期刊
NEW ENGLAND JOURNAL OF MEDICINE
卷 373, 期 18, 页码 1697-1708出版社
MASSACHUSETTS MEDICAL SOC
DOI: 10.1056/NEJMoa1506859
关键词
-
资金
- Cancer Research UK [C12540/A12829, C12540/A13230, C1491/A9895, C1491/A15955]
- Cancer-Prostate Cancer Foundation
- National Institute for Health Research
- Medical Research Council-Prostate Cancer UK
- Swiss Cancer League [BIL KLS-02592-02-2010]
- Marie Curie International Incoming Fellowship [625792]
- Prostate Cancer UK
- AstraZeneca
- National Institute for Health Research Cancer Research Network
- MRC [MR/M003272/1] Funding Source: UKRI
- Cancer Research UK [13230, 15007, 12829, 14276, 17528, 13239, 8336] Funding Source: researchfish
- Medical Research Council [MR/M003272/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0510-10096, CL-2008-22-001] Funding Source: researchfish
- Prostate Cancer UK [PG12-49] Funding Source: researchfish
- Public Health Agency [SPI/3315/06] Funding Source: researchfish
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.)
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据