scholarly journals Meta-analysis on the PARP-inhibitor olaparib reveals therapeutic efficacy in ovarian cancer independent of BRCA1/2 mutation status

2016 ◽  
Vol 2 (2) ◽  
pp. 91 ◽  
Author(s):  
Ines Vasconcelos ◽  
Oscar Gaspar
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trials ◽  
Cancer Patients ◽  
Fallopian Tube ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
High Grade ◽  
Wild Type ◽  
Mutation Status ◽  
Platinum Sensitive

<p> </p><div><p>Poly(ADP-ribose) polymerase (PARP) inhibitors are one of the most promising drugs for ovarian cancer treatment. This study investigated clinical trials of PARP inhibitors, in order to obtain a more complete prognosis of ovarian cancer patients, which is usually dependent on their <em>BRCA1/2</em> mutation status. The PubMed database was searched using the key terms “PARP inhibitor OR olaparib OR veliparib OR niraparib OR rucaparib OR (BMN 673) AND (ovarian cancer OR solid tumors)”, while narrowing the selection of the article type to “clinical trial” only. Women included in the study had been histologically diagnosed with recurrent high-grade serous ovarian-, fallopian tube- or primary peritoneal-carcinoma, regardless of the presence of <em>BRCA</em> germline mutation or platinum-sensitive disease recurrence. Data from three Phase I and eight Phase II clinical trials were obtained, two of which evaluated veliparib, eight olaparib and one niraparib. A total of 1042 patients with either high-grade serous ovarian-, fallopian tube- or primary peritoneal cancer were enrolled, of which 587 had a <em>BRCA1/2</em> germline mutation and at least 370 were platinum-sensitive. The overall response rate (ORR) for patients who underwent treatment with olaparib was 44.5% (95% confidence interval = 0.396–0.496). Patients with <em>BRCA1/2</em> mutation and those with wild-type <em>BRCA1/2</em> showed no significant difference in ORR (<em>p</em> = 0.35), even when considering solely Phase II trials (<em>p</em> = 0.13). PARP inhibitors, particularly olaparib, proved effective in the management of ovarian cancer patients. This study identified the existence of patients who presented wild-type <em>BRCA1/2</em> and possibly <em>BRCA</em>-independent homologous-recombination deficient tumors, or patients with wild-type <em>BRCA1/2</em> and tumors presenting other forms of <em>BRCA</em>ness, who benefit from treatment with olaparib.</p></div>

scholarly journals Real-world treatment patterns and outcomes in platinum-sensitive recurrent high-grade serous ovarian cancer patients

2021 ◽  
Author(s):  
Carlota Moya-Alarcón ◽  
Guiomar Piera ◽  
Ángel Callejo ◽  
Amaya Gascó
Keyword(s):  
Ovarian Cancer ◽  
Treatment Outcomes ◽  
Cancer Patients ◽  
Negative Impact ◽  
Treatment Patterns ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Wild Type ◽  
Platinum Sensitive ◽  
Study Results

Aim: To describe the overall cancer-related healthcare utilization patterns, treatment patterns and outcomes in women diagnosed with platinum-sensitive recurrent high-grade serous ovarian cancer. Patients & methods: Subanalysis of the Spanish sample of a retrospective, noninterventional, multinational, observational study. Results: BRCA-mutated patients had better outcomes in terms of progression-free survival and overall survival than patients who were BRCA wild-type. It was observed that patients’ treatment outcomes after the first recurrence progressively worsened as the patient underwent subsequent chemotherapy lines. Healthcare resource utilization when accounting for the follow-up time did not substantially differ between BRCA1/ 2-mutated and BRCA wild-type patients. Conclusion: BRCA1/2 mutation carriers have better treatment outcomes, including longer survival, without a negative impact on the use of healthcare resources.

scholarly journals Efficacy and Safety of PARP Inhibitor Combination Therapy in Recurrent Ovarian Cancer: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Ning Ren ◽  
Leyin Zhang ◽  
Jieru Yu ◽  
Siqi Guan ◽  
Xinyang Dai ◽  
...  
Keyword(s):  
Systematic Review ◽  
Ovarian Cancer ◽  
Combination Therapy ◽  
Data Extraction ◽  
Meta Analysis ◽  
Parp Inhibitor ◽  
Recurrent Ovarian Cancer ◽  
Parp Inhibitors ◽  
High Grade ◽  
Efficacy And Safety

ObjectivesThough it is known to all that PARP inhibitors (PARPis) are effective when used as maintenance alone for women with recurrent ovarian cancer (ROC), little is known about whether using them in combination with other drugs would contribute to a better efficacy. We performed a systematic review and meta-analysis to explore the efficacy and safety of PARPi combination therapy compared with monotherapy.Materials and MethodsWe searched for randomized controlled trials (RCTs) that offered the date we needed in PubMed, Embase, Cochrane, and major conference. Data extraction and processing were completed by three investigators to compare OS, PFS, and ORR both in intervention and in control subset. Then, we calculated the pooled RR and 95% CI of all-grade and high-grade adverse effects to study its safety. And we evaluated the within-study heterogeneity by using subgroup and sensitivity analysis.Results and ConclusionA total of three eligible RCTs covering 343 women were included. In PFS analysis, PARP inhibitor (PARPi) combination therapy can significantly improve PFS for women with ROC when compared with the controls (HR: 0.46, 95% CI: 0.35 to 0.59), especially for those with mutated BRCA (HR: 0.29, 95% CI: 0.19 to 0.45). And in OS analysis, combination therapy is not inferior to monotherapy (HR: 0.90, 95% CI: 0.50 to 1.61). As for ORR, the effectiveness of combination therapy and monotherapy was almost the same (RR: 1.04, 95% CI: 0.82 to 1.31). Additionally, combination therapy seldom causes more adverse events, both in all-grade and in high grade.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, International Prospective Register of Systematic Reviews (PROSPERO) (identifier, CRD42018109933).

A randomized phase 2 trial comparing efficacy of the combination of the PARP inhibitor olaparib and the antiangiogenic cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer.

2014 ◽  
Vol 32 (18_suppl) ◽  
pp. LBA5500-LBA5500 ◽  
Author(s):  
Joyce Liu ◽  
William Thomas Barry ◽  
Michael J. Birrer ◽  
Jung-min Lee ◽  
Ronald J. Buckanovich ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Phase 1 ◽  
Parp Inhibitor ◽  
Objective Response ◽  
Progression Free Survival ◽  
Recurrent Ovarian Cancer ◽  
Parp Inhibitors ◽  
Open Label ◽  
Angiogenic Therapy ◽  
Platinum Sensitive

LBA5500 Background: PARP inhibitors and anti-angiogenics are clinically active in recurrent ovarian cancer (OvCa). Preclinical studies suggest these agents can synergize, and a phase 1 study showed that the combination of cediranib (ced) and olaparib (olap) is well-tolerated. We therefore compared the activity of olap alone (Olap) to combined ced and olap (Ced/Olap) in treatment of recurrent platinum-sensitive (plat-sens) high-grade serous (HGS) or BRCA-related OvCa (NCT 01116648). Methods: Patients (pts) across 9 centers were randomized 1:1 in this Ph 2 open label study to Olap (olap 400 mg capsules BID) or Ced/Olap (olap 200 mg capsules BID; ced 30 mg daily), stratified by BRCA status and prior anti-angiogenic therapy. Eligibility included pts with recurrent plat-sens HGS or BRCA-related OvCa. Pts had measurable disease by RECIST 1.1, PS 0 or 1, and the ability to take POs. No prior anti-angiogenics in the recurrent setting or prior PARP inhibitor was allowed. Progression-free survival (PFS) was defined as time from randomization to radiographic progression or death. With a target N=90 pts, the study was powered to detect a hazard ratio (HR) of 1.75 (median PFS 6 vs 10.5 mo). Results: Pts were enrolled from Oct 2011 to Jun 2013: 46 to Olap, 44 to Ced/Olap. 48 pts were known BRCA carriers (25 Olap; 23 Ced/Olap). At a planned interim analysis the DSMB recommended release of data. As of Jan 7, 2014, 41 pts had a PFS event. Median PFS was 9.0 mos for Olap and 17.7 mos for Ced/Olap (HR 2.9, 95% CI 1.5-5.6, p = 0.001). There were 2 complete responses (CR) and 21 partial responses (PR) in pts on Olap (56% objective response rate, ORR) and 3 CRs and 33 PRs in pts on Ced/Olap (84% ORR, p = 0.008). The overall rate of Gr3/4 toxicity was higher for pts on Ced/Olap (70%) than on Olap (7%). Differentially occurring toxicities included fatigue (27% Ced/Olap vs 7% Olap), diarrhea (23% vs 0%), and hypertension (39% vs 0%). Updated efficacy and exploratory subgroup analyses will be presented. Conclusions: Combined Ced/Olap significantly extended PFS and ORR compared to Olap in plat-sens OvCa. Further studies of this oral combination in plat-sens OvCa are warranted. Clinical trial information: NCT01116648.

scholarly journals Role of BRCA Mutation and HE4 in Predicting Chemotherapy Response in Ovarian Cancer: A Retrospective Pilot Study

Biomedicines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 55
Author(s):  
Francesco Plotti ◽  
Corrado Terranova ◽  
Federica Guzzo ◽  
Carlo De Cicco Nardone ◽  
Daniela Luvero ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Brca Mutation ◽  
Predictive Marker ◽  
Chemotherapy Response ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Wild Type ◽  
Platinum Sensitive ◽  
Platinum Resistant

Even though 80% of patients with High-Grade Serous Ovarian Cancer respond to standard first-line chemotherapy, a majority of them could relapse in the following five years due to a resistance to platinum. Human Epididymis protein 4 (HE4) is one of the most promising markers in predicting platinum therapy response. This pilot study aims to evaluate the potential role of HE4 value in predicting chemotherapy response in BRCA mutated patients and in BRCA wild-type (non-mutated) ones. We selected 69 patients, affected by High-Grade Serous Ovarian Cancer, and optimally debulked and submitted to standard chemotherapy protocols. HE4 was dosed during every chemotherapy course. Patients were classified as platinum-resistant and platinum-sensitive. According to BRCA mutation test, patients were further divided into BRCA wild-type (53 patients), and BRCA mutated (16 patients). 35 patients out of 69 (52%) were platinum-sensitive (recurrence > 12 months), while 33 patients (48%) were platinum-resistant (recurrence < 12 months). Thus, in the total population, HE4 performed as a marker of chemosensitivity with a sensibility of 79% and a specificity of 97%. In the BRCA WT group, 23 patients out of 53 (43%) were platinum-sensitive, while 30 patients out of 53 (57%) were platinum-resistant. In the BRCA WT group, HE4 performed as a predictive marker of chemosensitivity with a sensibility of 80% and a specificity of 100%. In the BRCA mutated group, 13 patients out of 16 (82%) were platinum-sensitive, while 3 patients (18%) were platinum-resistant. In the BRCA mutated group, HE4 performed as a predictive marker of chemosensitivity in all patients. The ability to detect platinum-resistant patients before tumor relapse probably could open new therapeutic scenarios.

scholarly journals Use of PARP Inhibitors for Ovarian Cancer

2021 ◽  
Vol 19 (5.5) ◽  
pp. 636-638
Author(s):  
Deborah K. Armstrong
Keyword(s):  
Ovarian Cancer ◽  
Parp Inhibitor ◽  
Progression Free Survival ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Free Survival ◽  
Platinum Sensitive ◽  
Resistant Disease ◽  
Relapsed Disease ◽  
Increased Activity

PARP inhibitors have been used to treat numerous diseases, but these agents have been approved the longest for use in ovarian cancer. All trials of PARP inhibitor maintenance in newly diagnosed ovarian cancer are positive for prolonged progression-free survival (PFS), but patients with BRCA mutations consistently derive the most benefit. Testing for homologous recombination deficiency may provide information regarding the degree of PFS benefit. In individuals without a BRCA mutation, PARP inhibition also prolongs PFS after chemotherapy for platinum-sensitive, PARP-naïve disease. As in the up-front setting, patients with BRCA mutations derive the most benefit in these trials. Finally, PARP inhibitors are active as monotherapy in PARP-naïve, BRCA-mutated relapsed disease, with increased activity observed in platinum-sensitive versus platinum-resistant disease.

scholarly journals Poly (ADP-Ribose) Polymerase Inhibitors: Recent Advances and Future Development

2015 ◽  
Vol 33 (12) ◽  
pp. 1397-1406 ◽  
Author(s):  
Clare L. Scott ◽  
Elizabeth M. Swisher ◽  
Scott H. Kaufmann
Keyword(s):  
Parp Inhibitor ◽  
Germline Mutations ◽  
Parp Inhibitors ◽  
Clinical Development ◽  
Preclinical Studies ◽  
High Grade ◽  
Platinum Sensitive ◽  
Ovarian Cancers ◽  
Recent Advances ◽  
Tumor Types

Poly (ADP-ribose) polymerase (PARP) inhibitors have shown promising activity in epithelial ovarian cancers, especially relapsed platinum-sensitive high-grade serous disease. Consistent with preclinical studies, ovarian cancers and a number of other solid tumor types occurring in patients with deleterious germline mutations in BRCA1 or BRCA2 seem to be particularly sensitive. However, it is also becoming clear that germline BRCA1/2 mutations are neither necessary nor sufficient for patients to derive benefit from PARP inhibitors. We provide an update on PARP inhibitor clinical development, describe recent advances in our understanding of PARP inhibitor mechanism of action, and discuss current issues in the development of these agents.

scholarly journals The Landscape and Therapeutic Implications of Molecular Profiles in Epithelial Ovarian Cancer

2020 ◽  
Vol 9 (7) ◽  
pp. 2239
Author(s):  
Ludivine Dion ◽  
Isis Carton ◽  
Sylvie Jaillard ◽  
Krystel Nyangoh Timoh ◽  
Sébastien Henno ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Genetic Alterations ◽  
High Grade ◽  
Dna Breaks ◽  
Brca Mutations ◽  
Platinum Based Chemotherapy

Epithelial ovarian cancer (EOC) affects 43,000 women worldwide every year and has a five-year survival rate of 30%. Mainstay treatment is extensive surgery and chemotherapy. Outcomes could be improved by molecular profiling. We conducted a review of the literature to identify relevant publications on molecular and genetic alterations in EOC. Approximately 15% of all EOCs are due to BRCA1 or BRCA2 mutations. Four histologic subtypes characterized by different mutations have been described: serous, endometrioid, mucinous, and clear-cell. Between 20–30% of high-grade serous EOCs have a BRCA mutation. Tumors with BRCA mutations are unable to repair double-strand DNA breaks, making them more sensitive to platinum-based chemotherapy and to PolyAdenosine Diphosphate-Ribose Polymerase (PARP) inhibitors. Olaparib is a PARP inhibitor with proven efficacy in BRCA-mutated ovarian cancer, but its effectiveness remains to be demonstrated in tumors with a BRCAness (breast cancer) profile (i.e., also including sporadic tumors in patients with deficient DNA repair genes). A universally accepted molecular definition of BRCAness is required to identify optimal theranostic strategies involving PARP inhibitors. Gene expression analyses have led to the identification of four subgroups of high-grade serous EOC: mesenchymal, proliferative, differentiated, and immunoreactive. These subtypes are not mutually exclusive but are correlated with prognosis. They are not yet used in routine clinical practice. A greater understanding of EOC subtypes could improve patient management.

Glucocorticoid receptor expression is associated with inferior overall survival independent of BRCA mutation status in ovarian cancer

2019 ◽  
Vol 29 (2) ◽  
pp. 357-364 ◽  
Author(s):  
Jennifer Taylor Veneris ◽  
Lei Huang ◽  
Jane E Churpek ◽  
Suzanne D Conzen ◽  
Gini F Fleming
Keyword(s):  
Gene Expression ◽  
Ovarian Cancer ◽  
Overall Survival ◽  
Glucocorticoid Receptor ◽  
Cancer Patients ◽  
Brca Mutation ◽  
Receptor Expression ◽  
High Grade ◽  
Mutation Status ◽  
Relationship Of

ObjectiveHigh glucocorticoid receptor (GR) protein expression is associated with decreased progression-free survival in ovarian cancer patients and decreased sensitivity to chemotherapy in preclinical models. Prior studies suggest wild type BRCA1 promotes GR activation. The objective of this study was to characterize the relationship of tumor GR gene expression to outcome in ovarian cancer, and to evaluate the relationship of GR expression with BRCA status.MethodsWhole exome and whole genome sequencing, gene expression, and clinical data were obtained for high-grade serous ovarian cancers in The Cancer Genome Atlas. Cases with pathogenic somatic or germline BRCA1 or BRCA2 mutations were identified and classified as BRCA mutated. High or low glucocorticoid receptor expression was defined as expression above or below median of the GR/nuclear receptor subfamily 3 C1 (NR3C1) gene level. Overall survival was estimated by the Kaplan-Meier method and compared by Cox regression analysis.ResultsCombined germline DNA sequencing and tumor microarray expression data were available for 222 high-grade serous ovarian cancer cases. Among these, 47 had a deleterious germline and/or somatic mutation in BRCA1 or BRCA2. In multivariate analysis, high glucocorticoid receptor gene expression was associated with decreased overall survival among ovarian cancer patients, independently of BRCA mutation status. No correlation of GR/NR3C1 gene expression with BRCA mutation status or BRCA1 or BRCA2 mRNA level was observed.ConclusionsIncreased GR gene expression is associated with decreased overall survival in ovarian cancer patients, independently of BRCA mutation status. High-grade serous ovarian cancers with high GR expression and wild type BRCA have a particularly poor outcome.

scholarly journals Overcoming PARP inhibitor resistance in ovarian cancer: what are the most promising strategies?

2020 ◽  
Vol 302 (5) ◽  
pp. 1087-1102
Author(s):  
Daniel Martin Klotz ◽  
Pauline Wimberger
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trials ◽  
Multiple Drug Resistance ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Resistance Mechanisms ◽  
Therapeutic Options ◽  
Parp Inhibition ◽  
Multiple Drug ◽  
Platinum Based Chemotherapy

Abstract Purpose Ovarian cancer is the most lethal gynaecological malignancy. Despite the introduction of bevacizumab, standard chemotherapy has remained largely unchanged and the vast majority of patients will relapse within the first two years of diagnosis. However, results from recent clinical trials demonstrating clinical benefits of PARP inhibitor treatment are rapidly changing therapeutic options for many patients with ovarian cancer. Methods Given the introduction of new therapeutic options in the treatment of ovarian cancer, we critically review key clinical trials, areas of scientific research and its clinical relevance. Results Most notably, patients with BRCA1/2 mutant ovarian cancer benefit from maintenance treatment with PARP inhibitors after (complete or partial) response to platinum-based chemotherapy. Here, we discuss the mechanism of PARP inhibition, multiple drug resistance mechanisms, including BRCA reverse mutations, altered PARP expression, changes in DNA repair pathways, kinase activation and additional drug targets that may augment PARP inhibition. Conclusion Although the use of PARP inhibitors is a huge step forward, it is apparent that patients, both with and without BRCA-mutant ovarian cancer, will eventually become resistant to PARP inhibitors. Therefore, novel combination therapies may enhance PARP inhibitor efficacy and overcome resistance mechanisms.

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