversion in mCRPC “a work in progress,” but something that is sorely needed.
“We are clearly limited with our interim endpoint assessments,” he said. “Novel effects on pain and bone scan changes are not validated, RECIST measurements largely ignore tumor burden in bone, radiographic changes are a poor measure of OS, and PSAs do not capture the complete treatment effects.”
In the study presented by Dr. Scher, CTC was highly associated with treatment effect, Dr. George noted, but it cannot yet be correlated with individual patient outcomes. In addition, more must be learned about whether there is heterogeneity in CTCs: whether the biology varies, for instance, in patients with low CTCs, and how CTC is affected by other treatments such as chemotherapy.
American Society of Clinical Oncology (ASCO)
[ PRESS RELEASE ]
