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 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>

ARIEL4: An international, multicenter randomized phase 3 study of the PARP inhibitor rucaparib vs chemotherapy in germline or somatic BRCA1- or BRCA2-mutated, relapsed, high-grade ovarian carcinoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS5603-TPS5603 ◽  
Author(s):  
Amit M. Oza ◽  
Domenica Lorusso ◽  
Ana Oaknin ◽  
Tamar Safra ◽  
Elizabeth Swisher ◽  
...  
Keyword(s):  
Ovarian Carcinoma ◽  
Parp Inhibitor ◽  
Brca2 Mutation ◽  
Single Agent ◽  
Objective Response ◽  
The United States ◽  
Parp Inhibitors ◽  
Ca 125 ◽  
High Grade ◽  
Platinum Sensitive

TPS5603 Background: In high-grade epithelial ovarian carcinoma (OC), ≈18% of patients (pts) have tumors with a germline BRCA1 or BRCA2 mutation; ≈7% have tumors with a somatic BRCA1 or BRCA2 mutation (Pennington et al. Clin Cancer Res. 2014;20:764-75). The poly(ADP-ribose) polymerase (PARP) inhibitor rucaparib is approved in the United States for treatment of pts with OC associated with a deleterious BRCA1 or BRCA2 mutation (germline and/or somatic) who have received ≥2 chemotherapies. Although PARP inhibitors have demonstrated clinical activity in OC in both treatment and maintenance settings, comparison to standard of care (SOC) has only been evaluated in the maintenance setting. Randomized studies are needed to assess the benefit-risk profile of PARP inhibitors vs current SOC as treatment for BRCA1- or BRCA2-mutated, relapsed, high-grade OC. Methods: ARIEL4 (NCT02855944) is evaluating rucaparib vs chemotherapy as treatment for pts with germline or somatic BRCA1- or BRCA2-mutated, relapsed, high-grade OC (regardless of histology) who have received ≥2 prior chemotherapy regimens. Approximately 345 pts will be randomized 2:1 to receive rucaparib (600 mg BID) (n = 230) or chemotherapy (n = 115) and stratified by progression-free interval after their most recent platinum regimen. Pts with platinum-resistant (progressive disease [PD] 1– < 6 mo after last platinum) or partially platinum-sensitive disease (PD 6– < 12 mo after last platinum) will be randomized to rucaparib or weekly paclitaxel; pts with platinum-sensitive disease (PD ≥12 mo after last platinum) will be randomized to rucaparib or platinum-based therapy (single-agent or doublet at the discretion of the investigator). Pts receiving chemotherapy have the option to cross over to rucaparib upon radiographic disease progression. The primary endpoint is progression-free survival. Secondary endpoints include investigator-assessed objective response rate (ORR) (RECIST version 1.1), ORR/CA-125 response, duration of response, overall survival, and pt-reported outcomes. Safety will be summarized descriptively using standard adverse event reporting. Clinical trial information: NCT02855944.

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).

scholarly journals The chromatin remodeler ALC1 underlies resistance to PARP inhibitor treatment

2020 ◽  
Vol 6 (51) ◽  
pp. eabb8626
Author(s):  
Szilvia Juhász ◽  
Rebecca Smith ◽  
Tamás Schauer ◽  
Dóra Spekhardt ◽  
Hasan Mamar ◽  
...  
Keyword(s):  
Homologous Recombination ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Dna Lesions ◽  
End Joining ◽  
Multiple Tumor ◽  
Genome Wide ◽  
A Genome ◽  
Inhibitor Resistance ◽  
Tumor Types

Poly(ADP-ribose) polymerase (PARP) inhibitors are used in the treatment of BRCA-deficient cancers, with treatments currently extending toward other homologous recombination defective tumors. In a genome-wide CRISPR knockout screen with olaparib, we identify ALC1 (Amplified in Liver Cancer 1)—a cancer-relevant poly(ADP-ribose)-regulated chromatin remodeling enzyme—as a key modulator of sensitivity to PARP inhibitor. We found that ALC1 can remove inactive PARP1 indirectly through binding to PARylated chromatin. Consequently, ALC1 deficiency enhances trapping of inhibited PARP1, which then impairs the binding of both nonhomologous end-joining and homologous recombination repair factors to DNA lesions. We also establish that ALC1 overexpression, a common feature in multiple tumor types, reduces the sensitivity of BRCA-deficient cells to PARP inhibitors. Together, we conclude that ALC1-dependent PARP1 mobilization is a key step underlying PARP inhibitor resistance.

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.

Association of secondary somatic mutations in BRCA1/2 with clinical resistance to PARP inhibitors and chemotherapy.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1087-1087
Author(s):  
Lingjun Zhu ◽  
Yan Zhang ◽  
Pingping Dai ◽  
Ping Zhou ◽  
Hui Li ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Parp Inhibitor ◽  
Germline Mutations ◽  
Parp Inhibitors ◽  
The Other ◽  
Targeting Therapy ◽  
Platinum Based Chemotherapy ◽  
Clinical Resistance ◽  
Somatic Reversion ◽  
Generation Sequencing

1087 Background: Somatic reversion mutations in either BRCA1/2 has been reported to lead to the resistance of platinum-based chemotherapy or PARPi. In this study we try to analyze the secondary somatic mutations in BRCA1/2 in patients with germline mutations. Methods: Using gene-panel target-captore next generation sequencing, we analyzed the secondary somatic mutations from 86 patients with BRCA1/2 germline mutations. Results: Eighty-six cases with BRCA1/2 gremline mutations were identified. Secondary somatic mutations restoring BRCA1/2 were identified in 7 patients, including 2 breast cancer, 3 ovarian cancer, 1 prostate cancer and 1cholangiocarcinoma patient. For these seven patients, five had been treated with platinum-based chemotherapy without PARPi and the other two (patient 1 and 2) with PARPi (olaparib). Patient 1 and 2 both received targeting therapy of PARP inhibitor olaparib after the germline BRCA1/2 mutation was detected. About six months later, plasma ctDNA was sequenced. Result showed that the germline mutations remained and additional larger deletions was detected. These secondary somatic mutations are not predicted to significantly affect the BRCA1/2 protein, and are likely to cause resistance to platinum-based chemotherapy or PARPi therapy by restoring BRCA1/2 ORF and DNA repair function. Conclusions: Secondary somatic mutations that restore BRCA1/2 in carcinomas with germline BRCA1/2 mutations predict resistance to platinum-based chemotherapy and PARP inhibitors, some strategies to reverse this type of drug resistance need further investigation. [Table: see text]

scholarly journals Recent Advances of Wee1 Inhibitors and Statins in Gynecologic Cancers with p53 Mutations

2021 ◽  
Author(s):  
Xiangbing Meng ◽  
Jason K Gao ◽  
Sean Michael T Gomendoza ◽  
John Li ◽  
Shujie Yang
Keyword(s):  
Cancer Progression ◽  
Tumor Suppressor Genes ◽  
Mevalonate Pathway ◽  
High Grade ◽  
P53 Mutations ◽  
Gynecological Cancers ◽  
Aberrant Expression ◽  
Ovarian Cancers ◽  
Recent Advances ◽  
Endometrial Cancers

p53 is among the most frequently mutated tumor suppressor genes given its prevalence in &gt;50% of all human cancers, including high grade serous endometrial cancers and ovarian cancers. In addition to loss of tumor suppression function, many mutated p53 (Mutp53) proteins acquire gain-of-function (GOF) activities as oncogenes to promote cancer progression, which manifest through aberrant expression of p53. As we have come to see, statins induce CHIP-mediated degradation of mutp53 by blocking the interaction between mutp53 and DNAJA1. Therefore, targeting critical downstream pathways of mutp53 provides an alternative strategy for treating cancers expressing mutp53. In this review, we summarize recent advances with Wee1 inhibitors and mevalonate pathway inhibitors, particularly statins, regarding their use in gynecological cancers with p53 mutations.

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 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.

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