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

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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PARP Inhibitor Resistance Mechanisms and Implications for Post-Progression Combination Therapies

Cancers ◽

10.3390/cancers12082054 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2054

Author(s):

Elizabeth K. Lee ◽

Ursula A. Matulonis

Keyword(s):

Synthetic Lethality ◽

Parp Inhibitor ◽

Parp Inhibitors ◽

Resistance Mechanisms ◽

Parp Inhibition ◽

Combination Therapies ◽

Mechanisms Of Resistance ◽

Damage Repair ◽

Inhibitor Resistance

The use of PARP inhibitors (PARPi) is growing widely as FDA approvals have shifted its use from the recurrence setting to the frontline setting. In parallel, the population developing PARPi resistance is increasing. Here we review the role of PARP, DNA damage repair, and synthetic lethality. We discuss mechanisms of resistance to PARP inhibition and how this informs on novel combinations to re-sensitize cancer cells to PARPi.

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Niraparib in ovarian cancer: results to date and clinical potential

Therapeutic Advances in Medical Oncology ◽

10.1177/1758834017718775 ◽

2017 ◽

Vol 9 (9) ◽

pp. 579-588 ◽

Cited By ~ 16

Author(s):

Davide Caruso ◽

Anselmo Papa ◽

Silverio Tomao ◽

Patrizia Vici ◽

Pierluigi Benedetti Panici ◽

...

Keyword(s):

Ovarian Cancer ◽

Synthetic Lethality ◽

Excision Repair ◽

Parp Inhibitor ◽

Parp Inhibitors ◽

Phase Iii ◽

Repair System ◽

Gynaecological Malignancy ◽

Platinum Based Chemotherapy ◽

Base Excision

Ovarian cancer is the first cause of death from gynaecological malignancy. Germline mutation in BRCA1 and 2, two genes involved in the mechanisms of reparation of DNA damage, are showed to be related with the incidence of breast and ovarian cancer, both sporadic and familiar. PARP is a family of enzymes involved in the base excision repair (BER) system. The introduction of inhibitors of PARP in patients with BRCA-mutated ovarian cancer is correlated with the concept of synthetic lethality. Among the PARP inhibitors introduced in clinical practice, niraparib showed interesting results in a phase III trial in the setting of maintenance treatment in ovarian cancer, after platinum-based chemotherapy. Interestingly, was niraparib showed to be efficacious not only in BRCA-mutated patients, but also in patients with other alterations of the homologous recombination (HR) system and in patients with unknown alterations. These results position niraparib as the first PARP-inhibitor with clinically and statistically significant results also in patients with no alterations in BRCA 1/2 and other genes involved in the DNA repair system. Even if the results are potentially practice-changing, the action of niraparib must be further studied and deepened.

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

Diagnostics ◽

10.3390/diagnostics9020055 ◽

2019 ◽

Vol 9 (2) ◽

pp. 55 ◽

Cited By ~ 16

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.

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Clinical Benefit With PARP Inhibitor for Pathogenic Germline FANCA-mutated Relapsed Epithelial Ovarian Cancer: a Case Report

10.21203/rs.3.rs-551734/v1 ◽

2021 ◽

Author(s):

Bing Qian ◽

Jin Lu ◽

Wenshu Leng ◽

Zhengqing Yan ◽

Shiqing Chen ◽

...

Keyword(s):

Ovarian Cancer ◽

Clinical Benefit ◽

Parp Inhibitor ◽

Susceptibility Gene ◽

Radical Resection ◽

Parp Inhibitors ◽

Fanconi Anaemia ◽

Platinum Based Chemotherapy ◽

Patient Consent ◽

Recombination Pathway

Abstract Background: PARP inhibitors have been approved as targeted therapy for BRCA-deficient metastatic ovarian cancer (OC). Fanconi anemia complementation group A (FANCA) is one of Fanconi anaemia-related genes and a susceptibility gene to breast and OC. However, whether germline FANCA-mutated relapsed epithelial OC could achieve clinical benefit from the treatment of PARP inhibitor is still unclear. Case presentation: A 49-year-old female patient was diagnosed with epithelial OC and underwent resection and first-line of platinum-based chemotherapy in 2016. After first recurrence, she underwent radical resection and received second-line of platinum-based chemotherapy in 2018. After the second relapse in July 2019, the patient underwent radical resection and the corresponding tumor tissue DNA suffered next generation sequencing (NGS) analysis revealed a germline FANCA mutation. Subsequently, the third-line treatment of liposomal doxorubicin hydrochloride plus lobaplatin was administrated for five cycles with patient consent and then oral niraparib (200 mg daily) was administered for maintenance treatment. During the follow-up, no evidence of tumor recurrence was observed. Currently, the PFS already exceeded 21 months and the treatment is still going on. Conclusions: This case highlighted that OC patients harboring with pathogenic gene alterations in homologous recombination pathway might achieved clinical benefit from PARP inhibitors, which should be confirmed in further studies.

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Alternate therapeutic pathways for PARP inhibitors and potential mechanisms of resistance

Experimental & Molecular Medicine ◽

10.1038/s12276-021-00557-3 ◽

2021 ◽

Vol 53 (1) ◽

pp. 42-51

Author(s):

Dae-Seok Kim ◽

Cristel V. Camacho ◽

W. Lee Kraus

Keyword(s):

Clinical Trials ◽

Homologous Recombination ◽

Cancer Cells ◽

Synthetic Lethality ◽

Parp Inhibitor ◽

Cancer Therapeutics ◽

Progression Free Survival ◽

Parp Inhibitors ◽

Parp Inhibition ◽

Combination Strategies

AbstractHomologous recombination (HR) repair deficiency impairs the proper maintenance of genomic stability, thus rendering cancer cells vulnerable to loss or inhibition of DNA repair proteins, such as poly(ADP-ribose) polymerase-1 (PARP-1). Inhibitors of nuclear PARPs are effective therapeutics for a number of different types of cancers. Here we review key concepts and current progress on the therapeutic use of PARP inhibitors (PARPi). PARPi selectively induce synthetic lethality in cancer cells with homologous recombination deficiencies (HRDs), the most notable being cancer cells harboring mutations in the BRCA1 and BRCA2 genes. Recent clinical evidence, however, shows that PARPi can be effective as cancer therapeutics regardless of BRCA1/2 or HRD status, suggesting that a broader population of patients might benefit from PARPi therapy. Currently, four PARPi have been approved by the Food and Drug Administration (FDA) for the treatment of advanced ovarian and breast cancer with deleterious BRCA mutations. Although PARPi have been shown to improve progression-free survival, cancer cells inevitably develop resistance, which poses a significant obstacle to the prolonged use of PARP inhibitors. For example, somatic BRCA1/2 reversion mutations are often identified in patients with BRCA1/2-mutated cancers after treatment with platinum-based therapy, causing restoration of HR capacity and thus conferring PARPi resistance. Accordingly, PARPi have been studied in combination with other targeted therapies to overcome PARPi resistance, enhance PARPi efficacy, and sensitize tumors to PARP inhibition. Moreover, multiple clinical trials are now actively underway to evaluate novel combinations of PARPi with other anticancer therapies for the treatment of PARPi-resistant cancer. In this review, we highlight the mechanisms of action of PARP inhibitors with or without BRCA1/2 defects and provide an overview of the ongoing clinical trials of PARPi. We also review the current progress on PARPi-based combination strategies and PARP inhibitor resistance.

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Use of PARP Inhibitors for Ovarian Cancer

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2021.5013 ◽

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.

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The evolving role of PARP inhibitors in advanced ovarian cancer

Forum of Clinical Oncology ◽

10.2478/fco-2021-0002 ◽

2021 ◽

Vol 12 (1) ◽

pp. 82-104

Author(s):

Sofia Levva ◽

Aglaia Skolariki ◽

Eleni Sogka ◽

Alexandros Bokas ◽

Avraam Assi ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Repair ◽

Parp Inhibitor ◽

Advanced Ovarian Cancer ◽

Parp Inhibitors ◽

Parp Inhibition ◽

Primary Analysis ◽

Serious Adverse Events ◽

Adverse Event Data ◽

Inhibitor Resistance

Abstract The field of ovarian cancer has been revolutionized with the use of poly (ADP-ribose) polymerase (PARP) inhibitors, which present greater inhibition effect in epithelial subtype due to high rates of homologous recombination deficiency. PARP inhibition exploits this cancer pitfall by disrupting DNA repair, leading to genomic instability and apoptosis. Three PARP inhibitors (olaparib, niraparib, and rucaparib) are now approved for use in women with epithelial ovarian cancer, while others are under development. Among women with BRCA1/2 mutations, maintenance PARP therapy has led to a nearly fourfold prolongation of PFS, while those without BRCA1/2 mutations experience an approximately twofold increase in PFS. Differences in trial design, patient selection and primary analysis population affect the conclusions on PARP inhibitors. Limited OS data have been published and there is also limited experience regarding long-term safety. With regard to toxicity profile, there are no differences in serious adverse events between the experimental and control groups. However, combining adverse event data from maintenance phases, a trend towards more events in the experimental group, compared with controls, has been shown. The mechanisms of PARP-inhibitor resistance include restoration of HR through reversion mutations in HR genes, leading to resumed HR function. Other mechanisms that sustain sufficient DNA repair are discussed as well. PARP inhibitors play a pivotal role in the management of ovarian cancer, affecting the future treatment choices. Defining exactly which patients will benefit from them is a challenge and the need for HRD testing to define ‘BRCA-ness’ will add additional costs to treatment.

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

Journal of Clinical Medicine ◽

10.3390/jcm9072239 ◽

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

Diagnostics ◽

10.3390/diagnostics9030087 ◽

2019 ◽

Vol 9 (3) ◽

pp. 87 ◽

Cited By ~ 24

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.

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Efficacy of PARP Inhibitors in the Treatment of Ovarian Cancer: A Literature-Based Review

Asian Journal of Oncology ◽

10.1055/s-0039-1700619 ◽

2019 ◽

Vol 05 (01) ◽

pp. 01-18

Author(s):

Vikas Goswami ◽

Venkata Pradeep Babu Koyyala ◽

Sumit Goyal ◽

Manish Sharma ◽

Varun Goel ◽

...

Keyword(s):

Ovarian Cancer ◽

Dna Repair ◽

Homologous Recombination ◽

Germ Line ◽

Brca Mutation ◽

Parp Inhibitor ◽

Parp Inhibitors ◽

Parp Inhibition ◽

Repair Mechanism ◽

Selection Of

AbstractPoly (ADP-ribose) polymerase (PARP) inhibitors are a unique class of therapeutic agents that focus on tumors with deficiencies in the homologous recombination DNA repair mechanism. Genomic instability outlines high-grade serous ovarian cancer, with 50% of all tumors displaying defects in the important DNA repair mechanism of homologous recombination. Earlier research studies have demonstrated considerable efficiency for PARP inhibitors in patients with germ line breast-related cancer antigens 1 and 2 (BRCA-1/BRCA-2) mutations. It has also been observed that BRCA wild-type patients with other defects in the homologous recombination repair mechanism get benefited from this therapy. 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 selection of PARP inhibitor is mainly dependent upon the number of prior therapies and the presence of a BRCA mutation or HRD. The identification of cases which are most likely to get benefited from PARP inhibitor therapy in view of HRD and other biomarker assessments is still challenging. The purpose of this review is to focus and describe the current evidences for PARP inhibitors in ovarian malignancy, their mechanism of action, and the outstanding issues, including the rate of long-term toxicities and the evolving resistance.

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