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Markers of bone metabolism and overall survival in men with bone-metastatic hormone sensitive prostate cancer (HSPC): A subset analysis of SWOG S1216, a phase III trial of androgen deprivation with or without orteronel

Prostate Cancer and Prostatic Diseases (2024)Cite this article

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Abstract

Background

Circulating biomarkers of bone metabolism are significantly associated with overall survival (OS) in men with advanced prostate cancer. In the SWOG S1216 phase III trial, we showed that elevated bone biomarkers are significantly associated with an increased risk of death in hormone-sensitive prostate cancer (HSPC) regardless of the status of bone metastases, identifying three risk groups with differential OS outcomes based on bone biomarker status. Here we report the association of bone biomarkers with OS in men with HSPC and documented skeletal metastases as part of a planned subset analysis of S1216.

Methods

Bone resorption [C-telopeptide (CTx); Pyridinoline (PYD)] and bone formation markers [C-terminal collagen propeptide (CICP); bone alkaline phosphatase (BAP)] were assessed in blood from men with bone metastatic HSPC. Patients were randomly divided into training (n = 238) and validation (n = 475) sets. In the training set, recursive partitioning that maximizes discrimination of OS was used to identify the dichotomous cut-point for each biomarker and for a combination of biomarker split points to define prognostic groups. In the validation set, Cox proportional hazards models were used to assess the impact of biomarkers on OS, adjusted for patient and tumor characteristics.

Results

Of 1279 men, 713 had both baseline bone metastases and evaluable bone biomarkers. Patient characteristics were similar between the overall population and the subset with bone metastases. Elevated levels of CICP, CTX, and PYD were strongly prognostic for OS. Hazard ratios (95% CI) for OS adjusted for treatment arm and baseline clinical variables were: BAP–1.31 (0.93, 1.84), p = 0.12; CICP–1.58 (1.09, 2.29), p < 0.02; CTx – 1.55 (1.12, 2.15), p = 0.008; and PYD–1.66 (1.27, 2.217), p = 0.0002. There was no evidence of interaction between elevated biomarkers and treatment (all p > 0.2). Recursive partitioning algorithms identified four groups of patients with differential OS outcomes based on bone biomarkers, adjusted for baseline clinical variables, with median OS ranging from 2.3 years (highest risk group) to 7.5 years (lowest risk group).

Conclusions

In this planned S1216 subset analysis of men with HSPC and bone metastases, elevated serum markers of bone metabolism were significantly associated with worse OS. Bone biomarker levels alone and in combination with patient and tumor characteristics identify unique subsets of men with differential OS outcomes.

ClinicalTrials.gov Identifier

NCT01809691

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Fig. 1: Dichotomized cutpoints for bone biomarker values.
Fig. 2: Differential survival outcomes based on bone biomarkers.

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Data availability

The data that support the findings of this study are available by request from the SWOG Cancer Research Network and the SWOG Statistical Center. (https://www.swog.org/)

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Funding

Research reported herein was supported by the U.S. National Cancer Institute of the National Institutes of Health under Award Numbers CA180888 and CA180819; and in part by Millennium Pharmaceuticals (Takeda Oncology Company). PNL is supported by NCI Cancer Center Support Grant P30 CA093373 and by Jerry and Susan Knapp. This work is dedicated to the memory of Nicholas J. Vogelzang, MD.

Author information

Authors and Affiliations

  1. University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA

    Primo N. Lara Jr. & Mamta Parikh

  2. SWOG Statistical Center, Seattle, WA, USA

    Edward Mayerson, Catherine Tangen, Marta van Loan & Michael LeBlanc

  3. US Department of Agriculture, Western Human Nutrition Research Center, University of California Davis, Davis, CA, USA

    Erik Gertz

  4. USC Norris Comprehensive Cancer Center, Los Angeles, CA, USA

    Amir Goldkorn & David I. Quinn

  5. Northwestern University, Chicago, IL, USA

    Maha Hussain

  6. Cleveland Clinic, Cleveland, OH, USA

    Shilpa Gupta

  7. Moffitt Cancer Institute, Tampa Bay, FL, USA

    Jingsong Zhang

  8. St. John’s Cancer Institute, Providence Health, Santa Monica, CA, USA

    Przemyslaw Twardowski

  9. Christus Santa Rosa Health System, San Antonio, TX Health, San Antonio, TX, USA

    Ian Thompson

  10. Huntsman Cancer Institute, Salt Lake City, UT, USA

    Neeraj Agarwal

Authors
  1. Primo N. Lara Jr.
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Contributions

PNL conceptualized, designed, developed, and coordinated the project, led the collection and analysis of data, and served as the primary author of the manuscript. EM, CT, and MLB served as biostatisticians for this project, assisting with the methodological design, participating in the primary data analysis, and assisting in subsequent data reporting. EG and MVL performed the high-quality molecular assays and assisted in the data analysis. PNL, CT, AG, MH, DIQ, IT, and NA participated in the design and conduct of the S1216 phase III clinical trial. AG, MH, SG, JZ, MP, PT, DIQ, IT, and NA participated in accruing patients to the S1216 trial and oversaw the collection of biospecimens for this project at their respective sites. PNL, EM, and CT developed the initial manuscript draft. All authors read and approved the final version of the manuscript.

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Correspondence to Primo N. Lara Jr..

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Presented in part at the 2023 American Society of Clinical Oncology Annual Meeting in Chicago, IL.

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Lara, P.N., Mayerson, E., Gertz, E. et al. Markers of bone metabolism and overall survival in men with bone-metastatic hormone sensitive prostate cancer (HSPC): A subset analysis of SWOG S1216, a phase III trial of androgen deprivation with or without orteronel. Prostate Cancer Prostatic Dis (2024). https://doi.org/10.1038/s41391-024-00813-3

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