scholarly journals Preventing and Overcoming Resistance to PARP Inhibitors: A Focus on the Clinical Landscape

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 44
Author(s):  
Rosario Prados-Carvajal ◽  
Elsa Irving ◽  
Natalia Lukashchuk ◽  
Josep V. Forment
Keyword(s):  
Ovarian Cancer ◽  
Targeted Therapies ◽  
Patient Population ◽  
Maintenance Treatment ◽  
Parp Inhibitors ◽  
Mechanisms Of Resistance ◽  
First Line ◽  
Clinical Models ◽  
Cancer Types

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are now a first-line maintenance treatment in ovarian cancer and have been approved in other cancer types, including breast, pancreatic and prostate. Despite their efficacy, and as is the case for other targeted therapies, resistance to PARPi has been reported clinically and is generating a growing patient population of unmet clinical need. Here, we discuss the mechanisms of resistance that have been described in pre-clinical models and focus on those that have been already identified in the clinic, highlighting the key challenges to fully characterise the clinical landscape of PARPi resistance and proposing ways of preventing and overcoming it.

scholarly journals Translational Research Opportunities Regarding Homologous Recombination in Ovarian Cancer

2018 ◽  
Vol 19 (10) ◽  
pp. 3249 ◽  
Author(s):  
Margarita Romeo ◽  
Juan Pardo ◽  
Anna Martínez-Cardús ◽  
Eva Martínez-Balibrea ◽  
Vanesa Quiroga ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Daily Practice ◽  
Parp Inhibitors ◽  
Repair Pathway ◽  
Mechanisms Of Resistance ◽  
First Line ◽  
Ovarian Carcinomas ◽  
Therapeutic Opportunity ◽  
Line Setting

Homologous recombination (HR) is a DNA repair pathway that is deficient in 50% of high-grade serous ovarian carcinomas (HGSOC). Deficient HR (DHR) constitutes a therapeutic opportunity for these patients, thanks to poly (ADP-ribose) polymerases (PARP) inhibitors (PARPi; olaparib, niraparib, and rucaparib are already commercialized). Although initially, PARPi were developed for patients with BRCA1/2 mutations, robust clinical data have shown their benefit in a broader population without DHR. This breakthrough in daily practice has raised several questions that necessitate further research: How can populations that will most benefit from PARPi be selected? At which stage of ovarian cancer should PARPi be used? Which strategies are reasonable to overcome PARPi resistance? In this paper, we present a summary of the literature and discuss the present clinical research involving PARPi (after reviewing ClinicalTrials.gov) from a translational perspective. Research into the functional biomarkers of DHR and clinical trials testing PARPi benefits as first-line setting or rechallenge are currently ongoing. Additionally, in the clinical setting, only secondary restoring mutations of BRCA1/2 have been identified as events inducing resistance to PARPi. The clinical frequency of this and other mechanisms that have been described in preclinics is unknown. It is of great importance to study mechanisms of resistance to PARPi to guide the clinical development of drug combinations.

Emerging molecular alterations leading to histology-specific targeted therapies in ovarian cancer beyond PARP inhibitors

2021 ◽  
Vol 101 ◽  
pp. 102298
Author(s):  
M. Bartoletti ◽  
L. Musacchio ◽  
G. Giannone ◽  
V. Tuninetti ◽  
A. Bergamini ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Targeted Therapies ◽  
Parp Inhibitors ◽  
Molecular Alterations

scholarly journals First-line PARP inhibitors in ovarian cancer: summary of an ESMO Open - Cancer Horizons round-table discussion

ESMO Open ◽  
2020 ◽  
Vol 5 (6) ◽  
pp. e001110
Author(s):  
Susana Banerjee ◽  
Antonio Gonzalez-Martin ◽  
Philipp Harter ◽  
Domenica Lorusso ◽  
Kathleen N Moore ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Maintenance Therapy ◽  
Parp Inhibitor ◽  
Advanced Ovarian Cancer ◽  
Round Table ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
European Medicines Agency ◽  
First Line ◽  
Phase Iii Trials

Poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is the latest breakthrough in the management of newly diagnosed advanced ovarian cancer. The results of the SOLO-1 trial in 2018 led to European Medicines Agency and Food and Drug Administration approval of olaparib as first-line maintenance therapy in patients with BRCA1/2 mutation, establishing a new standard of care. Subsequently, the results of three phase III trials (PRIMA, PAOLA-1, VELIA) evaluating the use of first-line PARP inhibitors beyond patients with BRCA1/2 mutations and as combination strategies were presented in 2019, leading to the recent approval of maintenance niraparib irrespective of biomarker status and olaparib in combination with bevacizumab in homologous recombination deficiency-positive-associated advanced ovarian cancer. An ESMO Open - Cancer Horizons round-table expert panel discussed the four phase III trials of first-line PARP inhibitor therapy and how they are changing the clinical management of advanced ovarian cancer.

scholarly journals Maintenance therapy for recurrent epithelial ovarian cancer: current therapies and future perspectives – a review

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Sudeep Gupta ◽  
Shona Nag ◽  
Shyam Aggarwal ◽  
Amit Rauthan ◽  
Narayanankutty Warrier
Keyword(s):  
Ovarian Cancer ◽  
Maintenance Therapy ◽  
Epithelial Ovarian Cancer ◽  
Maintenance Treatment ◽  
Progression Free Survival ◽  
Parp Inhibitors ◽  
Optimal Timing ◽  
Special Focus ◽  
Future Perspectives ◽  
Current Therapies

Abstract Epithelial ovarian cancer (EOC) is usually diagnosed late at an advanced stage. Though EOC initially responds to treatment, the recurrence rate is pretty high. The efficacy of different targeted therapies reduces with each recurrence. Hence there is need of effective maintenance therapy in recurrent EOC. Recently, polyADP-ribose polymerase (PARP) inhibitors (PARPi) have been approved both for initial treatment of EOC and as its maintenance treatment. PARPi have also been found to act regardless of BRCA status or homologous recombination (HR) deficiency. Several trials testing PARPi early in maintenance therapy are in progress and their results will shed light on the optimal timing of maintenance therapy that gives the most benefit with least toxicity. Right patient selection for maintenance treatment is also a challenge. Hence, though PARPi are emerging as a promising maintenance treatment in recurrent EOC with prolongation of progression free survival (PFS), results from further trials and overall survival (OS) data from current trials are awaited to fulfill the gaps in understanding the role of this pathway in treatment of EOC. This review discusses the current therapies for EOC, challenges in the treatment of recurrent EOC, recent developments and trials in recurrent EOC maintenance with special focus on PARPi and future perspectives.

Poly-(ADP-ribose) polymerase inhibitors: paradigm shift in the first-line treatment of newly diagnosed advanced ovarian cancer

2020 ◽  
Vol 21 (10) ◽  
pp. 721-727
Author(s):  
Fady Gh Haddad ◽  
Elias Karam ◽  
Elissar Moujaess ◽  
Hampig Raphael Kourie
Keyword(s):  
Ovarian Cancer ◽  
Homologous Recombination ◽  
Excision Repair ◽  
Advanced Ovarian Cancer ◽  
Progression Free Survival ◽  
Parp Inhibitors ◽  
First Line ◽  
Free Survival ◽  
Base Excision ◽  
Breast Cancer Gene

Debulking surgery associated with chemotherapy represent the backbone of ovarian cancer therapy. Adding bevacizumab has improved survival. Recently, PARP inhibitors were added in the first line as maintenance treatment for the patients who achieve a complete or partial response. These drugs act by blocking the activity of the PARP enzyme responsible for base-excision repair, and have shown positive responses when used for tumors lacking homologous recombination. Olaparib, niraparib and veliparib were evaluated and showed an increase in the duration of progression-free survival: 22.1 months (hazard ratio [HR] = 0.59), 13.8 (HR = 0.62) and 23.5 (HR = 0.68) with olaparib, niraparib and veliparib, respectively. This review describes the benefit of PARP inhibitors as maintenance therapy and discusses the efficacy according to breast cancer gene and homologous recombination status.

scholarly journals Genome-scale CRISPR knockout screen identifies TIGAR as a modifier of PARP inhibitor sensitivity

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Pingping Fang ◽  
Cristabelle De Souza ◽  
Kay Minn ◽  
Jeremy Chien
Keyword(s):  
Ovarian Cancer ◽  
Metabolic Pathways ◽  
Clinical Utility ◽  
Parp Inhibitor ◽  
Parp Inhibitors ◽  
Loss Of Function ◽  
Poor Overall Survival ◽  
Cytotoxic Effects ◽  
Cancer Types ◽  
Genome Scale

Abstract Treatment of cancer with poly (ADP-ribose) polymerase (PARP) inhibitors is currently limited to cells defective in the homologous recombination (HR) pathway. Identification of genetic targets that induce or mimic HR deficiencies will extend the clinical utility of PARP inhibitors. Here we perform a CRISPR/Cas9-based genome-scale loss-of-function screen, using the sensitivity of PARP inhibitor olaparib as a surrogate. We identify C12orf5, encoding TP53 induced glycolysis and apoptosis regulator (TIGAR), as a modifier of PARP inhibitor response. We show that TIGAR is amplified in several cancer types, and higher expression of TIGAR associates with poor overall survival in ovarian cancer. TIGAR knockdown enhances sensitivity to olaparib in cancer cells via downregulation of BRCA1 and the Fanconi anemia pathway and increases senescence of these cells by affecting metabolic pathways and increasing the cytotoxic effects of olaparib. Our results indicate TIGAR should be explored as a therapeutic target for treating cancer and extending the use of PARP inhibitors.

DUO-O: A randomized phase III trial of durvalumab (durva) in combination with chemotherapy and bevacizumab (bev), followed by maintenance durva, bev and olaparib (olap), in newly diagnosed advanced ovarian cancer patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS5598-TPS5598 ◽  
Author(s):  
Philipp Harter ◽  
Mariusz Bidziński ◽  
Nicoletta Colombo ◽  
Anne Floquet ◽  
Maria Jesús Rubio Pérez ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Maintenance Therapy ◽  
Maintenance Treatment ◽  
Brca Mutation ◽  
Parp Inhibitor ◽  
Phase Iii ◽  
Line Treatment ◽  
Newly Diagnosed ◽  
First Line ◽  
First Line Treatment

TPS5598 Background: Ovarian cancer (OC) is the leading cause of death from gynecologic cancers in US women. Despite high response rates to first-line treatment, ~70% of patients (pts) relapse within 3 years and then remain largely incurable. First-line treatment needs to be improved to achieve long-term remission in pts and improve the cure rate. The Phase III SOLO1 trial showed a meaningful clinical benefit for olap maintenance therapy in newly diagnosed OC pts with a BRCA mutation (Moore et al N Engl J Med 2018). Preliminary data suggest that combining a PD-L1 inhibitor, anti-angiogenic and PARP inhibitor (triplet therapy) may achieve a synergistic antitumor effect. The DUO-O study (NCT03737643) evaluates the efficacy and safety of treatment combinations involving standard-of-care platinum-based chemotherapy (chemo), VEGF inhibitor bev, anti-PD-L1 antibody durva and PARP inhibitor olap, in women with newly diagnosed advanced OC. Methods: Eligible pts for this double-blind, randomized, Phase III study must have newly diagnosed, advanced, high-grade epithelial OC and either have completed primary surgery or plan to have interval debulking surgery. Depending on their tumor BRCA mutation (tBRCAm) status (determined by central test), pts will join one of two independent cohorts. Pts in the non-tBRCAm cohort (n~906) will be randomized (1:1:1) before cycle 2 to: a) chemo + bev + placebo (for 6 cycles) followed by bev (15 mg/kg [total 15 months]) + placebo maintenance treatment (IV and tablets); b) chemo + bev + durva (6 cycles) followed by bev + durva (1120 mg q3w [total 15 months]) + placebo (tablets) maintenance treatment; or c) chemo + bev + durva (6 cycles) followed by bev + durva + olap (300 mg bd tablets [24 months]) maintenance treatment. Pts in the open-label tBRCAm cohort (n~150) will receive 6 cycles of chemo + durva followed by durva + olap maintenance therapy, with optional use of bev. The primary endpoint of progression-free survival will be assessed by modified RECIST 1.1. Key secondary endpoints include overall survival, overall response rate and duration of response. Enrollment began in January 2019. Clinical trial information: NCT03737643.

scholarly journals The latest first-line treatment options for ovarian cancer: focus on maintenance therapy

2020 ◽  
pp. 62-68
Author(s):  
A. A. Rumyantsev
Keyword(s):  
Ovarian Cancer ◽  
Comparative Analysis ◽  
Disease Progression ◽  
Treatment Options ◽  
Advanced Ovarian Cancer ◽  
Parp Inhibitors ◽  
Phase Iii ◽  
Published Data ◽  
Outpatient Basis ◽  
First Line

Ovarian cancer is one of the leading causes of death from gynecologic cancers in Russia: in 2018, 7616 women died from this disease and the proportion of patients who is under observation for 5 years or more was only 3.4%, which probably indicates very low 5-year survival. At the same time, there was is a tremendous paradigm shift in the treatment of BRCA-associated ovarian cancer. A number of large phase III trials have been published on the use of PARP inhibitors in this subtype of the disease. Their results demonstrated a marked reduction in the risk of disease progression or death with PARP inhibitors after first-line therapy for advanced ovarian cancer. Here we present a comparative analysis of the efficacy of various PARP inhibitors in BRCA-associated ovarian cancer. The relative risk reduction in disease progression or death for olaparib, niraparib and veliparib was 70%, 60% and 56%, respectively and advantage of using these drugs noted in all patient subgroups. Comparative analysis of the safety of various PARP inhibitors was carried out as well, the risks of developing various toxicity were assessed. Based on a comparison of published data on their safety profile, it was concluded that olaparib is the safest drug of this class, especially in the context of therapy on an outpatient basis. Possible ways to optimize the use of PARP inhibitors in disseminated ovarian cancer have been analyzed.

Sign in / Sign up

Export Citation Format

Share Document