Serum biomarkers of bone metabolism in castration-resistant prostate cancer patients with skeletal metastases: results from SWOG 0421

Abstract

Background: Prior studies suggest that elevated markers of bone turnover are prognostic for poor survival in castration-resistant prostate cancer (CRPC). The predictive role of these markers relative to bone-targeted therapy is unknown. We prospectively evaluated the prognostic and predictive value of bone biomarkers in sera from CRPC patients treated on a placebo-controlled phase III trial of docetaxel with or without the bone targeted endothelin-A receptor antagonist atrasentan (SWOG S0421).

Methods: Markers for bone resorption (N-telopeptide and pyridinoline) and formation (C-terminal collagen propeptide and bone alkaline phosphatase) were assayed in pretreatment and serial sera. Cox proportional hazards regression models were fit for overall survival. Models were fit with main effects for marker levels and with/without terms for marker-treatment interaction, adjusted for clinical variables, to assess the prognostic and predictive value of atrasentan. Analysis was adjusted for multiple comparisons. Two-sided P values were calculated using the Wald test.

Results: Sera from 778 patients were analyzed. Elevated baseline levels of each of the markers were associated with worse survival (P < .001). Increasing marker levels by week nine of therapy were also associated with subsequent poor survival (P < .001). Patients with the highest marker levels (upper 25th percentile for all markers) not only had a poor prognosis (hazard ratio [HR] = 4.3; 95% confidence interval [CI] = 2.41 to 7.65; P < .001) but also had a survival benefit from atrasentan (HR = 0.33; 95% CI = 0.15 to 0.71; median survival = 13 [atrasentan] vs 5 months [placebo]; P interaction = .005).

Conclusions: Serum bone metabolism markers have statistically significant independent prognostic value in CRPC. Importantly, a small group of patients (6%) with highly elevated markers of bone turnover appear to preferentially benefit from atrasentan therapy.

Trial registration: ClinicalTrials.gov NCT00134056.

Figure 1.

Unadjusted receiver operating characteristic curves for bone markers in the placebo and atrasentan arms, respectively, with corresponding areas under the curve (AUC). BAP = bone alkaline phosphatase; CICP = C-terminal of type 1 collagen; FP = False Positive; NTx = N-telopeptide of type 1 collagen; PYD = pyridinoline; TP = True Positive.

Figure 2.

Baseline serum markers of bone metabolism in castration-resistant prostate cancer (CRPC) patients: association with overall survival. A) Bone alkaline phosphatase (BAP). B) C-terminal of type 1 collagen (CICP). C) N-telopeptides of type 1 collagen (NTx). D) Pyridinoline (PYD). Kaplan–Meier curves are shown for each of the biomarkers. Y-axis represents survival probability. All P values are two-sided. Each of these comparisons has a P value less than .001.

Figure 3.

Kaplan–Meier survival curves of castration-resistant prostate cancer (CRPC) patients with low (<25th percentile; left image) and high (≥25th percentile; right image) bone marker levels. Y-axis represents overall survival probability. Patients with the highest levels of bone biomarkers not only have a very poor prognosis (hazard ratio [HR] = 4.3; 95% confidence interval [CI] = 2.41 to 7.65; P < .001) but have a statistically significant survival benefit from atrasentan (HR = 0.33; 95% CI = 0.15 to 0.71; P _interaction = .005). Patients whose bone biomarkers were not in the upper 25th percentile did not benefit from atrasentan therapy, with a median survival time of approximately 19.5 months in both arms (P = .83). P values were calculated using the Wald test and are two-sided.