| Title: |
DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. |
| Authors: |
Mateo, J; Carreira, S; Sandhu, S; Miranda, S; Mossop, H; Perez-Lopez, R; Nava Rodrigues, D; 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, CT; 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, LP; Eeles, R; Attard, G; Lord, CJ; Ashworth, A; Rubin, MA; Knudsen, KE; Feng, FY; Chinnaiyan, AM; Hall, E; de Bono, JS |
| Contributors: |
Carreira, Suzanne; Miranda, Susana; Nava Rodrigues, Daniel; Tunariu, Nina; Porta, Nuria; Gillman, Alexa; Figueiredo, Ines; Seed, George; Goodall, Jane; Yuan, Wei; AHern, Roger; Swain, Amanda; Eeles, Rosalind; Lord, Christopher; Hall, Emma; De Bono, Johann |
| Publisher Information: |
MASSACHUSETTS MEDICAL SOC |
| Publication Year: |
2016 |
| Collection: |
The Institute of Cancer Research (ICR): Publications Repository |
| Subject Terms: |
Humans; Prostatic Neoplasms; Neoplasm Metastasis; Anemia; Fatigue; Piperazines; Phthalazines; Antineoplastic Agents; Enzyme Inhibitors; DNA Repair; Drug Resistance; Neoplasm; Mutation; Genes; Tumor Suppressor; BRCA2; Adult; Aged; Middle Aged; Male; Ataxia Telangiectasia Mutated Proteins; Poly(ADP-ribose) Polymerase Inhibitors |
| Description: |
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. ... |
| Document Type: |
article in journal/newspaper |
| File Description: |
Print; 1708; application/pdf |
| Language: |
English |
| ISSN: |
1533-4406; 0028-4793 |
| Relation: |
The New England journal of medicine, 2015, 373 (18), pp. 1697 - 1708; https://repository.icr.ac.uk/handle/internal/188 |
| DOI: |
10.1056/nejmoa1506859 |
| Availability: |
https://doi.org/10.1056/nejmoa1506859; https://repository.icr.ac.uk/handle/internal/188 |
| Rights: |
https://www.rioxx.net/licenses/all-rights-reserved |
| Accession Number: |
edsbas.62BBD1BC |
| Database: |
BASE |