Developing imaging strategies for castration resistant prostate cancer

Abstract

Recent advances in the understanding of castrate-resistant prostate cancer (CRPC) have lead to a growing number of experimental therapies, many of which are directed against the androgen-receptor (AR) signaling axis. These advances generate the need for reliable molecular imaging biomarkers to non-invasively determine efficacy, and to better guide treatment selection of these promising AR-targeted drugs. Methods. We draw on our own experience, supplemented by review of the current literature, to discuss the systematic development of imaging biomarkers for use in the context of CRPC, with a focus on bone scintigraphy, F-18 fluorodeoxyglucose (FDG)-positron emission tomography (PET) and PET imaging of the AR signaling axis. Results. The roadmap to biomarker development mandates rigorous standardization and analytic validation of an assay before it can be qualified successfully for use in an appropriate clinical context. The Prostate Cancer Working Group 2 (PCWG2) criteria for "radiographic" progression by bone scintigraphy serve as a paradigm of this process. Implemented by the Prostate Cancer Clinical Trials Consortium (PCCTC), these consensus criteria may ultimately enable the co-development of more potent and versatile molecular imaging biomarkers. Purported to be superior to single-photon bone scanning, the added value of Na(18)F-PET for imaging of bone metastases is still uncertain. FDG-PET already plays an integral role in the management of many diseases, but requires further evaluation before being qualified in the context of CRPC. PET tracers that probe the AR signaling axis, such as (18)F-FDHT and (89)Zr-591, are now under development as pharmacodynamic markers, and as markers of efficacy, in tandem with FDG-PET. Semi-automated analysis programs for facilitating PET interpretation may serve as a valuable tool to help navigate the biomarker roadmap. Conclusions. Molecular imaging strategies, particularly those that probe the AR signaling axis, have the potential to accelerate drug development in CRPC. The development and use of analytically valid imaging biomarkers will increase the likelihood of clinical qualification, and ultimately lead to improved patient outcomes.

Figure 1

Example of scintigraphic progression per PCWG2: Two or more new lesions appear on first post-12 week assessment (arrows), followed by at least 2 additional new lesions on confirmation scan more than 6 weeks later.

Figure 2

The analytically validated PCWG2 bone scan assessment form currently undergoing clinical qualification in phase 3 registration trials.

Figure 3

(A). Kaplan-Meier survival curves for 22 patients with low (≤6.10) and 21 patients with high (>6.10) SUVmax, p = 0.002. Reprinted with permission from Meirelles et al. [29]. (B). 69-year-old male with CRPC. MIP and axial images shows markedly FDG-avid bone lesions in the thoracic spine, SUVmax 16.8. The patient died within 18 months after the scan.

Figure 3

(A). Kaplan-Meier survival curves for 22 patients with low (≤6.10) and 21 patients with high (>6.10) SUVmax, p = 0.002. Reprinted with permission from Meirelles et al. [29]. (B). 69-year-old male with CRPC. MIP and axial images shows markedly FDG-avid bone lesions in the thoracic spine, SUVmax 16.8. The patient died within 18 months after the scan.

Figure 4

(A). CRPC patient with multiple osteoblastic metastases. Sagittal fused PET/CT and PET images (FDG top row, FDHT bottom row) demonstrate prominent FDG and FDHT uptake, consistent with a “Glycolysis/AR Concordant” phenotype. (B). Second CRPC patient with multiple osteoblastic metastases. Sagittal fused PET/CT and PET images (FDG top row, FDHT bottom row) demonstrate intense FDHT uptake and relatively low level FDG uptake, consistent with an “AR Predominant” phenotype.

Figure 5

(A) Axial fused PET/CT and CT images show an example of a discordantly positive nodal mass on 18F-FDG (top, crosshairs), negative on 18F-FDHT (bottom). (B) In the same patient, axial images show an example of a discordantly positive bone lesion on 18F-FDHT (bottom, crosshairs), negative on 18F-FDG (top). (C) VCAR derived bar graph of total lesional SUVmax for the same patient demonstrating substantial heterogeneity in lesion avidity.

Figure 6

Pharmacodynamics of MDV3100. (A) Sagittal fused PET/CT and PET images 1 h after administration of FDHT at baseline and 4 weeks after start of MDV3100 therapy show a reduction in FDHT accumulation in tumor within the vertebrae, compared with the cardiac and aortic blood pool, in which FDHT metabolites circulate bound to serum proteins. (B) Percentage change in FDHT average maximum standard uptake value (SUVmax) from baseline to 4 weeks by dose. At baseline, all 22 patients had at least one FDHT-avid lesion that could serve as index lesions: 17 patients had five index lesions, three had three index lesions, and two had one index lesion. At baseline, the median FDHT SUVmax average was 7.81 (IQR 4.9–9.6). Reprinted with permission and modification from Scher et al. [5].