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CTC, LDH biomarker panel serves as surrogate for prostate cancer survival
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A biomarker panel composed of circulating tumor cell number and lactate dehydrogenase level accurately served as a surrogate for survival in men with castration-resistant prostate cancer who received prednisone with or without abiraterone acetate, according to results of a secondary analysis of a phase 3 trial.
“In a 3-year period, five different therapies were proven to prolong life in patients with progressive castration-resistant prostate cancer,” Howard I. Scher, MD, of the Sidney Kimmel Center for Prostate and Urologic Cancers at Memorial Sloan Kettering Cancer Center, and colleagues wrote. “The results give new hope to those in need of effective treatment, but at the same time, the availability of more life-prolonging treatments makes it more difficult to demonstrate the survival benefit for future new drugs.”
Howard L. Scher
Scher and colleagues sought to evaluate circulating tumor cells (CTCs) alone and in combination with other biomarkers as a surrogate for OS using Prentice criteria due to the need for surrogate markers in this setting to hasten the approval process, according to study background. Prentice criteria required that the treatment have a significant effect on the endpoint and on proposed biomarker, that the biomarker has a significant impact on the clinical endpoint, and that the full effect of treatment on the clinical endpoint is captured by the biomarker.
The analysis was a secondary objective of the phase 3 COU-AA-301 trial, which evaluated the addition of abiraterone acetate (Zytiga, Janssen Biotech) to prednisone in 711 men with castration-resistant prostate cancer (median age, 69 years; range, 42-95).
Researchers measured patients’ biomarkers — including CTCs, PSA, lactate dehydrogenase (LDH), hemoglobin, albumin and alkaline phosphate levels — at baseline, 4, 8 and 12 weeks.
Patients assigned abiraterone acetate plus prednisone demonstrated statistically significant and clinically meaningful estimated improvements in OS compared with patients assigned prednisone alone (17.7 months vs. 15.1 months; HR = 0.8, 95% CI, 0.65-0.98). This outcome satisfied Prentice criteria to justify evaluating potential surrogate endpoints for survival.
Overall, researchers observed that a biomarker panel composed of CTCs plus LDH satisfied the four Prentice criteria. The constructed panel categorized patients’ risks as low (CTC ≤ 4 cells/7.5 mL; any LDH), intermediate (CTC ≥ 5 cells/7.5 mL; LDH ≤ 250 U/L) or high (CTC ≥ 5 cells/7.5 mL; LDH ˃ 250 U/L).
Twelve-week surrogate biomarker data were available from 711 patients. The treatment effect on the surrogate was statistically significant (P < .001) and indicated that the surrogate outcome differed by treatment regimen. Researchers noted discriminatory power of the surrogate to predict mortality was high (weighted c-index, 0.81).
A greater proportion of patients who fit the biomarker panel criteria for low-risk disease achieved 2-year OS than patients with high-risk disease (46% vs. 2%).
The researchers acknowledged limitations to their study, including that only 59% of initially enrolled patients had CTC enumeration performed.
“CTC count and LDH level demonstrated individual patient-level surrogate in this single phase 3 trial, further supporting use as a clinical trial endpoint,” Scher and colleagues concluded. “Independent phase 3 trials are ongoing to validate the individual patient-level surrogacy shown here and to begin the process of testing trial-level surrogacy to enable the endpoint to become part of regulatory submissions.” – by Cameron Kelsall
Disclosure: Please see the full study for a list of the researchers’ relevant financial disclosures.
Perspective
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Donald L. Trump, MD, FACP
Scher and colleagues present an intriguing and important analysis of patients enrolled in COU-AA-301, a trial of abiraterone acetate plus prednisone vs prednisone alone in castration-resistant prostate cancer in which they evaluated in rigorous fashion the impact of the detection of circulating tumor cells (CTCs).These investigators previously have described the technology and choice of “cut points” for number of CTCs. Using this same methodology, they found that — among 711 patients with data available at 12 weeks — CTC count and lactate dehydrogenase (LDH) satisfied the Prentice criteria for individual level surrogacy, the rigorous principles defining surrogacy enunciated by Ross L. Prentice, PhD. The distribution of surrogate markers was not equal between the two arms of the trial and “adding the surrogate to the model eliminated the treatment effect on survival,” the researchers wrote.
These data remind us of several issues:
• The importance of biomarkers and impact that properly validated ones can have on trials analysis;
• The potential for well-validated biomarkers to influence the design of trials (assessing biomarkers such as these prior to randomization to establish balance among arms, and designing trials in which poor — or good — prognosis biomarkers are criteria for entry); and
• The possibility of using such well-validated biomarkers as endpoints in and of themselves, permitting perhaps a 12-week treatment trial in which decline of CTCs is predictive enough of survival that the endpoint can be assessed, shortening trial conduct and speeding drug development.
The path to FDA adoption of such changes in CTCs and LDH as validated surrogate markers of survival is not clear. Although the study by Scher and colleagues is scientifically rigorous and satisfies what many would argue is the “gold standard” of surrogacy, this is a difficult area. In this study, more than 40% of patients entered on the trial did not have serial CTCs assessed. In addition, some have raised the concern that use of surrogate endpoints does speed new drugs to the clinic, and results in many drugs reaching patients. But for too many of these agents, post-accelerated approval studies fail to confirm that extended time to treatment failure, for example, really does predict increased survival.
The Milwaukee Journal-Sentinel and MedPage Today conducted what must be described as a “lay analysis” of 26 drugs that received accelerated approval based on surrogate endpoint analysis and had been approved more than 2 years ago.
Their conclusion: “Only three of those 26 drugs have been proven to increase survival. One increased survival 10 months; one by 8 weeks; and another increased the 3-year survival rate to 70% from 61% compared with those who got a placebo.”
If this analysis is accurate, it emphasizes the considerable work still needed in this area. Changes in CTCs plus LDH appear to be a robust surrogate marker for survival and, in the current environment, one can envision the FDA adopting this surrogate if confirmed in one or more additional studies. How this will really impact patient care and drug approval processes (two different issues) will require additional work!
References:
FDA approves cancer drugs without proof they’re extending lives. Available at: www.jsonline.com/watchdog/watchdogreports/fda-approves-cancer-drugs-without-proof-theyre-extending-lives-b99348000z1-280437692.html. Accessed on Oct. 5, 2015.Prentice RL. Stat Med. 1989;8:431-440.
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