Bone Metabolism Biomarkers Predict Prostate Cancer Survival

Levels of biomarkers linked to bone metabolism (bone formation and resorption) are indicative of survival in patients with castration-resistant prostate cancer (CRPC), and identify a small group of patients who can benefit from treatment with the investigational drug atrasentan.

Prior studies have found that elevated markers of bone turnover were prognostic for poor survival in CRPC patients. The predictive role of these markers relative to bone-targeted therapy has not been clear. To better understand the relationship between bone metabolism biomarkers and cancer outcome, investigators at the University of California, Davis (USA) analyzed blood serum samples from 778 CRPC patients treated on a placebo-controlled phase III trial of docetaxel with or without the bone targeted endothelin-A receptor antagonist atrasentan. The serum samples were tested for biomarkers of both resorption (N-telopeptide, pyridinoline) and formation (C-terminal collagen propeptide, bone alkaline phosphatase).

Results revealed that elevated baseline levels of each of the markers were associated with worse survival, and increasing marker levels by week nine of therapy were also associated with subsequent poor survival. Approximately 6% of patients with the highest marker levels responded to atrasentan, an investigational drug abandoned because it had failed in clinical trials.

Atrasentan is an experimental drug that is under evaluation for the treatment of various types of cancer, including non-small-cell lung cancer. It is an endothelin receptor antagonist selective for subtype A. While other drugs of this type (sitaxentan, ambrisentan) exploit the vasoconstrictive properties of endothelin and they are mainly used for the treatment of pulmonary arterial hypertension, atrasentan blocks endothelin induced cell proliferation.

"We found that patients with high levels of these markers in the blood had a much shorter lifespan compared to patients with low levels," said senior author Dr. Primo Lara, associate director for translational research at the University of California, Davis. "By measuring bone turnover in prostate cancer patients, we can determine how well they do."

"Atrasentan kept coming up short in randomized trials because the drug only works for a small group," said Dr. Lara. "Because certain drugs only succeed in a fraction of patients, drug makers need to factor in these bone metabolism markers in their trial design. They need to target the patients most likely to benefit. I think the days of doing empirical studies on all comers should end. You need to have an appropriate database of patients and perform a rigorous analysis to find the subset who will benefit from an investigational drug."

The study on bone metabolism biomarkers was published in the February 24, 2014, online edition of the Journal of the National Cancer Institute.

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