Howard Scher, MD
Prostate cancer research lacks surrogate biomarkers for survival that could hasten the study and approval of new medications. Without these early indicators, regulatory approval for new treatments requires large, lengthy trials demonstrating a definitive survival benefit.
A new analysis of a phase III abiraterone acetate (Zytiga) trial supports previous research suggesting circulating tumor cell (CTC) levels could be a predictor of survival. The study was presented in a late-breaking abstract at the 2011 ASCO Annual Meeting in Chicago, Illinois.
Circulating tumor cells are cells that break off from the tumor and flow through the bloodstream. Research has shown that when treatments reduce CTC levels to <5 cells/7.5 mL of blood, it often correlates with improved survival outcomes.
The research presented at ASCO examined CTCs as part of an updated analysis of the phase III randomized COU-AA-301 trial of abiraterone, which involved 1195 patients with metastatic castrate-resistant prostate cancer (mCRPC) previously treated with docetaxel. The COU-AA-301 trial was the basis of the FDA’s approval in April of abiraterone’s indication for mCRPC.
The initial COU-AA-301 trial data demonstrated a median survival benefit of 3.9 months (14.8 mo vs 10.9 mo) in patients receiving abiraterone with prednisone versus the control group combination of placebo and prednisone. The updated analysis found an even higher survival benefit of 4.6 months (15.8 mo vs 11.2 mo) in the abiraterone cohort versus the placebo arm.
The researchers then reviewed whether CTC levels correlated with abiraterone’s survival benefit. “We were particularly interested in CTCs because we know the genesis of metastatic disease is typically from cancer cells that spread through the bloodstream,” said Howard Scher, MD, Memorial Sloan-Kettering Cancer Center, New York, the lead author of the analysis.
Researchers had tracked CTC levels as part of the design of the COU-AA-301 trial. Data included CTC levels at baseline and 4, 8, and 12 weeks’ follow-up for 972, 838, 783, and 723 patients, respectively. The results demonstrated that abiraterone lowered CTC levels to favorable levels of <5 at all follow-up points. These CTC reductions correlated with overall survival, demonstrating CTCs’ potential as a surrogate biomarker.
According to Scher, the study is the first trial to demonstrate improved overall survival that also considered CTCs as a surrogate biomarker. Additionally, the CTC evaluation was coordinated with federal regulators. “We collaborated with the Food and Drug Administration in a formal regulatory [pact] in order to officially qualify this as a potential surrogate or endpoint in clinical trials to enable drugs to be available sooner,” said Scher.
Based on their positive analysis, researchers are now examining CTCs as part of a biomarker panel for survival in studies of mCRPC treatments. Although the initial data is encouraging, Scher said establishing CTCs as a surrogate endpoint will require additional supporting research. “In order to qualify the biomarker, ultimately we need to show the same effect in multiple phase III trials. Three of these are ongoing.
Scher HI, Heller G, Molina A, et al. Evaluation of circulating tumor cell (CTCs) enumeration as an efficacy response biomarker of overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC): Planned final analysis (FA) of COU-AA-301, a randomized, double-blind, placebo-controlled, phase III study of abiraterone acetate (AA) plus low-dose prednisone (P) post docetaxel. (abstract LBA4517)