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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 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 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.

Introduction: Next generation sequencing (NGS) has identified genomic aberrations causing DNA repair defects in sporadic metastatic castration resistant prostate cancer (mCRPC). We hypothesized that single agent olaparib would have antitumor activity in a sub-population of mCRPC patients (pts) and that exome and transcriptome studies would identify this population. Methods: TOPARP is an open-label, investigator-initiated phase II trial with a novel multi-step adaptive design (CRUK/11/029). The first part of the study (TOPARP-A) has a two-stage design evaluating the antitumor activity of single agent olaparib in unselected mCRPC pts (p0 = 0.05; p1 = 0.20; α = 0.02; β = 0.10) with a preplanned analysis to identify a biomarker defined sensitive subgroup. Primary endpoint, response rate (RR), was defined as objective response by RECIST 1.1 and/or PSA fall ≥50% and/or confirmed circulating tumor cell (CTC) count falls from ≥5 to Results: Fifty pts were enrolled from 7 UK centers; all had had prior docetaxel, 48 (96%) prior abiraterone and 29 (58%) prior cabazitaxel. Overall, 16 of 49 evaluable pts experienced a response (RR 32.7%, 95% CI: 20.0 to 47.5), with 11 and 4 pts having been on treatment for >6 and >12 months respectively at data cut-off. NGS identified homozygous deletions and/or putatively deleterious mutations in DNA repair genes in 15/49 (30.6%) evaluable pts. While a majority of these genomic aberrations occurred in BRCA2 and ATM, biallelic loss of other relevant genes, including members of the Fanconi Anemia complementation group and CHEK2, were also observed. Among these fifteen pts, 13 (86.7%) responded to olaparib. All seven pts with BRCA2 loss (somatic [4/7] or germline [3/7]) and 4/5 pts with ATM truncating mutations responded to olaparib. The specificity of the biomarker suite was 94% in this population. Conversely, PTEN loss and ERG rearrangements were not associated with response. Finally, consistent with previous studies of olaparib, anemia (10/50, 20%) and fatigue (6/50, 12%) were the most common grade>3 adverse events, with 13 (26%) pts requiring a dose reduction. Conclusions: Olaparib has durable antitumor activity in heavily pre-treated pts with sporadic mCRPC with a 32.7% overall response rate. Genomic defects in DNA repair genes associate with olaparib sensitivity in sporadic mCRPC, offering a possibility for the very first molecular treatment stratification of advanced prostate cancer. Citation Format: Joaquin Mateo, Shahneen Sandhu, Susana Miranda, Suzanne Carreira, Suneil Jain, Christy Ralph, Andrew Protheroe, Syed Hussain, Robert Jones, Tony Elliot, Ursula McGovern, Alexa Gillman, Claire Paulding, Helen Mossop, Nuria Porta, Diletta Bianchini, Zafeiris Zafeiriou, Gunther Boysen, Daniel Nava Rodrigues, Penelope Flohr, George Seed, Jane Goodall, Ines Figueiredo, Raquel Perez-Lopez, Nina Tunariu, Aurelius Omlin, Roberta Ferraldeschi, Lakshmi P. Kunju, Rosalind Eeles, Gerhardt Attard, Dan Robinson, Arul Chinnaiyan, Emma Hall, Johann S. de Bono. DNA repair defects and antitumor activity with PARP inhibition: TOPARP, a phase II trial of olaparib in metastatic castration resistant prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT322. doi:10.1158/1538-7445.AM2015-CT322