Novel Drug Studies Yield Biomarker Candidates for Prostate Cancer Bone Turnover

Primo N. Lara Jr, MD

Prostate cancer has a propensity to metastasize to bone. High turnover ultimately results in a net loss of bone tissue; prostate cancer treatment contributes to the loss of bone integrity, as androgen- deprivation therapy often causes abnormally low bone density. These factors all contribute to increasing the risk for fractures and other so-called skeletal-related events. While studying a novel drug being developed against castration-resistant prostate cancer that also had been reported to affect bone metabolism, we found that secreted bone turnover biomarkers could help us prognosticate and perhaps even predict patient benefit from bone-targeted therapy.

Our latest research validated preliminary findings in castration-resistant prostate cancer patients in which baseline (or pretreatment) blood levels of proteins associated with bone turnover were found to be strongly associated with survival. As part of a phase III Southwest Oncology Group (SWOG) trial (S0421), we reported that patients with high baseline levels of these blood markers had a much shorter lifespan than those with low levels. However, and more importantly, patients with the highest marker levels—those with levels in the upper 25th percentile—appeared to preferentially benefit from an investigational bonetargeted therapy being tested in S0421.

The findings are the result of our collaboration with the US Department of Agriculture’s Western Human Nutrition Research Center (WHNR) co-located at the University of California, Davis. The center houses a dozen senior scientists conducting basic research on immunity, obesity, and other nutrition-related topics.

At the time of our first joint research project, we were conducting a phase II study of a novel drug (BMS-275291, a matrix metalloproteinase inhibitor that also had anti-collagenase properties), and needed a laboratory-based expert to help assay each patient’s bone metabolism by measuring blood levels of proteins associated with bone resorption and formation. Marta Van Loan, PhD, a scientist at WHNRC who specializes in bone metabolism and who also holds an adjunct faculty position at UC Davis, was enlisted to help on the initial project, which included 80 subjects with metastatic castration-resistant prostate cancer. BMS-275291 was later shown to have minimal activity in this patient population. But, as a correlative study embedded within the trial, we found that patients with lower levels of bone turnover markers tended to survive longer, and their disease was less likely to progress during the four-month study period. In contrast, patients with high bone markers and higher bone turnover had much shorter survival times. This demonstrated the strong prognostic value of these markers in this patient cohort. We also found that these bone biomarkers had the promise to predict who would respond to bone-targeted treatment and also help monitor the patient’s response to treatment.

We then tested this approach in a much larger, national SWOG trial involving patients with castration-resistant disease that had metastasized to bone. All of the patients in that trial received standard- of-care chemotherapy (docetaxel). Patients were randomized to concurrently receive atrasentan, an experimental endothelin antagonist that also had bone-targeted properties, or a matched placebo. The analysis of 4000 blood samples collected from more than 800 patients in the study (and performed in Van Loan’s lab) confirmed our earlier findings: bone turnover biomarkers secreted in the bloodstream had strong prognostic value. Importantly, in a small subset of patients, a survival benefit from atrasentan was detected, but only in patients whose bone turnover markers were in the highest quartile. This showed for the first time that bone markers might have clinical utility in helping select patients for appropriate bone-targeted treatment.

Although atrasentan is no longer under development in prostate cancer, orteronel, a new drug that inhibits androgen production, is now being tested in metastatic prostate cancer patients who are just initiating androgen deprivation therapy as part of a new phase III SWOG trial. Again, we will investigate the role of bone turnover biomarkers in this patient population in the hopes of predicting which patients would benefit from a drug such as orteronel in the noncastrate-resistant setting.

Ultimately, we hope the test could help us treat only those most likely to benefit from specific therapies. This approach will spare patients who are not going to benefit from the side effects of ineffective therapy.