Circulating Tumor Cell Count and LDH Level as Patient-Level Surrogate for Survival in Metastatic Castration-Resistant Prostate Cancer
In an analysis reported in the Journal of Clinical Oncology, Scher et al found that circulating tumor cell count and LDH level served as an individual-level surrogate for survival among patients with metastatic castration-resistant prostate cancer receiving abiraterone acetate (Zytiga) plus prednisone vs prednisone in the phase III COU-AA-301 trial.
Study Details
The double-blind COU-AA-301 trial included 1,195 patients previously treated with paclitaxel. The current analysis includes 711 patients (484 in the abiraterone-prednisone group, 227 in the prednisone group) with available 12-week biomarker data. Biomarker analysis was a secondary objective of the trial.
Performance of Surrogate Marker
The combination of circulating tumor cell count and LDH level at 12 weeks was shown to satisfy the four Prentice criteria for individual-level surrogacy (ie, treatment must have a significant effect on the clinical endpoint and a significant effect on the biomarker, the biomarker must have a significant impact on the endpoint, and the full effect of treatment on the endpoint must be captured by the biomarker).
Among patients included in the analysis, the abiraterone-prednisone group had significantly better overall survival vs prednisone alone (17.7 vs 15.1 months, hazard ratio = 0.80, P = .034). Risk categorization for circulating tumor cell count plus LDH was circulating tumor cells ≤ 4/7.5 mL of blood plus any LDH = low; circulating tumor cells ≥ 5/7,5 mL of blood plus LDH < 250 U/L = intermediate; and circulating tumor cells ≥ 5/7.5 mL of blood plus LDH ≥ 250 U/L = high.
Median overall survival for the high-, intermediate-, and low-risk groups was 8.71, 12.02, and 22.18 months (P < .001 on stratified log-rank test for the surrogate effect on survival). The discriminatory power of the surrogate in predicting survival was high, with a weighted c-index of 0.81.
Finally, a test of equivalence between a Cox survival model based on treatment assignment and the surrogate measure and the model based on the surrogate measure was performed, with P values for the test being calculated for each month between 6 and 24 months and adjusted for multiple testing. The maximum adjusted P value was < .001, with the significant result showing equivalence of the models and indicating little added value of including treatment assignment in the model.
Overall, 1-year survival in the circulating tumor cell–LDH low-, intermediate-, and high-risk groups was 82%, 51%, and 25%, and 2-year survival was 46%, 10%, and 2%.
The investigators concluded: “A biomarker panel containing [circulating tumor cell] number and LDH level was shown to be a surrogate for survival at the individual-patient level in this trial of abiraterone acetate plus prednisone versus prednisone alone for patients with metastatic [castration-resistant prostate cancer]. Additional trials are ongoing to validate the findings.”
Howard I. Scher, MD, of Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer Center, is the corresponding author of the Journal of Clinical Oncology article.
The study was supported by Cougar Biotechnology (now Janssen Oncology), Prostate Cancer Foundation, and Veridex (now Janssen Diagnostics), Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer Center, Department of Defense Prostate Cancer Research Program, Mr. William H. and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research and the Memorial Sloan Kettering Cancer Center Experimental Therapeutics Center, Starr Cancer Consortium, Medical Research Council, and Prostate Cancer UK.
For full disclosures of the study authors, visit jco.ascopubs.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
