Absence of circulating tumor cells (CTCs) after 13 weeks of treatment outperformed other potential markers of improved survival in patients with metastatic castration-resistant prostate cancer (mCRPC), a retrospective analysis of five randomized trials showed.
A decline in CTCs from nonzero at baseline to 0 at 13 weeks (CTC0) had a discriminatory power of 0.81 for predicting improved survival versus patients who did not achieve CTC0 status. The FDA-cleared response measure of CTC conversion (≥5 at baseline, ≤4 at 13 weeks) followed with a discriminatory power of 0.79. However, substantially more patients were evaluable for CTC0 than CTC conversion.
Six other response endpoints (CTC and PSA values) had discriminatory power ranging from 0.71 to 0.79, as reported online in the Journal of Clinical Oncology.
“The CTC0 endpoint is an indicator that cancer cells that were circulating in the blood are no longer detectable, an easily recognized outcome that is clinically meaningful to patients,” . “It is an outcome that occurs shortly after treatment initiation, providing researchers and practitioners with objective and reliable evidence that the therapy being administered had altered the patient’s prognosis in a favorable way.
“Taken together, the results of this study support the use of CTC0 as a response endpoint in early-phase clinical trials.”
The author of an accompanying editorial said that “the unambiguous interpretation of a positive and negative [CTC0] test should make this early efficacy marker an attractive intermediate endpoint for consideration of accelerated drug approval by regulatory bodies.”
“However, whether this endpoint should be used in routine clinical practice outside of a clinical trial (ie., as a measure of clinical benefit itself) is far less certain and seems premature at this time,” wrote Emanuel Antonarakis, MD, of Johns Hopkins University in Baltimore.
Antonarakis also acknowledged that PSA-based endpoints had less discriminatory power for predicting overall survival but pointed out that they could be evaluated in almost all patients across the five trials included in the analysis.
The need for clinically meaningful measures of response that occur early in the course of treatment for mCRPC has increased with the expansion of treatment options, including six new agents with diverse mechanisms of action approved since 2010. Each therapy’s approval was based on demonstration of a survival benefit in a large phase III trial, Scher and co-authors noted in their introduction.
In parallel with therapeutic expansion, advances in molecular profiling increased clinicians’ ability to identify subsets of patients and determine their likelihood of response to a given therapy. Historically, PSA-based tests were used to assess treatment efficacy, although the assessments did not provide a strong indication of survival, the authors continued.
In studies of mCRPC, patients with bone disease had higher numbers of CTCs compared with patients who have lymph node involvement, suggesting an association with metastatic spread. Inhibiting the spread of CTCs, therefore, should represent a clinically meaningful therapeutic objective, the authors continued. After phase II studies of abiraterone (Zytiga) and enzalutamide (Xtandi) showed CTC conversion rates of 30-40%, a research collaboration was formed in association with the FDA to study post-treatment CTC-based endpoints in phase III clinical trials.
Scher and colleagues reported findings from an analysis of short-term changes in CTC and PSA and their association with overall survival. The analysis comprised 6,081 patients with mCRPC from five prospective, randomized, phase III trials. Investigators examined the discriminatory power of CTC0 and CTC conversion at 13 weeks for identifying patients who would have improved survival. They also evaluated the endpoints of 30%, 50%, and 70% decreases in CTC count, as well as 30%, 50%, and 70% decreases in PSA level at 13 weeks.
To determine the discriminatory strength of each endpoint, investigators used assessment of the weighted c-index, which has a range of 0.5 to 1.0. A value of 0.5 reflected no discriminatory power between response and nonresponse, and a value of 1.0 indicated that almost all non-responding patients died before responding patients with the shortest survival. The analysis yielded the following discriminatory values:
- CTC0: 0.81
- CTC conversion: 0.79
- CTC30: 0.72
- CTC50: 0.72
- CTC70: 0.73
- PSA30: 0.71
- PSA50: 0.72
- PSA70: 0.74
The authors found that 75% of the patients could be evaluated for CTC0 compared with 51% for CTC conversion. As compared with a 70% decrease in PSA at 13 weeks, CTC0 offered significantly better discriminatory power (P=0.026) and, by extension, significantly better discrimination compared with PSA30 and PSA50.
“In addition to greater discrimination, the CTC0 and CTC conversion response endpoints were more robust, producing consistent weighted c-indices across the five trials,” the authors noted.
This work was partially supported by the FDA as part of a program to develop intermediate endpoints in castration-resistant prostate cancer. Some co-authors were employees of firms with commercial interests in such biomarkers.
Scher disclosed relationships with Asterias Biotherapeutics, Ferring Pharmaceuticals, WIRB-Copernicus Group, Merck, Clovis Oncology, Janssen Research & Development, Astellas Pharma, Sanofi, Physician’s Education Resource, OncLive Insights, Innocrin Pharmaceuticals, and Illumina.
Antonarakis disclosed relationships with Sanofi, Dendreon, Medivation, Janssen Biotech, ESSA, Astellas Pharma, Johnson & Johnson, Aragon Pharmaceuticals, Exelixis, Millennium, Genentech, Novartis, Tokai Pharmaceuticals, and patent/royalty/intellectual property interest.
F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner