Biomarkers of Bone Metabolism in CRPC With Skeletal Metastases
Biomarkers of Bone Metabolism in CRPC With Skeletal Metastases
Deaths from prostate cancer are commonly due to CRPC, the virulent end-stage form of the disease. The vast majority of patients with CRPC will suffer from skeletal metastases, a frequent source of morbidity, including bone pain or fracture. Because there are no established biomarkers relevant to bone metabolism that are currently used in clinic to prognosticate survival or to select therapy, research on candidate bone biomarkers remains critically warranted.
Several bone markers have been used to monitor cancer patients' responses to therapy and include blood and urine products of bone collagen breakdown and serum markers of osteoblast activity and bone collagen synthesis. Circulating serum biomarkers are attractive to use in clinic because of their practicality and ease of availability. These markers also reflect the totality of the cancer's biologic heterogeneity, instead of molecular readouts from small tumor biopsies or archival specimens that capture only a fragment of an otherwise highly heterogeneous tumor.
Some markers of bone turnover—specifically urine NTx and serum bone alkaline phosphatase—have previously shown prognostic significance in the context of bisphosphonate use. In a pooled analysis of phase III trials of zoledronic acid, an elevated baseline BAP level in prostate cancer patients was associated with an increased risk for a skeletal related event (odds ratio [OR] = 1.53; P = .03) and progression (OR = 2.64; P < .001). High baseline urine NTx levels were associated with higher rates of progression (relative risk [RR] = 2.2; P < .001) and death (RR = 5.72; P < .001). Serial reductions in serum BAP and urinary NTx during protocol therapy for either hormone-sensitive prostate cancer or CRPC were associated with better survival. However, there have been no prospective studies before this report to show that elevated baseline markers of bone metabolism in CRPC are predictive of benefit from bone-targeted therapy.
In CRPC patients with nonmetastatic disease, atrasentan appeared to have modest effects on time to disease progression (TTP), with a reported 93-day delay in the median TTP with atrasentan; however, the TTP difference compared with placebo was not statistically significant (P = .29). In two other prior randomized trials of atrasentan vs placebo in the metastatic CRPC setting, a trend was detected for a TTP benefit in favor of atrasentan. In one of those trials (a phase III study involving >800 patients), atrasentan therapy was reported to yield a TTP hazard ratio of 0.88 (95% CI = 0.75 to 1.03) with a P value of .12. In a post hoc subset analysis of that trial, patients with bone metastases at baseline were found to have an even better hazard ratio for TTP—0.8 with a 95% confidence interval (0.67 to 0.95) that did not cross unity. These hints of atrasentan activity in the phase III setting suggest that only a small subset of patients preferentially benefit from this agent and that perhaps a biologic marker can be used to detect those patients a priori. The results we report herein not only validate the strong prognostic value of serum markers of bone resorption and formation but also appear to identify the likely subset of CRPC patients who benefit from treatment with atrasentan. These data also provide proof of principle for the concept of bone marker–driven patient and treatment selection to be tested with other osteoblast milieu-targeted agents in prostate cancer.
These results are limited by issues related to generalizability because only 6% of patients appear to preferentially benefit and by the fact that the predictive value of bone biomarkers may not necessarily be applicable to all bone-directed treatments. It is also uncertain whether additional bone biomarkers can improve the prognostic and predictive performance of the existing biomarker group.
In conclusion, our results show serum baseline levels of bone turnover can serve as biomarkers for both prognosis and prediction in metastatic CRPC. Future studies of bone-targeted therapies in this disease should consider using bone marker levels (dichotomized at the median) as a stratification factor and designing cohort enrichment strategies using these markers.
Discussion
Deaths from prostate cancer are commonly due to CRPC, the virulent end-stage form of the disease. The vast majority of patients with CRPC will suffer from skeletal metastases, a frequent source of morbidity, including bone pain or fracture. Because there are no established biomarkers relevant to bone metabolism that are currently used in clinic to prognosticate survival or to select therapy, research on candidate bone biomarkers remains critically warranted.
Several bone markers have been used to monitor cancer patients' responses to therapy and include blood and urine products of bone collagen breakdown and serum markers of osteoblast activity and bone collagen synthesis. Circulating serum biomarkers are attractive to use in clinic because of their practicality and ease of availability. These markers also reflect the totality of the cancer's biologic heterogeneity, instead of molecular readouts from small tumor biopsies or archival specimens that capture only a fragment of an otherwise highly heterogeneous tumor.
Some markers of bone turnover—specifically urine NTx and serum bone alkaline phosphatase—have previously shown prognostic significance in the context of bisphosphonate use. In a pooled analysis of phase III trials of zoledronic acid, an elevated baseline BAP level in prostate cancer patients was associated with an increased risk for a skeletal related event (odds ratio [OR] = 1.53; P = .03) and progression (OR = 2.64; P < .001). High baseline urine NTx levels were associated with higher rates of progression (relative risk [RR] = 2.2; P < .001) and death (RR = 5.72; P < .001). Serial reductions in serum BAP and urinary NTx during protocol therapy for either hormone-sensitive prostate cancer or CRPC were associated with better survival. However, there have been no prospective studies before this report to show that elevated baseline markers of bone metabolism in CRPC are predictive of benefit from bone-targeted therapy.
In CRPC patients with nonmetastatic disease, atrasentan appeared to have modest effects on time to disease progression (TTP), with a reported 93-day delay in the median TTP with atrasentan; however, the TTP difference compared with placebo was not statistically significant (P = .29). In two other prior randomized trials of atrasentan vs placebo in the metastatic CRPC setting, a trend was detected for a TTP benefit in favor of atrasentan. In one of those trials (a phase III study involving >800 patients), atrasentan therapy was reported to yield a TTP hazard ratio of 0.88 (95% CI = 0.75 to 1.03) with a P value of .12. In a post hoc subset analysis of that trial, patients with bone metastases at baseline were found to have an even better hazard ratio for TTP—0.8 with a 95% confidence interval (0.67 to 0.95) that did not cross unity. These hints of atrasentan activity in the phase III setting suggest that only a small subset of patients preferentially benefit from this agent and that perhaps a biologic marker can be used to detect those patients a priori. The results we report herein not only validate the strong prognostic value of serum markers of bone resorption and formation but also appear to identify the likely subset of CRPC patients who benefit from treatment with atrasentan. These data also provide proof of principle for the concept of bone marker–driven patient and treatment selection to be tested with other osteoblast milieu-targeted agents in prostate cancer.
These results are limited by issues related to generalizability because only 6% of patients appear to preferentially benefit and by the fact that the predictive value of bone biomarkers may not necessarily be applicable to all bone-directed treatments. It is also uncertain whether additional bone biomarkers can improve the prognostic and predictive performance of the existing biomarker group.
In conclusion, our results show serum baseline levels of bone turnover can serve as biomarkers for both prognosis and prediction in metastatic CRPC. Future studies of bone-targeted therapies in this disease should consider using bone marker levels (dichotomized at the median) as a stratification factor and designing cohort enrichment strategies using these markers.
