Howard I. Scher, MD
An analysis of results from 5 clinical trials showed that circulating tumor cell (CTC) conversion and CTC value ≥ 1 at baseline (CTC0) were superior predictors of overall survival (OS) than PSA in men with metastatic castration-resistant prostate cancer (mCRPC).
Investigators examined 8 endpoints across 5 prospective randomized phase III trials: COU-AA-301, AFFIRM, ELM-PC-5, ELM-PC-4, and COMET-1. A total of 6801 patients were included.
At 13 weeks, the ability to differentiate the survival outcomes for week-13 responders and nonresponders was greatest using the CTC0 and CTC conversion endpoints. Researchers found the absence of CTCs after treatment, or if the value had converted from above to below the threshold of 5 CTCs, provided greater discrimination for patient survival than the percent change in CTC or PSA response endpoints.
The average weighted c-index for the CTC0 was 0.81 and 0.79 for CTC conversion response endpoints. The average weighted c-indices for the percent change CTC and PSA endpoints ranged from 0.71 to 0.74.
“To develop new therapeutic agents requires the ability to determine whether a systemic therapy has clinical benefit (eg, improving how a patient feels and functions and how long the patient survives). This seemingly simple need has been one of the most challenging aspects of drug development for patients with mCRPC, because reliable and informative early-occurring indicators of clinical benefit are lacking,” corresponding author Howard I. Scher, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, and coauthors wrote.
“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 has 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,” added Scher et al.
CTC counts and PSA levels at baseline and week 13 were used to define the response endpoints. The evaluable study cohorts from each trial were patients who survived at least 13 weeks and had a recorded baseline CTC or PSA value.
The 8 CTC and PSA response measures considered were CTC0 (patients with CTC count ≥1 at baseline and 0 at week 13); CTC conversion (patients with CTC count ≥5 at baseline and ≤4 at week 13); percent change in CTC (CTC30, CTC50, CTC70; patients with CTC count ≥5 at baseline and a 30%, 50%, or 70% decline from baseline to week 13, respectively); and percent change in PSA (PSA30, PSA50, PSA70; PSA level ≥5 ng/mL at baseline and a 30%, 50%, or 70% decline from baseline to week 13, respectively).
Patients who achieved these biomarker thresholds were recorded as responders. All other patients were recorded as nonresponders, including those with recorded baseline data who survived more than 13 weeks but dropped out of the biomarker component of the study before week 13.
In addition to greater discrimination, investigators found the CTC0 and CTC conversion response endpoints were more robust. Those 2 endpoints consistently produced weighted c-indices across the 5 trials.
Importantly, investigators found that CTC0 was applicable to a significantly higher percentage of patients than CTC conversion.
Overall, 75% of eligible patients were evaluable for the CTC0 endpoint compared with 51% for the CTC conversion endpoint. In these 5 studies, the relative increase in the percentage of patients evaluable for the CTC0 endpoint compared with CTC conversion ranged from 29% to 71%. The greatest proportional increase occurred among chemotherapy-naïve patients and the least difference occurred among those who had been exposed to at least 2 prior treatments.
Heller G, McCormack R, Kheoh T, et al. Circulating tumor cell number as a response measure of prolonged survival for metastatic castration-resistant prostate cancer: comparison with prostate-specific antigen across five randomized phase III clinical trials [published online December 22, 2017]. J Clin Oncol doi: 10.1200/JCO.2017.75.2998.