Mateo, J., Carreira, S., Sandhu, S., Miranda, S., Mossop, H., Perez-Lopez, R., Rodrigues, D. N., Robinson, D., Omlin, A., Tunariu, N., Boysen, G., Porta, N., Flohr, P., Gillman, A., Figueiredo, I., Paulding, C., Seed, G., Jain, S., Ralph, C., Protheroe, A., Hussain, S., Jones, R., Elliott, T., McGovern, U., Bianchini, D., Goodall, J., Zafeiriou, Z., Williamson, C. T., Ferraldeschi, R., Riisnaes, R., Ebbs, B., Fowler, G., Roda, D., Yuan, W., Wu, Y. M., Cao, X., Brough, R., Pemberton, H., A'Hern, R., Swain, A., Kunju, L. P., Eeles, R., Attard, G., Lord, C. J., Ashworth, A., Rubin, M. A., Knudsen, K. E., Feng, F. Y., Chinnaiyan, A. M., Hall, E., de Bono, J. S. (2015) DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. NEW ENGLAND JOURNAL OF MEDICINE, 373 (18). pp. 1697-1708. ISSN 0028-4793

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Abstract

BACKGROUND Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib. METHODS We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies. RESULTS Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes - including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2 - in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib. CONCLUSIONS Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. (Funded by Cancer Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research UK number, CRUK/11/029.)

Item Type:	Article
Authors (ICR Faculty only):	De Bono, Johann and Ahern, Roger and Eeles, Ros and Ashworth, Alan and Hall, Emma and Lord, Chris
All Authors:	Mateo, J., Carreira, S., Sandhu, S., Miranda, S., Mossop, H., Perez-Lopez, R., Rodrigues, D. N., Robinson, D., Omlin, A., Tunariu, N., Boysen, G., Porta, N., Flohr, P., Gillman, A., Figueiredo, I., Paulding, C., Seed, G., Jain, S., Ralph, C., Protheroe, A., Hussain, S., Jones, R., Elliott, T., McGovern, U., Bianchini, D., Goodall, J., Zafeiriou, Z., Williamson, C. T., Ferraldeschi, R., Riisnaes, R., Ebbs, B., Fowler, G., Roda, D., Yuan, W., Wu, Y. M., Cao, X., Brough, R., Pemberton, H., A'Hern, R., Swain, A., Kunju, L. P., Eeles, R., Attard, G., Lord, C. J., Ashworth, A., Rubin, M. A., Knudsen, K. E., Feng, F. Y., Chinnaiyan, A. M., Hall, E., de Bono, J. S.
Additional Information:	ISI Document Delivery No.: CU4QH Times Cited: 0 Cited Reference Count: 41 Mateo, J. Carreira, S. Sandhu, S. Miranda, S. Mossop, H. Perez-Lopez, R. Rodrigues, D. Nava Robinson, D. Omlin, A. Tunariu, N. Boysen, G. Porta, N. Flohr, P. Gillman, A. Figueiredo, I. Paulding, C. Seed, G. Jain, S. Ralph, C. Protheroe, A. Hussain, S. Jones, R. Elliott, T. McGovern, U. Bianchini, D. Goodall, J. Zafeiriou, Z. Williamson, C. T. Ferraldeschi, R. Riisnaes, R. Ebbs, B. Fowler, G. Roda, D. Yuan, W. Wu, Y. -M. Cao, X. Brough, R. Pemberton, H. A'Hern, R. Swain, A. Kunju, L. P. Eeles, R. Attard, G. Lord, C. J. Ashworth, A. Rubin, M. A. Knudsen, K. E. Feng, F. Y. Chinnaiyan, A. M. Hall, E. de Bono, J. S. Cancer Research UK Funded by Cancer Research UK and others 0 Massachusetts medical soc Waltham 1533-4406
Uncontrolled Keywords:	brca mutation carriers poly(adp-ribose) polymerase homologous recombination maintenance therapy ionizing-radiation parp inhibitors ovarian-cancer atm damage sensitivity General & Internal Medicine
Research teams:	ICR divisions > Breast Cancer Research > Gene Function ICR divisions > Molecular Pathology > Gene Function ICR divisions > Genetics and Epidemiology > Oncogenetics ICR divisions > Radiotherapy and Imaging > Oncogenetics ICR divisions > Clinical Studies > Clinical Trials & Statistics Unit ICR divisions > Cancer Therapeutics > Cancer Biomarkers ICR divisions > Clinical Studies > Cancer Biomarkers ICR divisions > Clinical Studies > ICR-CTSU Urology and Head and Neck Trials Team ICR divisions > Clinical Studies > Prostate Cancer Targeted Therapy Group
Depositing User:	Franziska Noessig
Date Deposited:	16 Nov 2015 15:52
Last Modified:	10 Jul 2017 14:52
URI:	http://publications.icr.ac.uk/id/eprint/14526

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