Prognostic and predictive analyses of circulating plasma biomarkers in men with metastatic castration resistant prostate cancer treated with docetaxel/prednisone with or without bevacizumab

Andrew B Nixon; Yingmiao Liu; Qian Yang; Bin Luo; Mark D Starr; John C Brady; Wm Kevin Kelly; Himisha Beltran; Michael J Morris; Daniel J George; Andrew J Armstrong; Susan Halabi

doi:10.1038/s41391-024-00794-3

Prognostic and predictive analyses of circulating plasma biomarkers in men with metastatic castration resistant prostate cancer treated with docetaxel/prednisone with or without bevacizumab

Prostate Cancer Prostatic Dis. 2024 Feb 12. doi: 10.1038/s41391-024-00794-3. Online ahead of print.

Authors

Affiliations

¹ Department of Medicine, Duke University Medical Center, Durham, NC, USA. anixon@duke.edu.
² Department of Medicine, Duke University Medical Center, Durham, NC, USA.
³ Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA.
⁴ Division of Solid Tumor Oncology, Department of Medical Oncology and Urology, Thomas Jefferson University and Sidney Kimmel Cancer Center, Philadelphia, PA, USA.
⁵ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
⁶ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁷ Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University Medical Center, Durham, NC, USA.
⁸ Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA. susan.halabi@duke.edu.

PMID: 38347114
DOI: 10.1038/s41391-024-00794-3

Abstract

Background: CALGB 90401 (Alliance) was a phase III trial of 1050 patients with metastatic castration-resistant prostate cancer (mCRPC) comparing docetaxel, prednisone, bevacizumab (DP+B) versus DP alone. While this trial did not show an improvement in overall survival (OS), there were improved intermediate outcomes suggesting that subsets of men may derive benefit from this combination. The purpose of this analysis was to identify prognostic and predictive biomarkers associated with OS and progression-free survival (PFS) benefit from DP+B.

Methods: Baseline EDTA plasma samples from 650 consenting patients were analyzed for 24 biomarkers. The proportional hazards model was utilized to test for the prognostic and predictive importance of the biomarkers for OS. The statistically significant biomarkers of OS were further investigated for prognostic and predictive importance for other secondary outcomes.

Results: 15 markers [ICAM-1, VEGF-R3, TIMP-1, TSP-2, Ang-2, Her-3, Osteopontin (OPN), PlGF, VCAM-1, HGF, VEGF, Chromogranin A, IL-6, VEGF-R1, BMP-9] were prognostic of OS, while 9 markers (ICAM-1, VEGF-R3, Her-3, TIMP-1, Ang-2, OPN, PlGF, HGF, and VEGF) were also prognostic of PFS. All markers were statistically significant in univariate analyses after adjustment for multiplicity (FDR < 0.1). In multivariable analyses of OS adjusting for risk score, seven markers had FDR < 0.1, including ICAM-1, VEGF-R3, TIMP-1, Ang-2, VEGF, TSP-2 and HGF. In unadjusted analysis, OPN was predictive of PFS improvement with DP+B, in both univariate and multivariable analysis. However, none of the biomarkers tested were predictive of clinical outcomes after adjusting for multiple comparisons.

Conclusions: Multiple biomarkers were identified in CALGB 90401 as prognostic of clinical outcomes but not predictive of OS. While OPN may have promise as a potential biomarker for anti-angiogenic therapies, further mechanistic and clinical studies are needed to determine the underlying biology and potential clinical application.

Abstract

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