DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer

By J. Mateo, S. Carreira, S. Sandhu, S. Miranda, H. Mossop, R. Pérez-López, Daniel Nava Rodrigues, D. Robinson, A. Omlin, N. Tunariu and 41 more. New England Journal of Medicine, 2015

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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.

Subfields: Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/bb7566336d7406bba1386f63ce33b5fe0788834d

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Citations in the corpus

Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: A report from the ESMO Precision Medicine Working Group. (2020, background): “Data about PALB2, RAD50, RAD51 or BRIP1 mutations are promising but sparse due to the low frequency of these aberrations.(93,95) Other genes involved in DNA repair, like MLH1/ MSH2/MSH6 lead to MSI-H when mutated.”
A decade of clinical development of PARP inhibitors in perspective (2019, background): “Retrospective genomic assessment of trial biopsies identified a strong association between antitumour activity and alterations in different DNA repair genes [46].”
Genomic correlates of clinical outcome in advanced prostate cancer (2019, methodology): “Subjects with mCRPC who were receiving standard-ofcare therapy or treatment in a clinical trial [including trials combining AR therapies with other agents, a trial of the PARP inhibitor olaparib (37), and a trial of the Aurora kinase A inhibitor alisertib in patients with neuroendocrine features (14”
PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance (2020, background): “Several HR repair mutations have been identified as potential prospective PARPi biomarkers, including ATM, FANC A/F, CHK2, RAD51B/C and CDK12 (Mateo et al., 2015; Criscuolo et al., 2019).”
EAU-EANM-ESTRO-ESUR-SIOG Guidelines on Prostate Cancer. Part II-2020 Update: Treatment of Relapsing and Metastatic Prostate Cancer. (2020, background): “Men previously treated with both docetaxel and at least one novel hormonal agent, and whose tumours demonstrated homozygous deletions or deleterious mutations in DNA-repair genes (BRCA1/2, ATM, Fanconi's anaemia genes, and CHEK2), showed an 88% response rate [138].”
Integrative Clinical Genomics of Metastatic Cancer (2017, positive): “Mutations in DNA repair pathways have therapeutic implications; hypermutated tumors may respond to immune checkpoint inhibitors 42 , while HR deficiency could suggest sensitivity to PARP inhibitors 42,43 .”
HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational-signatures (2017, background): “Of these, 30 were confirmed as having germline or somatic BRCA1 or BRCA2 mutations with loss of the wild-type parental allele (14 with germline mutations, 6 with somatic mutations and 10 with altered DNA methylation) ( Supplementary Table 8 ).”
PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes (2017, background): “Itmayalso have efficacy in breast cancer and castration-resistant prostate cancer (Fong et al. 2009; Mateo et al. 2015).”