Abstract 3973: Diffusion-weighted imaging of bone metastases as treatment response biomarker in prostate cancer
Authors: Perez-Lopez Raquel , Blackledge Matthew D. , Mossop Helen , Mateo Joaquin , Collins David , Morgan Veronica A. , McDonald Alison , Sandhu Shahneen , Omlin Aurelius , Bianchini Diletta , Zafeiriou Zafeiris , Rescigno Pasquale , Kolinsky Michael , Nava Rodrigues Daniel , Flohr Penny , Ebbs Berni , Fowler Gemma , Porta Nuria , Hall Emma , Leach Martin , de Bono Johann S. , Koh Dow-Mu , Tunariu Nina 
Published: July 2016

Abstract
INTRODUCTION: Response assessment of bone metastases (BM) remains a challenge for drug development in metastatic castration resistant prostate cancer (mCRPC) as standard imaging techniques, computed tomography and bone scintigraphy, fail to characterize BM. Diffusion-weighted imaging (DWI) is a functional MRI technique that studies the motion of water molecules within a tissue informing on cellularity. We hypothesized that changes in whole body (WB) DWI informs on BM response to treatment in mCRPC.
METHODS: We conducted a phase II trial of the PARP inhibitor olaparib in mCRPC (TOPARP-A; CRUK/11/029); the primary endpoint was response rate defined using RECIST 1.1, PSA falls of ≥50% and conversion of circulating tumour cell (CTC) counts from ≥5 to &lt;5. Optional WB-DWI in patients (pt) was performed prior to starting olaparib and after 12 weeks (w) of treatment on a 1.5 T MRI (Siemens Avanto). Images were analyzed with open-access imaging software (Osirix v5.6). Areas of DWI signal abnormality consistent with BM in the axial skeleton (C4 to mid-thigh) were delineated. We estimated disease volume and apparent diffusion coefficient (ADC), a parameter derived from DWI correlated with cellularity. BM volume and median ADC (mADC) changes between baseline and 12w were associated with binary response to treatment using Mann-Whitney tests and logistic regression; associations with best percentage PSA and CTC change after treatment were assessed using Spearman's correlation.
RESULTS: Overall, 33/42 pt consented to the WB-DWI substudy of whom 21 had WB-DWI at baseline and at 12w. Of these 29% (6/21) were classified as responders to olaparib as per the primary endpoint definition and had not progressed prior to 12w. At baseline, median CTC count was 46 CTC/7.5ml blood and median PSA was 411 ng/ml for this cohort. When assessing all the areas of DWI signal abnormality, median volume of BM per patient was 445ml and mADC was 782 x10-6 mm2/s. Baseline CTC counts and PSA were significantly associated with volume of BM (ρ = 0.59, p = 0.005; ρ = 0.64, p = 0.002 respectively). All pts who responded to olaparib showed a decrease in volume of BM (median -41.1%, range -58.8%, -6.3%), whilst in non-responders a decrease was not observed in any pt (median 20.7%, range 0.0%, 76.9%); the difference between responders and non-responders was statistically significant (p = 0.001). Increases in mADC after 12 weeks of treatment were associated with increased odds of response (Odds Ratio: 1.08, 95% CI 1.00, 1.15, p = 0.04). Additionally, we detected a significant positive association between changes in volume of BM estimated by DWI and best percentage change in PSA and CTC (ρ = 0.63, p = 0.002 and ρ = 0.77, p&lt;0.001 respectively).
CONCLUSION: Decrease in volume and increase in mADC of BM assessed by WB-DWI are indicators of response to olaparib in BM from mCRPC. These data require validation but support the use of WB-DWI for assessing BM during treatment.
Citation Format: Raquel Perez-Lopez, Matthew D. Blackledge, Helen Mossop, Joaquin Mateo, David Collins, Veronica A. Morgan, Alison McDonald, Shahneen Sandhu, Aurelius Omlin, Diletta Bianchini, Zafeiris Zafeiriou, Pasquale Rescigno, Michael Kolinsky, Daniel Nava Rodrigues, Penny Flohr, Berni Ebbs, Gemma Fowler, Nuria Porta, Emma Hall, Martin Leach, Johann S. de Bono, Dow-Mu Koh, Nina Tunariu. Diffusion-weighted imaging of bone metastases as treatment response biomarker in prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3973.