scholarly journals The BET inhibitor INCB054329 reduces homologous recombination efficiency and augments PARP inhibitor activity in ovarian cancer

2018 ◽  
Vol 149 (3) ◽  
pp. 575-584 ◽  
Author(s):  
Andrew J. Wilson ◽  
Matthew Stubbs ◽  
Phillip Liu ◽  
Bruce Ruggeri ◽  
Dineo Khabele
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Parp Inhibitor ◽  
Inhibitor Activity ◽  
Bet Inhibitor ◽  
Recombination Efficiency

scholarly journals Perspectives on PARP Inhibitor Combinations for Ovarian Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Renata Colombo Bonadio ◽  
Maria del Pilar Estevez-Diz
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Current Knowledge ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Treatment Resistance ◽  
Parp Inhibitors ◽  
Wild Type ◽  
Inhibitor Activity ◽  
Secondary Resistance

Poly (ADP-ribose) polymerase (PARP) inhibitors constitute an important treatment option for ovarian cancer nowadays. The magnitude of benefit from PARP inhibitors is influenced by the homologous recombination status, with greater benefit observed in patients with BRCA mutated or BRCA wild-type homologous recombination deficient (HRD) tumors. Although some PARP inhibitor activity has been shown in homologous recombination proficient (HRP) ovarian tumors, its clinical relevance as a single agent is unsatisfactory in this population. Furthermore, even HRD tumors present primary or secondary resistance to PARP inhibitors. Strategies to overcome treatment resistance, as well as to enhance PARP inhibitors’ efficacy in HRP tumors, are highly warranted. Diverse combinations are being studied with this aim, including combinations with antiangiogenics, immunotherapy, and other targeted therapies. This review discusses the rationale for developing therapy combinations with PARP inhibitors, the current knowledge, and the future perspectives on this issue.

scholarly journals 53BP1 as a potential predictor of response in PARP inhibitor-treated homologous recombination-deficient ovarian cancer

2019 ◽  
Vol 153 (1) ◽  
pp. 127-134 ◽  
Author(s):  
Rachel M. Hurley ◽  
Andrea E. Wahner Hendrickson ◽  
Daniel W. Visscher ◽  
Peter Ansell ◽  
Maria I. Harrell ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Parp Inhibitor ◽  
Potential Predictor

scholarly journals PARP Inhibitors in Ovarian Cancer: The Route to “Ithaca”

Diagnostics ◽  
2019 ◽  
Vol 9 (2) ◽  
pp. 55 ◽  
Author(s):  
Boussios ◽  
Karathanasi ◽  
Cooke ◽  
Neille ◽  
Sadauskaite ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Parp Inhibition ◽  
Current Evidence ◽  
Repair Pathway ◽  
Significant Efficacy

Poly (ADP-ribose) polymerase (PARP) inhibitors are a novel class of therapeutic agents that target tumors with deficiencies in the homologous recombination DNA repair pathway. Genomic instability characterizes high-grade serous ovarian cancer (HGSOC), with one half of all tumors displaying defects in the important DNA repair pathway of homologous recombination. Early studies have shown significant efficacy for PARP inhibitors in patients with germline breast related cancer antigens 1 and 2 (BRCA1/2) mutations. It has also become evident that BRCA wild-type patients with other defects in the homologous recombination repair pathway benefit from this treatment. Companion homologous recombination deficiency (HRD) scores are being developed to guide the selection of patients that are most likely to benefit from PARP inhibition. The choice of which PARP inhibitor is mainly based upon the number of prior therapies and the presence of a BRCA mutation or HRD. The identification of patients most likely to benefit from PARP inhibitor therapy in view of HRD and other biomarker assessments is still challenging. The aim of this review is to describe the current evidence for PARP inhibitors in ovarian cancer, their mechanism of action, and the outstanding issues, including the rate of long-term toxicities and the evolution of resistance.

Elucidation of PARP inhibitor activity in BRCAwt recurrent ovarian cancer by hrr mutational gene profile analysis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5568-5568
Author(s):  
Mansoor Raza Mirza ◽  
Bin Feng ◽  
Ming Shan ◽  
Kaiming Sun ◽  
Ilkar Yalcin ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Clinical Benefit ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Gene Mutations ◽  
Recurrent Ovarian Cancer ◽  
Exploratory Analysis ◽  
Platinum Based Chemotherapy ◽  
Biomarker Analysis

5568 Background: Niraparib is an oral, selective poly(ADP-ribose) polymerase inhibitor (PARPi) approved for maintenance treatment of BRCA mutated ( BRCAmut) and BRCA wild-type ( BRCAwt) recurrent ovarian cancer patients (pts) who are in response to platinum-based chemotherapy. In the non-germline BRCA mutated (non-g BRCAmut) cohort of the ENGOT-OV16/NOVA trial, clinical benefit with niraparib vs placebo was seen in pts regardless of their Myriad myChoice HRD test status ( BRCAmut and homologous recombination deficiency [HRD] score), with a hazard ratio (HR) of 0.38 in HRD-positive (HRDpos) and 0.58 in HRD-negative (HRDneg) pts. To determine if treatment benefit in HRDneg pts may result from mutations in other homologous recombination repair ( HRR) genes, we examined the relationship between progression-free survival and other HRR gene mutations in the NOVA non-gBRCAmut cohort. Methods: A retrospective, exploratory biomarker analysis was conducted using all available tumor samples from 331 pts enrolled in the NOVA non-g BRCAmut cohort. Mutation status of HRR genes was evaluated using a 43-gene NGS assay (Myriad Genetics), including BRCA1/2 and 16 additional HRR genes. Results: In this exploratory analysis of the NOVA non-g BRCAmut cohort, niraparib demonstrated clinical benefit in pts with somatic BRCA mutation (HR, 0.27) and in BRCAwt pts (HR, 0.47). In addition, BRCAwt pts with other HRR gene mutations also derived benefit from niraparib (HR, 0.31), as did BRCAwt/ HRRwt pts (HR, 0.49). When BRCAwt/ HRRwt pts were categorized by HRD score, clinical benefit was also observed in both HRDpos and HRDneg pts, with HRs of 0.33 and 0.60, respectively. These results suggest that, although these biomarkers have good positive predictive value, they are not good negative predictors for niraparib benefit in this indication. Conclusions: This retrospective, exploratory analysis of the ENGOT-OV16/NOVA non-g BRCAmut cohort suggests that although pts with somatic BRCA mutation and other HRR mutations benefit from niraparib treatment, clinical benefit is also seen in HRDneg pts without HRR mutations, perhaps related to other genomic, epigenetic, or functional alterations within ovarian tumors yet to be defined.

Comparison of genomic instability test scores used for predicting PARP activity in ovarian cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1586-1586
Author(s):  
Kirsten M Timms ◽  
Gordon B. Mills ◽  
Michael Perry ◽  
Alexander Gutin ◽  
Jerry Lanchbury ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Clinical Trials ◽  
Homologous Recombination ◽  
Genomic Instability ◽  
Clinical Laboratory ◽  
Parp Inhibitor ◽  
Mutation Screening ◽  
Gene Panel ◽  
Snp Analysis ◽  
Gene Panels

1586 Background: Clinical trials have explored the utility of various genomic instability (GI) scores or gene panels to assess deficiencies in the homologous recombination (HR) DNA repair pathway and support PARP inhibitor use in ovarian cancer; however, these methods of assessing homologous recombination deficiency (HRD) may not be equivalent. The myChoice HRD test is the only analytically and clinically validated, FDA-approved HRD test that includes BRCA1/2 mutation status and three measures of GI. We compared the proportion of patients identified as candidates for PARP inhibitor use by two measures of HRD [percent loss of heterozygosity (%LOH), 11-gene panel] to myChoice HRD. Methods: Whole-genome SNP analysis was used to reconstruct ovarian tumor genomic profiles to calculate the myChoice HRD score and %LOH in 2 cohorts (clinical laboratory cohort, N = 3,278; SCOTROC4 trial, N = 248). Mutation screening for a set of 11 genes in the HR pathway ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, MRE11A, NBN, PALB2, RAD51C, RAD51D) was performed for a subset of tumors from the SCOTROC trial (n = 187). Samples were considered positive if the myChoice HRD score was above the threshold (threshold scores of 42 and 33 were assessed), %LOH above the threshold (16%), or a pathogenic variant in one of the 11 HR genes. The correlation between positive results from %LOH and the 11-gene panel were compared to myChoice HRD. Percent positive agreement (PPA) was the proportion of positive test results from myChoice HRD that were also positive by %LOH or the 11-gene panel. Results: The table shows the correlation and PPA between myChoice HRD, %LOH, and the 11-gene panel. Overall, 19%-61% of patients identified as positive by myChoice HRD would have been missed by %LOH or the 11-gene panel in these two cohorts. Conclusions: These data show that HRD tests used in published and ongoing clinical trials are not equivalent, and they should not be considered interchangeable in predicting PARP inhibitor response in clinical practice. [Table: see text]

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