Authors

Joaquin Mateo, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom; Royal Marsden NHS Foundation Trust, London, United Kingdom
Suzanne Carreira, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom
Shahneen Sandhu, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom; Royal Marsden NHS Foundation Trust, London, United Kingdom
Susana Miranda, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom
Helen Mossop, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom
Raquel Perez-Lopez, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom; Royal Marsden NHS Foundation Trust, London, United Kingdom
Daniel Nava Rodrigues, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom
Dan Robinson, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom; University of Michigan, Ann Arbor, United States
Aurelius Omlin, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom; Royal Marsden NHS Foundation Trust, London, United Kingdom
Nina Tunariu, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom; Royal Marsden NHS Foundation Trust, London, United Kingdom
Gunther Boysen, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom
Nuria Porta, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom
Penny Flohr, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom
Alexa Gillman, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom
Ines Figueiredo, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom
Claire Paulding, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom
George Seed, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom
Suneil Jain, Queen's University, Belfast, United Kingdom
Christy Ralph, University of Leeds, Leeds, United Kingdom
Andrew Protheroe, Churchill Hospital, Oxford, United Kingdom
Syed Hussain, University of Liverpool, Liverpool, United Kingdom
Robert Jones, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
Tony Elliott, Christie Hospital, Manchester, United Kingdom
Ursula McGovern, University College London Hospital, London, United Kingdom
Diletta Bianchini, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom; Royal Marsden NHS Foundation Trust, London, United Kingdom
Jane Goodall, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom
Zafeiris Zafeiriou, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom; Royal Marsden NHS Foundation Trust, London, United Kingdom
Chris T Williamson, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom
Roberta Ferraldeschi, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom; Royal Marsden NHS Foundation Trust, London, United Kingdom
Ruth Riisnaes, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom
Bernardette Ebbs, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom
Gemma Fowler, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom
Desamparados Roda, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom; Royal Marsden NHS Foundation Trust, London, United Kingdom
Wei Yuan, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom
Yi-Mi Wu, University of Michigan, Ann Arbor, United States
Xuhong Cao, University of Michigan, Ann Arbor, United States
Rachel Brough, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom
Helen Pemberton, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom
Roger A'Hern, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom
Amanda Swain, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom
Lakshmi P Kunju, University of Michigan, Ann Arbor, United States
Rosalind Eeles, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom; Royal Marsden NHS Foundation Trust, London, United Kingdom
Gerhardt Attard, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom; Royal Marsden NHS Foundation Trust, London, United Kingdom
Christopher J Lord, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom
Alan Ashworth, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom
Mark A Rubin, Weill Cornell Medical College, New York, United States
Karen E Knudsen, Thomas Jefferson University, Philadelphia, United StatesFollow
Felix Y Feng, University of Michigan, Ann Arbor, United States
Arul M Chinnaiyan, University of Michigan, Ann Arbor, United States
Emma Hall, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom
Johann S de Bono, Division of Clinical Studies, Institute of Cancer Research, Royal Marsden NHS Foundation Trust, Downs Rd., Sutton, Surrey, United Kingdom; Royal Marsden NHS Foundation Trust, London, United Kingdom

Document Type

Article

Publication Date

10-29-2015

Comments

This article has been peer reviewed. It was published in: New England Journal of Medicine.

Volume 373, Issue 18, 29 October 2015, Pages 1697-1708.

The published version is available at DOI: 10.1056/NEJMoa1506859

Copyright © 2015 Massachusetts Medical Society

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.).

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