Castration-Resistant Prostate Cancer Bone Metastasis Response Measured by 18F-Fluoride PET After Treatment with Dasatinib and Correlation with Progression-Free Survival: Results from American College of Radiology Imaging Network 6687

The determination of therapeutic response in prostate cancer bone metastases is challenging because traditional imaging relies on measuring changes in bone turnover with bone scintigraphy or bone structure with CT or MR imaging. However, these imaging modalities are limited by a lack of quantitative ability. Prostate-specific antigen (PSA) decline is also used as a treatment response measure; however, PSA does not differentiate variability in tumor response across different disease sites. PET imaging is inherently quantitative and offers regional measures of both in vivo tumor and normal tissue biology using tracers for glucose, lipid, or bone metabolism, among other processes. 18F-FDG is a radioactive tracer used in routine PET imaging for many malignancies, but it generally lacks sensitivity for imaging osteoblastic prostate cancer lesions (1). 18F-fluoride offers a quantitative measure of new bone formation and turnover in both normal bone and bone metastases, making it well suited for blastic lesions (2,3). Recent studies with 18F-fluoride PET show improved sensitivity over bone scintigraphy for multiple solid tumors, including prostate cancer (2,4). Therefore, 18F-fluoride PET offers the ability to image metastatic lesions with excellent sensitivity while offering quantitative capability for measuring treatment response, especially for therapeutics with bone remodeling effects such as dasatinib (5–8). Dasatinib (SPRYCEL; Bristol-Myers Squibb) is an oral tyrosine kinase inhibitor with potent activity against the SRC family kinases (SFKs), BCR-ABL, platelet-derived growth factor receptor (PDGFR), and mast/stem cell growth factor receptor (c-KIT) (9). SFKs are overexpressed in prostate cancer and SRC inhibition results in reduced cancer cell proliferation, invasion, and migration (10,11). Furthermore, SFKs play an important role in osteoclast and osteoblast function, with SRC inhibition delaying the appearance and decreasing the size of bone metastases in murine models of breast cancer (12,13). Dasatinib treatment of orthotopic murine bone prostate tumor models has demonstrated decreased PSA, increased bone mineral density, decreased serum calcium, and potentiated docetaxel chemotherapy effects (14). Phase 2 trials in patients with metastatic castration-resistant prostate cancer (mCRPC) showed significant decreases in bone turnover markers (15,16). An open-label combination phase 1–2 trial with a dasatinib/docetaxel combination also confirmed significant bone turnover activity with impressive antitumor effect (17). In a randomized, placebo-controlled, phase 3 trial, an overall survival benefit could not be confirmed with the dasatinib/docetaxel combination over placebo/docetaxel, yet the time to first skeletal-related event was in favor of patients who received dasatinib (hazard ratio, 0.81; 95% confidence interval [CI], 0.64–1.02; P = 0.08) (18). The discrepancy between clear activity of dasatinib in bone and antitumor endpoints such as overall survival raises the question whether the activity of dasatinib is primarily as an osteoclast inhibitor in normal bone or whether there is preferential activity on bone metastases. This imaging trial sought to determine the comparative pharmacodynamic effect of dasatinib in normal bone and bone metastases. Given expression of SRC both in osteoclasts and in prostate cancer, and the observed clinical activity on bone turnover markers, 18F-fluoride PET, as a quantitative imaging method targeted to bone, was ideally suited for this purpose. Therefore, patients were imaged with 18F-fluoride PET/CT both at baseline and 12 weeks after initiation of dasatinib to determine whether the nature of the drug effect could be ascertained by imaging. Specifically, could 18F-fluoride PET/CT discern dasatinib response in normal bone and bone metastases and identify a preferential drug effect in the tumor? An exploratory aim was to test the ability of 18F-fluoride PET to measure clinical outcomes with dasatinib, assessed by progression-free survival (PFS).