Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer

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; Macpherson, Euan; Watkins, Claire; Carmichael, James; Matulonis, Ursula A.

doi:10.1056/nejmoa1105535

Cited by 1,618 publications

(1,409 citation statements)

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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%

“…6 In patients with platinum-sensitive, recurrent serous ovarian cancer, maintenance monotherapy with a capsule formulation of olaparib 400 mg bid significantly prolonged progression-free survival (PFS) versus placebo. 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.…”

Section: Introductionmentioning

confidence: 99%

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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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“…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%

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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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

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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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“…These included high-grade serous ovarian cancer, a disease in which tumors are characterized by a relatively high frequency of HR gene mutations ( 4 ), and triple-negative breast cancer, in which tumors lack ERBB2 amplifi cation as well as estrogen receptor (ER) and progesterone receptor (PR) expression but share a number of characteristics with BRCA1 mutant breast cancer. Although a phase II study in high-grade serous ovarian cancer showed that olaparib can reduce the risk of recurrence when used as maintenance therapy after chemotherapy ( 5 ), small studies of olaparib as a single agent in triple-negative breast cancer have been relatively disappointing ( 6 ). Second, based on preclinical studies showing additive or synergistic effects of combining PARP inhibitors with a number of chemotherapeutic agents, clinical trials assessing PARP inhibitor drug combination regimens have been conducted.…”

mentioning

confidence: 99%