DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer.
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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
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
Document Type
Journal Article
Date
2015-10-29
Date Accepted
2015-10-01
Date Available
2016-10-26T16:24:31Z
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.).
Citation
The New England journal of medicine, 2015, 373 (18), pp. 1697 - 1708
Source Title
Publisher
MASSACHUSETTS MEDICAL SOC
ISSN
0028-4793
eISSN
1533-4406
Research Team
Cancer Biomarkers
ICR-CTSU Urology and Head and Neck Trials Team
Development & Cancer
Gene Function
Treatment Resistance
Oncogenetics
Cancer Biomarkers
ICR-CTSU Urology and Head and Neck Trials Team
Development & Cancer
Gene Function
Treatment Resistance
Oncogenetics
ICR-CTSU Urology and Head and Neck Trials Team
Development & Cancer
Gene Function
Treatment Resistance
Oncogenetics
Cancer Biomarkers
ICR-CTSU Urology and Head and Neck Trials Team
Development & Cancer
Gene Function
Treatment Resistance
Oncogenetics