High Bone Biomarker Levels Linked to Preferential Survival Benefit of Atrasentan in Castration-Resistant Prostate Cancer With Skeletal Metastases
Although elevated markers of bone turnover are associated with poor survival in castration-resistant prostate cancer, the association of these markers with outcome in the setting of bone-targeted therapy is uncertain. In a study reported in the Journal of the National Cancer Institute, Lara et al evaluated the relationship of bone biomarkers with outcome in castration-resistant prostate cancer patients with skeletal metastases receiving docetaxel with or without the bone targeted endothelin-A receptor antagonist atrasentan in the phase III SWOG S0421 trial. They found that bone turnover markers have independent prognostic value and that a small group of patients characterized by elevated markers have preferential survival benefit from atrasentan.
Study Details
In the study, markers for bone resorption (N-telopeptide and pyridinoline) and formation (C-terminal collagen propeptide and bone alkaline phosphatase) were measured in pretreatment and serial sera from 778 study patients, 382 of whom had received docetaxel/atrasentan and 396 of whom had received docetaxel/placebo. A Bonferroni correction for multiple comparisons was used in the analyses, setting statistical significance at a P value of ≤ .006.
Prognostic Value
On analysis adjusting for clinical covariates, twofold increases in baseline levels were associated with significantly poorer overall survival for bone alkaline phosphatase (hazard ratio [HR] = 1.23), C-terminal collagen propeptide (HR = 1.38), N-telopeptide (HR = 1.40), and pyridinoline (HR = 1.52; P < .001 for all). Increasing bone marker levels at week 9 were also associated with significantly poorer overall survival, with hazard ratios of 1.28 (P < .001) for bone alkaline phosphatase, 1.35 (P < .001) for C-terminal collagen propeptide, 1.36 (P = .002) for N-telopeptide, and 1.36 (P = .002) for pyridinoline. Patients in the atrasentan group had a greater reduction in pyridinoline (P < .001) and C-terminal collagen propeptide levels (P = .02) vs the placebo group at 9 weeks.
Survival Effect
There was some evidence of a survival benefit with atrasentan in patients with upper quartile levels of bone alkaline phosphatase (ratio of HRs = 0.65, P = .04) or C-terminal collagen propeptide (ratio of HRs = 0.61, P = .02), although these interactions did not achieve statistical significance. However, the subgroup of patients with upper quartile levels of all four markers, representing 6% of the study population, had both markedly increased risk of mortality (HR = 4.3, P < .001) and a 67% improvement in median overall survival with atrasentan treatment (HR = 0.33, median survival 13 vs 5 months, P = .005 for interaction). There was no evidence that bisphosphonate use modified the treatment effect of atrasentan on overall survival in this subgroup.
The investigators concluded, “Serum bone metabolism markers have statistically significant independent prognostic value in [castration-resistant prostate cancer]. Importantly, a small group of patients (6%) with highly elevated markers of bone turnover appear to preferentially benefit from atrasentan therapy.”
Primo N. Lara, Jr, MD, of University of California Davis School of Medicine, is the corresponding author of the Journal of the National Cancer Institute article.
The study was supported by grants from the National Cancer Institute.
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