Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial

Ledermann, Jonathan A.; Harter, Philipp; Gourley, Charlie; Friedlander, Michael; Vergote, Ignace; Rustin, G. J. S.; Scott, Clare L.; Meier, W.; Shapira‐Frommer, Ronnie; Safra, Tamar; Matei, Daniela; Fielding, Anitra; Spencer, Stuart; Dougherty, Brian; Orr, Maria; Hodgson, Darren; Barrett, J. Carl; Matulonis, Ursula A.

doi:10.1016/s1470-2045(14)70228-1

Cited by 1,316 publications

(1,210 citation statements)

References 23 publications

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“…Other biomarkers for homologous recombination defi ciency have been assessed in previous studies, 4,35,36 for example, through retrospective analysis of BRCA mutations in ovarian carcinoma 21 or prospective identifi cation of homozygous deletions or mutations through next-generation sequencing in prostate cancer. 22 Additionally, the NOVA trial (NCT01847274) prospectively tested a homologous recombination defi ciency-based assay in a trial of niraparib as maintenance therapy in patients with platinum-sensitive ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial

Swisher

Lin

Oza

et al. 2017

The Lancet Oncology

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SummaryBackground Poly(ADP-ribose) polymerase (PARP) inhibitors have activity in ovarian carcinomas with homologous recombination defi ciency. Along with BRCA1 and BRCA2 (BRCA) mutations genomic loss of heterozygosity (LOH) might also represent homologous recombination defi ciency. In ARIEL2, we assessed the ability of tumour genomic LOH, quantifi ed with a next-generation sequencing assay, to predict response to rucaparib, an oral PARP inhibitor.

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Section: Discussionmentioning

confidence: 99%

Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial

Swisher

Lin

Oza

et al. 2017

The Lancet Oncology

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1,044

930

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“…7 Further analysis of this patient population has shown that patients with a BRCAm receive greater treatment benefit. 8 In a study of patients with a germline BRCA1/2m and solid tumors refractory to standard therapy, treatment with a capsule formulation of olaparib 400 mg bid prolonged tumor responses across a spectrum of malignancies, including ovarian, breast, pancreatic, and prostate cancers. 9 To receive the recommended 400 mg bid dose of olaparib, patients are required to take 16 x 50 mg large capsules per day and consequently patient compliance may be compromised.…”

Section: Introductionmentioning

confidence: 99%

Effect of Itraconazole and Rifampin on the Pharmacokinetics of Olaparib in Patients With Advanced Solid Tumors: Results of Two Phase I Open-label Studies

Dirix

Swaisland

Verheul

et al. 2016

Clinical Therapeutics

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Purpose: The metabolism of olaparib, a potent inhibitor of poly(ADP-ribose) polymerase (PARP) with demonstrated efficacy in patients with BRCA-mutated ovarian cancer, is mediated by cytochrome P450 (CYP) enzymes (predominantly CYP3A4/5). We assessed the potential of a CYP3A4 inhibitor (itraconazole) and inducer (rifampin) to alter the pharmacokinetic (PK) profile of olaparib following single oral tablet doses. Methods

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“…Alternatively, as methylation in cytosine residues of CpG dinucleotides is an epigenetic alteration it seems plausible that demethylation of the BRCA1 promoter occurs after interim chemotherapy and leads to reactivation of BRCA1 mRNA expression and therefore to resistance of therapy. Whereas tumors with BRCA1/2 mutations (germline or somatic) show the most favourable outcome and response to the recently by the Food and Drug Administration (FDA) approved polyadenosine diphosphate [ADP]-ribose polymerase (PARP) inhibitors 'olaparib', 'niraparib' and 'rucaparib' [19][20][21][22] the clinical significance and response to PARP inhibitors in non BRCA1/2 mutated tumors remains less clear. Tests to define 'BRCAness' and predict response to PARP inhibitors have been developed by different companies (e.g.…”

Section: Follow Up From Fd (Months)mentioning

confidence: 99%

Loss of BRCA1 promotor hypermethylation in recurrent high grade ovarian cancer

Prieske

Joosse

Trillsch

et al. 2016

Geburtshilfe Frauenheilkd

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Background: Approximately 20-25% of ovarian cancers are attributable to germline or somatic BRCA1/2 mutations, resulting in defects in the homologous recombination pathway. Inactivation of these genes can also be mediated by epigenetic changes, e.g., hypermethylation of CpG islands in the promoter regions. In such homologous recombination deficient tumors, platinum based chemotherapy is in general effective, however, loss of hypermethylation might lead to refractory disease. The aim of this study was to evaluate the stability of BRCA1 promoter hypermethylation in recurrent disease after platinum based chemotherapy.Methods: Tumor tissue from 76 patients with primary and 48 patients with platinum-sensitive recurrent high-grade ovarian cancer was collected. In a subgroup of 12 patients, 'paired' tumor tissue from primary and recurrent surgery was available. BRCA1 promoter methylation status was assessed using methylation specific polymerase chain reaction and was verified by Sanger Sequencing.Results: 73.7% (56/76) of primary and 20.8% (10/48) of recurrent tumors displayed BRCA1 promoter hypermethylation. BRCA1 promoter methylation status was not associated with progression-free-or overall survival. In the paired subgroup 83.3% (10/12) of the primary vs. 16.7% (2/12) of the recurrent tumors showed hypermethylation. In eight patients loss of BRCA1 hypermethylation was observed, whereas two patients had stable methylation status.Conclusions: Loss of BRCA1 promoter methylation may be a mechanism to restore BRCA1 function in recurrent disease. However, currently the clinical significance is still unclear and should be evaluated in prospective clinical trials.

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Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial

Cited by 1,316 publications

References 23 publications

Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial

Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial

Effect of Itraconazole and Rifampin on the Pharmacokinetics of Olaparib in Patients With Advanced Solid Tumors: Results of Two Phase I Open-label Studies

Loss of BRCA1 promotor hypermethylation in recurrent high grade ovarian cancer

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