Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study

Gelmon, Karen A.; Tischkowitz, Marc; Mackay, Helen; Swenerton, Kenneth D.; Robidoux, André; Tonkin, Katia; Hirte, Hal W.; Huntsman, David G.; Clemons, Mark; Gilks, Blake; Yerushalmi, Rinat; Macpherson, Euan; Carmichael, James; Oza, Amit M.

doi:10.1016/s1470-2045(11)70214-5

Cited by 1,042 publications

(785 citation statements)

References 28 publications

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“…The fact that no differences were observed in this series of 103 high-grade serous cases, when patients were stratified based on BRCA status, highlights the inability of BRCA mutation testing to serve as a tool that can accurately predict outcome in individual patients with high-grade serous carcinoma. The HR of B0.7 associated with BRCA mutation in the Bolton's series is less 58 There are presumably other molecular parameters that are equally if not more important than BRCA status in influencing response to treatment and outcome. Within high-grade serous cancers there are immunohistochemistry features (ie, TP53 and immune cell infiltrates) that were significantly associated with genetic changes in BRCA1 and BRCA2 (group 1).…”

Section: Discussionmentioning

confidence: 87%

BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma

et al. 2012

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We characterized BRCA1 and BRCA2 status (mutation/methylation) in a consecutive series of cases of ovarian carcinoma in order to identify differences in clinicopathological features, molecular characteristics, and outcome between the pelvic high-grade serous cancers with (i) germline or somatic mutations in BRCA1 or BRCA2, (ii) methylation of BRCA1, and (iii) normal BRCA1 or BRCA2. In all, 131 women were identified prospectively, who were undergoing surgical staging and agreed to germline testing for BRCA1 and BRCA2 mutations. Histopathology, germline and somatic BRCA1 or BRCA2 mutations, BRCA1 methylation, and BRCA1 and BRCA2 mRNA expression levels distinguished four subgroups. In all, 103 cases were high-grade serous carcinoma and of these 31 (30%) had germline or somatic BRCA1 or BRCA2 mutations (20% BRCA1 and 10% BRCA2) (group 1), 21 (20%) had methylation of BRCA1 (group 2), and in 51 (50%) there was no BRCA loss (group 3). Group 4 consisted of 28 cases of non-high-grade serous, none of which had BRCA loss. BRCA1 and BRCA2 mRNA expression levels correlated with designated group (P ¼ 0.0008). Among high-grade serous carcinomas, there were no differences between groups 1-3 with respect to stage, ascites, CA125 level, platinum sensitivity, cytoreduction rate, neoadjuvant chemotherapy, or survival. Tumors with BRCA1 or BRCA2 mutations had increased immune infiltrates (CD20 and TIA-1) compared with high-grade serous without mutations (P ¼ 0.034, 0.027). TP53 expression differed between groups (Po0.0001), with abnormal TP53 expression in 49/50 tumors from groups 1 and 2. Wild-type TP53 expression was associated with worse outcome in high-grade serous (Po0.001). BRCA loss (mutation/methylation) is a common event in the pelvic high-grade serous (50%). TP53 abnormalities and increased immune cell infiltrates are significantly more common in high-grade serous with germline and somatic mutations in BRCA1 or BRCA2, compared with tumors lacking BRCA abnormalities.

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Section: Discussionmentioning

confidence: 87%

BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma

et al. 2012

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“…7,[22][23][24][25] The majority of AEs reported were of mild or moderate severity. Olaparib showed an acceptable tolerability profile, and no new safety findings were observed.…”

Section: Study 8 (Cyp3a4 Induction)mentioning

confidence: 99%

“…No interaction between itraconazole and olaparib was to be concluded if 2-sided 90% confidence intervals (CIs) for the treatment ratios of area under the curve (AUC; and/or AUC0-t) and maximum plasma concentration (Cmax) fell within the bioequivalence range of 0.80-1. 25. An interaction between rifampin and olaparib was to be concluded if the lower limit of the 90% CI for the treatment ratios was <0.5 (ie, >50% decrease in olaparib AUC or Cmax in the presence of rifampin compared with olaparib alone).…”

mentioning

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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“…Several studies have confirmed anti-tumour effects in human breast and ovarian cancers in patients carrying BRCA1 or BRCA2 germline mutations. [249][250][251][252][253][254] Of note, although ovarian cancer patients treated for high-grade epithelial cancers not harbouring BRCA1/2 germline mutations responded to PARP inhibition with Olaparib with a response rate similar to that of BRCA1/2 mutation carriers, no response to Olaparib monotherapy was recorded among patients treated for triple-negative breast cancer harbouring wild-type BRCA1/2. 253 BRCA1/2 somatic and germline mutations are observed more frequently in ovarian (420%) as compared with breast cancers; 255 yet, the finding of a high response rate to PARP inhibitors in high-grade ovarian cancers suggests alternative mechanisms of HRR inactivation may operate in addition.…”

Section: Homologous Recombination Repairmentioning

confidence: 99%

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Lønning

Knappskog

2013

Oncogene

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Although new agents are implemented to cancer therapy, we lack fundamental understandings of the mechanisms of chemoresistance, the main obstacle to cure in cancer. Here we review clinical evidence linking molecular defects to drug resistance across different tumour forms and discuss contemporary experimental evidence exploring these mechanisms. Although evidence, in general, is sparse and fragmentary, merging knowledge links drug resistance, and also sensitivity, to defects in functional pathways having a key role in cell growth arrest or death and DNA repair. As these pathways may act in concert, there is a need to explore multiple mechanisms in parallel. Taking advantage of massive parallel sequencing and other novel high-throughput technologies and base research on biological hypotheses, we now have the possibility to characterize functional defects related to these key pathways and to design a new generation of studies identifying the mechanisms controlling resistance to different treatment regimens in different tumour forms.

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Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study

Cited by 1,042 publications

References 28 publications

BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma

BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma

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

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

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