Olaparib for the treatment of BRCA-mutated advanced ovarian cancer

2016 ◽  
Vol 73 (14) ◽  
pp. 1037-1041 ◽  
Author(s):  
Marklie Munroe ◽  
Jill Kolesar
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Clinical Trials ◽  
Dna Repair ◽  
Tumor Cell ◽  
Synthetic Lethality ◽  
Plasma Concentrations ◽  
Advanced Ovarian Cancer ◽  
Tumor Cell Death ◽  
Ovarian Cancers

Abstract Purpose The pharmacology, clinical efficacy, safety, dosage and administration, and role in therapy of olaparib, a first-in-class treatment for advanced treatment-refractory ovarian cancer, are reviewed. Summary Olaparib (Lynparza, AstraZeneca) is an oral inhibitor of poly(ADP-ribose) polymerase (PARP) proteins that play a key role in DNA repair and genomic stability. Olaparib is indicated for use in treating certain patients with advanced, recurrent ovarian cancer who have mutations of the breast cancer 1 gene (BRCA1) or breast cancer 2 gene (BRCA2). In patients with BRCA-mutated cancers, olaparib blocks vital PARP-mediated tumor cell DNA repair mechanisms, leading to “synthetic lethality” and selective tumor cell death. In Phase II clinical trials including patients with platinum-sensitive, platinum-resistant, and platinum-refractory ovarian cancers, olaparib significantly improved progression-free survival, with similar rates of response reported in patients with BRCA1- and BRCA2-mutated disease. Olaparib is generally well tolerated; the most commonly reported adverse events in clinical trials were mild nausea, fatigue, vomiting, and diarrhea. Severe anemia and severe fatigue can occur in association with olaparib treatment. Concurrent administration of olaparib and strong or moderate inducers or inhibitors of cytochrome P-450 isozyme 3A should be avoided, as use of those agents may alter plasma concentrations of olaparib. Conclusion Olaparib is a novel PARP inhibitor that is efficacious and well tolerated in patients with BRCA-mutated advanced ovarian cancers who have received three or more lines of prior treatment.

scholarly journals Combined Strategies with Poly (ADP-Ribose) Polymerase (PARP) Inhibitors for the Treatment of Ovarian Cancer: A Literature Review

Diagnostics ◽  
2019 ◽  
Vol 9 (3) ◽  
pp. 87 ◽  
Author(s):  
Stergios Boussios ◽  
Peeter Karihtala ◽  
Michele Moschetta ◽  
Afroditi Karathanasi ◽  
Agne Sadauskaite ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Synthetic Lethality ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Advanced Ovarian Cancer ◽  
Pegylated Liposomal Doxorubicin ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Biologic Agent

Poly (ADP-ribose) polymerase (PARP) inhibitors are the first clinically approved drugs designed to exploit synthetic lethality, and were first introduced as a cancer-targeting strategy in 2005. They have led to a major change in the treatment of advanced ovarian cancer, and altered the natural history of a disease with extreme genetic complexity and defective DNA repair via homologous recombination (HR) pathway. Furthermore, additional mechanisms apart from breast related cancer antigens 1 and 2 (BRCA1/2) mutations can also result in HR pathway alterations and consequently lead to a clinical benefit from PARP inhibitors. Novel combinations of PARP inhibitors with other anticancer therapies are challenging, and better understanding of PARP biology, DNA repair mechanisms, and PARP inhibitor mechanisms of action is crucial. It seems that PARP inhibitor and biologic agent combinations appear well tolerated and clinically effective in both BRCA-mutated and wild-type cancers. They target differing aberrant and exploitable pathways in ovarian cancer, and may induce greater DNA damage and HR deficiency. The input of immunotherapy in ovarian cancer is based on the observation that immunosuppressive microenvironments can affect tumour growth, metastasis, and even treatment resistance. Several biologic agents have been studied in combination with PARP inhibitors, including inhibitors of vascular endothelial growth factor (VEGF; bevacizumab, cediranib), and PD-1 or PD-L1 (durvalumab, pembrolizumab, nivolumab), anti-CTLA4 monoclonal antibodies (tremelimumab), mTOR-(vistusertib), AKT-(capivasertib), and PI3K inhibitors (buparlisib, alpelisib), as well as MEK 1/2, and WEE1 inhibitors (selumetinib and adavosertib, respectively). Olaparib and veliparib have also been combined with chemotherapy with the rationale of disrupting base excision repair via PARP inhibition. Olaparib has been investigated with carboplatin and paclitaxel, whereas veliparib has been tested additionally in combination with temozolomide vs. pegylated liposomal doxorubicin, as well as with oral cyclophosphamide, and topoisomerase inhibitors. However, overlapping myelosuppression observed with PARP inhibitor and chemotherapy combinations requires further investigation with dose escalation studies. In this review, we discuss multiple clinical trials that are underway examining the antitumor activity of such combination strategies.

M-TRAP: Safety and performance of metastatic tumor cell trap device in advanced ovarian cancer patients

2021 ◽  
Author(s):  
Antonio Gil-Moreno ◽  
Lorena Alonso-Alconada ◽  
Berta Díaz-Feijoo ◽  
Santiago Domingo ◽  
Ana Vilar ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Cell ◽  
Cancer Patients ◽  
Advanced Ovarian Cancer ◽  
Metastatic Tumor ◽  
Metastatic Tumor Cell ◽  
And Performance

Identification of Eleven Novel BRCA Mutations in Tunisia: Impact on the Clinical Management of BRCA Related Cancers

2021 ◽  
Author(s):  
Yosr Hamdi ◽  
Najah Mighri ◽  
Maroua Boujemaa ◽  
Nesrine Mejri ◽  
Sonia Ben Nasr ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Large Fraction ◽  
Age At Onset ◽  
Tunisian Population ◽  
North African ◽  
Brca Mutations ◽  
Access To Treatment ◽  
Genetic Components ◽  
Ovarian Cancers

Abstract Background Breast cancer is the world's most common cancer among women. It is becoming an increasingly urgent problem in low- and middle-income countries (LMICs) where a large fraction of women is diagnosed with advanced-stage disease and have no access to treatment or basic palliative care. About 5-10% of all breast cancers can be attributed to hereditary genetic components and up to 25% of familial cases are due to mutations in BRCA1/2 genes. Since their discovery in 1994 and 1995, as few as 18 mutations have been identified in BRCA genes in the Tunisian population. The aim of this study is to identify additional BRCA mutations, to estimate their contribution to the hereditary breast and ovarian cancers in Tunisia and to investigate the clinicopathological signatures associated with BRCA mutations. Methods A total of 354 patients diagnosed with breast and ovarian cancers, including 5 male breast cancer cases, have been investigated for BRCA1/2 mutations using traditional and/or next generation sequencing technologies. Clinicopathological signatures associated with BRCA mutations have been also investigated. Results 16 distinct mutations were detected: 10 in BRCA1 and 6 in BRCA2, of which 11 are described for the first time in Tunisia including 3 variations that have not been reported previously in public databases namely BRCA1_c.915T>A; BRCA2_c.-227-?_7805+? and BRCA2_c.249delG. Early age at onset, family history of ovarian cancer and high tumor grade were significantly associated with BRCA status. BRCA1 carriers were more likely to be triple negative breast cancer compared to BRCA2 carriers. A relatively high frequency of contralateral breast cancer and ovarian cancer occurrence was observed among BRCA carriers and was more frequent in patients carrying BRCA1 mutations. Conclusion Our study provides new insights into breast and ovarian cancer genetic landscape in the under-represented North African populations. The prevalence assessment of novel and recurrent BRCA1/2 pathogenic mutations will enhance the use of personalized treatment and precise screening strategies by both affected and unaffected North African cancer cases.

scholarly journals Precision Medicine for Metastatic Breast Cancer

2015 ◽  
pp. e2-e7 ◽  
Author(s):  
Elise Deluche ◽  
Elisa Onesti ◽  
Fabrice Andre
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Dna Repair ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Precision Medicine ◽  
Metastatic Breast ◽  
Nucleotide Polymorphisms ◽  
Genomic Alterations ◽  
Pik3ca Mutations

Genomic studies have shown that large numbers of candidate targets are observed in breast cancer. Nevertheless, only a few of them are validated as relevant targets in clinical studies. Estrogen receptor (ER) and HER2 expressions could be associated with a level I evidence. Beyond ER and HER2, BRCA and PIK3CA mutations (when targeted with alpha-specific PI3K inhibitors) could be considered as promising targets in breast cancer since they have been associated with objective responses in phase I/II trials. In addition to these four molecular alterations, several others have shown promising results in preclinical studies and are being investigated in clinical trials. These genomic alterations include AKT1, ERBB2, and ESR1 mutations. These considerations highlight the lack of evidence for using multiplex technologies to individualize therapy in metastatic breast cancer. Sequencing multiple genes to treat metastatic breast cancer is very promising but should be done in the context of clinical trials, either to enrich phase I/II trials in patients with genomic alterations or to show medical usefulness of new biotechnologies like next-generation sequencing (NGS). Although most current approaches of precision medicine are aiming at targeting drivers, additional applications could be developed in the future. This includes the identification of DNA repair deficiencies, mechanisms of immune suppression, and identification of minority lethal subclones. Finally, one of the very promising applications of genomics for metastatic breast cancer is the identification of pathway activation or defects at the individual level. For example, gene expression and single nucleotide polymorphisms (SNP) signatures are being developed to detect kinase (such as mammalian target of rapamycin [mTOR]/CDK4) activations or DNA repair deficiencies.

First-in-human trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2580-2580 ◽  
Author(s):  
Johann Sebastian De Bono ◽  
Lida A. Mina ◽  
Michael Gonzalez ◽  
Nicola J. Curtin ◽  
Evelyn Wang ◽  
...  
Keyword(s):  
Dna Repair ◽  
Dose Escalation ◽  
Synthetic Lethality ◽  
Dose Range ◽  
Single Agent ◽  
Plasma Concentrations ◽  
Ca 125 ◽  
Brca 1 ◽  
Anti Tumor Activity ◽  
Brca Carrier

2580 Background: BMN 673 is the most potent and specific inhibitor of PARP1/2 in clinical development (IC50<1nM). In tumors genetically dependent on DNA repair by homologous recombination PARP inhibition induces synthetic lethality. Methods: Pharmacokinetics (PK), pharmacodynamics (PD), safety and anti-tumor activity of BMN 673 were evaluated in a 2-stage dose-escalation study with 3-6 patients (pts)/dose level. In dose escalation (Stage 1) cycle 1 was 6 wks, with drug taken on days 1 and 8-35, for PK and PD assays, followed by daily continuous dosing in 4-wk cycles. Stage 2 (expansion at MTD) recruits pts with tumors defective in DNA repair: Ewing sarcoma, small cell lung cancer or tumors associated with BRCA mutation (mut). Results: 39 pts (33F/6M) were enrolled in 9 cohorts from 25 to 1100 µg/d that defined a MTD of 1000 µg/d. Median (range) age was 58 (19-81), PS 0 (0-1) and # of prior therapies 4 (1-13). Tumors (# with deleterious BRCA 1/2 mut) included 23 ovarian/primary peritoneal (17); 8 breast (6); 3 pancreas; 2 colon; 1 prostate (1), and 1 mullerian carcinosarcoma. 17 and 8 pts had BRCA 1 and 2 mut, respectively. Dose-limiting thrombocytopenia occurred in 1/6 and 2/5 pts at 900 and 1100 µg/d, respectively. Potentially-related adverse events in >10% of pts (# grade 1 and 2/grade 3 and 4) included fatigue (10/0); nausea (10/0); flatulence (4/0); anemia (5/2); neutropenia (4/3); thrombocytopenia (1/3); and grade 1 alopecia (10). Inhibition of PARP activity in PBMCs was observed at doses ≥ 100 µg/d. BMN 673 plasma concentrations peaked 1-2 hrs post-dose; exposure increased dose proportionally. Steady state plasma concentrations were reached by the end of the 2nd week of daily dosing; mean Cmax: 0.30 - 25.4 ng/mL and AUC0-24: 3.96 - 203 ng-hr/mL across the 25 to 1100 µg/d dose range after 28d of daily dosing. RECIST and/or CA-125 responses occurred at doses ≥ 100 µg/d in 11/17 BRCA carrier ovarian/peritoneal cancer pts. Objective responses occurred in 2/6 BRCA-carrier breast cancer pts. Conclusions: BMN 673 is well tolerated with impressive anti-tumor activity in pts with BRCA mut with a single agent recommended Phase II trial dose of 1000 µg/d due to dose-limiting thrombocytopenia. Clinical trial information: NCT01286987.

scholarly journals Enhancement of Tumor Cell Death by Combining gef Gene Mediated Therapy and New 1,4-Benzoxazepin-2,6-Dichloropurine Derivatives in Breast Cancer Cells

2018 ◽  
Vol 9 ◽  
Author(s):  
Alberto Ramírez ◽  
Ana Conejo-García ◽  
Carmen Griñán-Lisón ◽  
Luisa C. López-Cara ◽  
Gema Jiménez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Tumor Cell ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Tumor Cell Death

Personalization of breast cancer chemotherapy using noninvasive imaging methods to detect tumor cell death responses

2014 ◽  
Vol 3 (1) ◽  
pp. 31-35 ◽  
Author(s):  
Lakshmanan Sannachi ◽  
Hadi Tadayyon ◽  
Ali Sadeghi-Naini ◽  
Michael C Kolios ◽  
Gregory Czarnota
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Tumor Cell ◽  
Cancer Chemotherapy ◽  
Noninvasive Imaging ◽  
Tumor Cell Death ◽  
Imaging Methods ◽  
Breast Cancer Chemotherapy

scholarly journals VRK1 Depletion Facilitates the Synthetic Lethality of Temozolomide and Olaparib in Glioblastoma Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Elena Navarro-Carrasco ◽  
Pedro A. Lazo
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Tumor Cell ◽  
Dna Damage Response ◽  
Synthetic Lethality ◽  
Glioblastoma Cell ◽  
Glioblastoma Cells ◽  
Tumor Cell Death ◽  
Damage Response ◽  
Parp 1

BackgroundGlioblastomas treated with temozolomide frequently develop resistance to pharmacological treatments. Therefore, there is a need to find alternative drug targets to reduce treatment resistance based on tumor dependencies. A possibility is to target simultaneously two proteins from different DNA-damage repair pathways to facilitate tumor cell death. Therefore, we tested whether targeting the human chromatin kinase VRK1 by RNA interference can identify this protein as a novel molecular target to reduce the dependence on temozolomide in combination with olaparib, based on synthetic lethality.Materials and MethodsDepletion of VRK1, an enzyme that regulates chromatin dynamic reorganization and facilitates resistance to DNA damage, was performed in glioblastoma cells treated with temozolomide, an alkylating agent used for GBM treatment; and olaparib, an inhibitor of PARP-1, used as sensitizer. Two genetically different human glioblastoma cell lines, LN-18 and LN-229, were used for these experiments. The effect on the DNA-damage response was followed by determination of sequential steps in this process: H4K16ac, γH2AX, H4K20me2, and 53BP1.ResultsThe combination of temozolomide and olaparib increased DNA damage detected by labeling free DNA ends, and chromatin relaxation detected by H4K16ac. The combination of both drugs, at lower doses, resulted in an increase in the DNA damage response detected by the formation of γH2AX and 53BP1 foci. VRK1 depletion did not prevent the generation of DNA damage in TUNEL assays, but significantly impaired the DNA damage response induced by temozolomide and olaparib, and mediated by γH2AX, H4K20me2, and 53BP1. The combination of these drugs in VRK1 depleted cells resulted in an increase of glioblastoma cell death detected by annexin V and the processing of PARP-1 and caspase-3.ConclusionDepletion of the chromatin kinase VRK1 promotes tumor cell death at lower doses of a combination of temozolomide and olaparib treatments, and can be a novel alternative target for therapies based on synthetic lethality.

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