Elevated bone markers prevalent in men on ADT

April 18, 2019

Nearly 90% of men with hormone-sensitive prostate cancer (HSPC) who initiate androgen deprivation therapy (ADT) have at least one bone metabolism biomarker that is elevated. 

Nearly 90% of men with hormone-sensitive prostate cancer (HSPC) who initiate androgen deprivation therapy (ADT) have at least one bone metabolism biomarker that is elevated. As expected, a high proportion of men with bone metastases had at least one bone metabolism biomarker elevated above the median, Primo N. Lara, MD, reported at the 2018 European Society of Medical Oncology annual congress in Munich.

In an earlier study, the phase III SWOG S0421, blood-based bone biomarkers were shown to be independently prognostic of outcome in men with castration-resistant prostate cancer with bone metastases, and patients with highly elevated levels of bone markers preferentially benefited from bone-targeted therapy (atrasentan). Atrasentan had no effect on survival or progression-free survival in the overall study cohort. The study was therefore instructive, said Dr. Lara, director of the National Cancer Institute-designated University of California Davis Comprehensive Cancer Center, Sacramento.

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“It is unclear whether prognostic or predictive value of bone metabolism biomarkers applies to the earlier HSPC state,” he said. Therefore, Dr. Lara and colleagues prospectively assessed bone metabolism biomarkers in men enrolled in the S1216 trial, a National Institutes of Health-funded phase III study of ADT with or without a novel CYP17 inhibitor (orteronel). The main purpose of S1216 is to compare overall survival in patients with newly diagnosed metastatic prostate cancer randomly assigned to ADT plus orteronel or ADT plus bicalutamide (Casodex). S1216 is still collecting events, with the first read-out anticipated next year, he told Urology Times.

“We’re hypothesizing that maybe the same observations we saw in castration-resistant disease will be seen in this different, earlier population of men with HSPC,” he said. “We hope to see that the patients with the highest levels of bone biomarkers are the ones who benefit preferentially from orteronel.”

The data presented at the ESMO annual congress were the distribution of baseline bone metabolism biomarkers from S1216 and their relationship to other baseline clinical variables. Median baseline PSA level of the study cohort was 29.16 ng/mL. Of the 799 men with baseline serum assessable for bone metabolism biomarkers, 604 (75.6%) had bone metastases at baseline and 5.5% were taking a bisphosphonate or denosumab (Xgeva). About half of the men (49.7%) were treated with hormone therapy prior to enrollment.

The bone resorption markers C-telopeptide and pyridinoline and the bone formation markers C-terminal collagen propeptide and bone alkaline phosphatase were measured.

Median levels of bone metabolism markers at baseline in the overall cohort and the patients with bone metastases were as follows:

  • bone alkaline phosphatase, 1.66 U/L and 2.093 U/L, respectively

  • C-terminal of type I collagen, 116.39 ng/mL and 125.28 ng/mL, respectively

  • C-telopeptide, 0.46 ng/mL and 0.49 ng/mL, respectively

  • pyridinoline, 1.68 nmol/L and 1.74 nmol/L, respectively.

A bone marker was considered elevated if it was above the median or in the upper quartile. Men were grouped as having all four, one to three, or no bone metabolism biomarker elevated.

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A total of 429 patients (53.7%) had one to three bone markers elevated, and 28 (3.5%) had all four bone markers elevated. At least one bone metabolism biomarker was above the median in 87% and in the top quartile in 57%.

Among the 604 patients with bone metastases, 305 (50.5%) had elevations in one to three bone markers, 25 (4.1%) had all four bone markers elevated, and 513 had at least one bone metabolism biomarker elevated above the median.

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The distribution of bone metabolism biomarker elevation above the median differed significantly within groups defined by baseline PSA (p<.0001), Gleason score (p=.0001), performance status (p<.0001), and disease extent (p<.0001). For example, in 292 patients with serum PSA level >29 ng/mL, 30% had all four bone metabolism biomarkers elevated, whereas in those with serum PSA <29 ng/mL, only 6% had all four elevated.

“Expectedly, if you have bone metastases, your bone turnover biomarkers will be elevated,” said Dr. Lara. “And that’s what we see. Elevated bone biomarkers tend to track with clinical features, such as tumor grade, lower performance status, and disease extent.”

Bone metabolism biomarker distribution in the entire cohort did not differ within race/ethnicity, age, and bisphosphonate/denosumab groupings.

Millennium Pharmaceuticals provided funding for the study.