Abstract
The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) has substantially evolved over the last decade. Nonetheless, a better understanding of bone-targeted agents (BTAs) action in mCRPC remains an unmet need. Theuse of BTAs aims to reduce the incidence of skeletal-related events (SREs) in patients with mCRPC. Less frequent BTA schedules are currently being studied to minimize adverse events. In this study, the impact of metastatic compartment (bone and extraskeletal metastases (BESM) vs. bone-only metastases (BOM)) on bone biomarker kinetics, time to first on-study SRE, and symptomatic skeletal events (SSEs) is evaluated. This is a retrospective analysis of the prospective, randomized, multicenter clinical trial of denosumab vs. zoledronic acid in patients with mCRPC and bone metastases. A total of 1901 patients were included, 1559 (82.0%) with BOM and 342 with BESM (18.0%). Bone metastases burden was balanced between groups. Baseline levels and normalization rates of corrected urinary N-terminal telopeptide and bone alkaline phosphatase did not differ between groups. However, BESM patients had a higher risk of SREs (adjusted HR 1.21; 95% CI 1.01–1.46; p = 0.043) and SSEs (adjusted HR 1.30; 95% CI 1.06–1.61; p = 0.014). This difference was more pronounced in the first 12 months of BTA treatment.In mCRPC, strategies of BTA schedule de-escalation may take into account presence of extraskeletal metastases.
Highlights
Prostate carcinoma is one of the most common cancers in men globally and the second cause of cancer death in this gender in Europe [1,2]
(95% confidence interval (CI) 17.8–20.7 months) for those with lung metastases compared with 20.8 months for patients with bone-only metastases (BOM) [7]
We hypothesized that patients with BESM may have increased bone marker levels and higher risk of skeletal-related events (SREs) and symptomatic skeletal events (SSEs) than those with BOM. In this large study of metastatic castration-resistant prostate cancer (mCRPC) with bone metastases, we investigated the impact of themetastatic compartment (BOM vs. BESM) onbone biomarker levels at baseline and after bone-targeted agents (BTAs) introduction, time to first and subsequent on-study SREs/SSEs and overall survival (OS)
Summary
Prostate carcinoma is one of the most common cancers in men globally and the second cause of cancer death in this gender in Europe [1,2] In these patients, bone is the most common site of metastatic disease (>90% of patients) [3] and bone metastases are frequently associated with detrimental bone outcomes—collectively referred to as skeletal-related events (SREs; pathological fracture, spinal cord compression, and radiotherapy or surgery to bone), which negatively impact quality of life and Cancers 2020, 12, 2034; doi:10.3390/cancers12082034 www.mdpi.com/journal/cancers. Prostate cancer cells secrete factors, such as bone morphogenic proteins (BMPs), TGFβ, and endothelin-1 (ET-1), which increase osteoblastic activity and lead to osteoblastic metastases [10,11]. Bone-targeted agents (BTAs; denosumab and zoledronic acid (ZA)) reduce bone resorption and bone metastases-associated morbidity [1,4,5]
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