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Circulating tumor cell count may be an effective surrogate endpoint for OS in prostate cancer
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SAN FRANCISCO — A reduction to no circulating tumor cells at week 13 appeared to be a stronger indicator of survival outcomes than a 50% or greater reduction in PSA from baseline in phase 2 trials of metastatic castration-resistant prostate cancer, according to a study presented at Genitourinary Cancers Symposium.
“When we look at the past few years, there have been dramatic changes in the number of treatment options for metastatic castration-resistant prostate cancer, and it continues to improve,” Howard I. Scher, MD, co-chair of the Center for Mechanism Based Therapy, head of the biomarker development initiative and D. Wayne Calloway chair in urologic oncology at Memorial Sloan Kettering Cancer Center, said during his presentation. “However, if we look carefully, we see that most of these drugs were approved based on endpoints that occur late, such as skeletal events, metastasis-free survival or prolongation of life. With the exception of the control of pain, there are no drugs approved based on a favorable change in disease manifestation, whether it is PSA decline, tumor shrinkage or a favorable change in a bone scan.”
Scher and colleagues sought to determine whether various circulating tumor cell and PSA response endpoints could act as traditional surrogates for OS in phase 2 trials. They used data from five randomized metastatic, castration-resistant prostate cancer trials to evaluate four 13-week response endpoints among 6,081 patients: PSA50 (50% or greater reduction in PSA from baseline); CTC0 (decrease to no circulating tumor cells [CTCs] in men who had at least one circulating tumor cell per 7.5 ml of blood at baseline); both PSA50 and CTC0; and either PSA50 or CTC0.
Scher described CTC0 as a “new endpoint.”
“This essentially means that there was at least one circulating tumor cell pretreatment, and then zero cells post-treatment,” he said.
Researchers evaluated the efficacy of these endpoints at OS surrogates at the patient level by discrimination, or the separation between responder and nonresponder survival curves, and at the trial level through explained variation and the effectiveness in predicting k-month survival in a trial with the response proportion.
Of the enrolled participants, 5,660 (93%) survived until week 13. Of these, 3,080 (54%) had a baseline CTC count of at least one and baseline PSA of 5 ng/ml or greater.
At the patient level, researchers observed a greater separation between responder and nonresponder survival curves over time with CTC0 (0.35) than PSA50 (0.29).
At the trial level, CTC0 also showed greater explained variation in survival over time (average R-squared, 0.67) than PSA50 (average R-squared, 0.58).
Response endpoints combining CTC and PSA did not improve on CTC0 at either the patient or trial level.
Scher noted that CTC0 has shown superiority over PSA50 in predicting survival across all timepoints, but that the 95% CIs are wide and not definitive, suggesting the need for further study.
—failure to decline portends a poor prognosis. For a population in a phase 2 trial, the proportion in which CTC0 is achieved provides a meaningful measure of efficacy. More trials are needed to show trial-level surrogacy along with further validation for drugs that do not affect androgen receptor signaling.” – by Jennifer Byrne
Reference: Sher HI, et al. Abstract 143. Presented at: Genitourinary Cancers Symposium; Feb 14-16, 2019; San Francisco.
Disclosures: Scher reports a leadership role with Asterias Biotherapeutics; stock and other ownership interests in Asterias Biotherapeutics; consultant/advisory roles with Ambry Genetics Corp., Janssen Biotech, Janssen Research & Development, Konica Minolta Inc., OncLive Insights, Physician Education Resource, Sanofi and WIRB-Copernicus Group; institutional research funding from Illumina, Innocrin Pharma and Janssen; and travel, accommodations and expenses from Asterias Biotherapeutics, OncLive Insights, Physician Education Resource, Sanofi and WIRB-Copernicus Group. Please see the study for all other authors’ relevant financial disclosures.