Ovid: Welcome to Ovid

DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer.
Mateo, Joaquin M.D.; Carreira, Suzanne Ph.D.; Sandhu, Shahneen M.D.; Miranda, Susana B.Sc.; Mossop, Helen M.Math.Stat.; Perez-Lopez, Raquel M.D.; Rodrigues, Daniel Nava M.D.; Robinson, Dan Ph.D.; Omlin, Aurelius M.D.; Tunariu, Nina M.D.Res.; Boysen, Gunther Ph.D.; Porta, Nuria Ph.D.; Flohr, Penny B.Sc.; Gillman, Alexa B.Sc.; Figueiredo, Ines B.Sc.; Paulding, Claire B.Sc.; Seed, George M.Sc.; Jain, Suneil M.D.; Ralph, Christy M.D.; Protheroe, Andrew M.D., Ph.D.; Hussain, Syed M.D.; Jones, Robert M.D., Ph.D.; Elliott, Tony M.D., Ph.D.; McGovern, Ursula M.D., Ph.D.; Bianchini, Diletta M.D.; Goodall, Jane B.Sc.; Zafeiriou, Zafeiris M.D.; Williamson, Chris T. Ph.D.; Ferraldeschi, Roberta M.D., Ph.D.; Riisnaes, Ruth F.I.B.M.S.; Ebbs, Bernardette B.T.E.C.; Fowler, Gemma B.Sc.; Roda, Desamparados M.D.; Yuan, Wei Ph.D.; Wu, Yi-Mi Ph.D.; Cao, Xuhong M.S.; Brough, Rachel Ph.D.; Pemberton, Helen Ph.D.; A'Hern, Roger Ph.D.; Swain, Amanda Ph.D.; Kunju, Lakshmi P. M.D.; Eeles, Rosalind M.D., Ph.D.; Attard, Gerhardt M.D., Ph.D.; Lord, Christopher J. Ph.D.; Ashworth, Alan Ph.D.; Rubin, Mark A. M.D.; Knudsen, Karen E. Ph.D.; Feng, Felix Y. M.D., Ph.D.; Chinnaiyan, Arul M. M.D., Ph.D.; Hall, Emma Ph.D.; de Bono, Johann S. M.B., Ch.B., Ph.D.
[Article] New England Journal of Medicine. 373(18):1697-1708, October 29, 2015.

(Format: HTML, PDF)

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.)