Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial

Tutt, Andrew; Robson, Mark E.; Garber, Judy E.; Domchek, Susan M.; Audeh, M. William; Weitzel, Jeffrey N.; Friedlander, Michael; Arun, Banu K.; Loman, Niklas; Schmutzler, Rita K.; Wardley, Andrew M; Mitchell, Gillian; Earl, Helena; Wickens, Mark; Carmichael, James

doi:10.1016/s0140-6736(10)60893-8

Cited by 1,593 publications

(955 citation statements)

References 27 publications

Supporting

Mentioning

908

Contrasting

Unclassified

Order By: Relevance

“…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%

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

View full text Add to dashboard Cite

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

show abstract

“…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%

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

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

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.

show abstract

“…Multiple clinical trials with PARP inhibitors, including olaparib and niraparib, have demonstrated tolerability and efficacy of these treatments in OC patients [Audeh et al., 2010; Sandhu et al., 2013]. Moreover, progression‐free survival of OC patients is further improved when olaparib is administered in combination with other treatments (e.g., paclitaxel, carboplatin, and cediranib) [Liu et al., 2014; Oza et al., 2015].…”

Section: Introductionmentioning

confidence: 99%

NovelBRCA1andBRCA2Tumor Test as Basis for Treatment Decisions and Referral for Genetic Counselling of Patients with Ovarian Carcinomas

et al. 2016

View full text Add to dashboard Cite

With the recent introduction of Poly(ADP‐ribose) polymerase inhibitors, a promising novel therapy has become available for ovarian carcinoma (OC) patients with inactivating BRCA1 or BRCA2 mutations in their tumor. To select patients who may benefit from these treatments, assessment of the mutation status of BRCA1 and BRCA2 in the tumor is required. For reliable evaluation of germline and somatic mutations in these genes in DNA derived from formalin‐fixed, paraffin‐embedded (FFPE) tissue, we have developed a single‐molecule molecular inversion probe (smMIP)‐based targeted next‐generation sequencing (NGS) approach. Our smMIP‐based NGS approach provides analysis of both strands of the open reading frame of BRCA1 and BRCA2, enabling the discrimination between real variants and formalin‐induced artefacts. The single molecule tag enables compilation of unique reads leading to a high analytical sensitivity and enabling assessment of the reliability of mutation‐negative results. Multiplex ligation‐dependent probe amplification (MLPA) and Methylation‐specific multiplex ligation‐dependent probe amplification (MS‐MLPA) were used to detect exon deletions of BRCA1 and methylation of the BRCA1 promoter, respectively. Here, we show that this combined approach allows the rapid and reliable detection of both germline and somatic aberrations affecting BRCA1 and BRCA2 in DNA derived from FFPE OCs, enabling improved hereditary cancer risk assessment and clinical treatment of ovarian cancer patients.

show abstract

Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial

Cited by 1,593 publications

References 27 publications

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

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

NovelBRCA1andBRCA2Tumor Test as Basis for Treatment Decisions and Referral for Genetic Counselling of Patients with Ovarian Carcinomas

Contact Info

Product

Resources

About