Poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer.
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ABSTRACT:
SUBMITTER: Tattersall A
PROVIDER: S-EPMC8848772 | biostudies-literature | 2022 Feb
REPOSITORIES: biostudies-literature
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Poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer.
Tattersall Abigail A Ryan Neil N Wiggans Alison J AJ Rogozińska Ewelina E Morrison Jo J
The Cochrane database of systematic reviews 20220216
<h4>Background</h4>Ovarian cancer is the sixth most common cancer in women world-wide. Epithelial ovarian cancer (EOC) is the most common; three-quarters of women present when disease has spread outside the pelvis (stage III or IV). Treatment consists of a combination of surgery and platinum-based chemotherapy. Although initial responses to chemotherapy are good, most women with advanced disease will relapse. PARP (poly (ADP-ribose) polymerase) inhibitors (PARPi), are a type of anticancer treat ...[more]
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Project description:BackgroundOvarian cancer is the sixth most common cancer and seventh most common cause of cancer death in women world-wide. Three-quarters of women present when the disease has spread throughout the abdomen (stage III or IV) and treatment consists of a combination of debulking surgery and platinum-based chemotherapy. Although initial responses to chemotherapy are good, most women will relapse and require further chemotherapy and will eventually develop resistance to chemotherapy.PARP (poly (ADP-ribose) polymerase) inhibitors, are a novel type of medication that works by preventing cancer cells from repairing their DNA once they have been damaged by other chemotherapy agents. It is not clear how PARP inhibitors compare to conventional chemotherapy regimens for the treatment of ovarian cancer, with respect to survival, side effects and quality of life.ObjectivesTo determine the benefits and risks of PARP inhibitors for the treatment of epithelial ovarian cancer (EOC).Search methodsWe identified randomised controlled trials (RCTs) by searching the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 4), the Cochrane Gynaecological Cancer Group Trial Register, MEDLINE (1990 to May 2014), EMBASE (1990 to May 2014), ongoing trials on www.controlled-trials.com/rct, www.clinicaltrials.gov, www.cancer.gov/clinicaltrials and the National Research Register (NRR), the FDA database and pharmaceutical industry biomedical literature.Selection criteriaWomen with histologically proven EOC who were randomised to treatment groups in trials that either compared PARP inhibitors with no treatment, or PARP inhibitors versus conventional chemotherapy, or PARP inhibitors together with conventional chemotherapy versus conventional chemotherapy alone.Data collection and analysisWe used standard Cochrane methodology. Two review authors independently assessed whether studies met the inclusion criteria. We contacted investigators for additional data, where possible. Outcomes included survival, quality of life and toxicity.Main resultsWe included four RCTs involving 599 women with EOC. Data for veliparib were limited and of low quality, due to small numbers (75 women total). Olaparib, on average, improved progression-free survival (PFS) when added to conventional treatment and when used as maintenance treatment in women with platinum-sensitive disease compared with placebo (hazard ratio (HR) 0.42, 95% confidence interval (CI) 0.29 to 0.60; 426 participants ; two studies), but did not improve overall survival (OS) (HR 1.05, 95% CI 0.79 to 1.39; 426 participants; two studies). We graded this evidence as moderate quality using the GRADE approach. Olaparib was associated with more severe adverse events (G3/4) during the maintenance phase compared with controls (risk ratio (RR) 1.74, 95% CI 1.22 to 2.49; 385 participants, two studies; moderate quality evidence). Quality of life data were insufficient for meta-analysis. We identified four ongoing studies.Authors' conclusionsPARP inhibitors appear to improve PFS in women with recurrent platinum-sensitive disease. Ongoing studies are likely to provide more information about whether the improvement in PFS leads to any change in OS in this subgroup of women with EOC. More research is needed to determine whether PARP inhibitors have any role to play in platinum-resistant disease.
| S-EPMC6457589 | biostudies-literature
Project description:Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality among women, potentially due to ineffectiveness of screening tests for early detection. Patients typically present with advanced disease at diagnosis, whereas, up to 80% relapse and the estimated median progression-free survival (PFS) is approximately 12-18 months. Increased knowledge on the molecular biology of EOC resulted in the development of several targeted therapies, including poly(ADP-ribose) polymerase (PARP) inhibitors. These agents have changed the therapeutic approach of the EOC and exploit homologous recombination (HR) deficiency through synthetic lethality, especially in breast cancer genes 1 and 2 (BRCA1/2) mutation carriers. Furthermore, BRCA wild-type patients with other defects in the HR repair pathway, or those with platinum-resistant tumors may obtain benefit from this treatment. While PARP inhibitors as a class display many similarities, several differences in structure can translate into differences in tolerability and antitumor activity. Currently, olaparib, rucaparib, and niraparib have been approved by Food and Drug Administration (FDA) and/or European Medicines Agency (EMA) for the treatment of EOC, while veliparib is in the late stage of clinical development. Finally, since October 2018 talazoparib is FDA and EMA approved for BRCA carriers with metastatic breast cancers. In this article, we explore the mechanisms of DNA repair, synthetic lethality, efficiency of PARP inhibition, and provide an overview of early and ongoing clinical investigations of the novel PARP inhibitors veliparib and talazoparib.
| S-EPMC7812175 | biostudies-literature
Project description: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.
| S-EPMC6787707 | biostudies-literature
Project description:Inhibition of poly(ADP-ribose) polymerase (PARP) activity induces synthetic lethality in mutated BRCA1/2 cancers by selectively targeting tumor cells that fail to repair DNA double strand breaks (DSBs). Clinical studies have confirmed the validity of the synthetic lethality approach and four different PARP inhibitors (PARPi; olaparib, rucaparib, niraparib and talazoparib) have been approved as monotherapies for BRCA-mutated or platinum-sensitive recurrent ovarian cancer and/or for BRCA-mutated HER2-negative metastatic breast cancer. PARPi therapeutic efficacy is higher against tumors harboring deleterious germline or somatic BRCA mutations than in BRCA wild-type tumors. BRCA mutations or intrinsic tumor sensitivity to platinum compounds are both regarded as indicators of deficiency in DSB repair by homologous recombination as well as of favorable response to PARPi. However, not all BRCA-mutated or platinum-responsive patients obtain clinical benefit from these agents. Conversely, a certain percentage of patients with wild-type BRCA or platinum-resistant tumors can still get benefit from PARPi. Thus, additional reliable markers need to be validated in clinical trials to select patients potentially eligible for PARPi-based therapies, in the absence of deleterious BRCA mutations or platinum sensitivity. In this review, we summarize the mechanisms of action of PARPi and the clinical evidence supporting their use as anticancer drugs as well as the additional synthetic lethal partners that might confer sensitivity to PARPi in patients with wild-type BRCA tumors.
| S-EPMC6316750 | biostudies-literature
Project description:Poly(ADP-ribose)polymerase-1 (PARP1) is a DNA repair enzyme highly expressed in the nuclei of mammalian cells, with a structure and function that have attracted interest since its discovery. PARP inhibitors, moreover, can be used to induce synthetic lethality in cells where the homologous recombination (HR) pathway is deficient. Several small molecule PARP inhibitors have been approved by the FDA for multiple cancers bearing this deficiency These PARP inhibitors also act as radiosensitizing agents by delaying single strand break (SSB) repair and causing subsequent double strand break (DSB) generation, a concept that has been leveraged in various preclinical models of combination therapy with PARP inhibitors and ionizing radiation. Researchers have determined the efficacy of various PARP inhibitors at sub-cytotoxic concentrations in radiosensitizing multiple human cancer cell lines to ionizing radiation. Furthermore, several groups have begun evaluating combination therapy strategies in mouse models of cancer, and a fluorescent imaging agent that allows for subcellular imaging in real time has been developed from a PARP inhibitor scaffold. Other PARP inhibitor scaffolds have been radiolabeled to create PET imaging agents, some of which have also entered clinical trials. Most recently, these highly targeted small molecules have been radiolabeled with therapeutic isotopes to create radiotherapeutics and radiotheranostics in cancers whose primary interventions are surgical resection and whole-body radiotherapy. In this review we discuss the utilization of these small molecules in combination therapies and in scaffolds for imaging agents, radiotherapeutics, and radiotheranostics. Development of these radiolabeled PARP inhibitors has presented promising results for new interventions in the fight against some of the most intractable cancers.
| S-EPMC7062869 | biostudies-literature
Project description:Synthetic lethal targeting of homologous recombination (HR)-deficient ovarian cancers (OvCas) with poly(ADP-ribose) polymerase inhibitors (PARPis) has attracted considerable attention. Olaparib was the first PARPi approved by the Food and Drug Administration, offering significant clinical benefits in BRCA1/2-deficient OvCas. However, only approximately 20% of OvCa patients harbor BRCA1/2 mutations. Given the shared roles that BRCA1/2 have with other HR regulators, alterations in HR genes may also contribute to "BRCAness profiles" in OvCas. RAD54B has been considered a key player in HR repair, although its roles and therapeutic potential in cancers need further investigation. Here, we identified 22 frequently mutated HR genes by whole-exome sequencing of OvCa tissues from 82 patients. To our surprise, 7.3% of patients were found to harbor mutations of RAD54B, the third-highest mutated gene among patients. We determined that RAD54B-mutated tumor tissues harbored more DNA double-strand breaks than normal tissues. Additionally, we found that RAD54B knockdown inhibited HR repair, enhanced sensitivities of OvCa cells with increased DNA double-strand breaks to olaparib, and induced apoptosis. Enhanced inhibitory effects of olaparib on the growth of ES2 xenograft tumors were further demonstrated by RAD54B knockdown. Finally, we show that restoration with wildtype RAD54B rather than RAD54BN593S and RAD54BH219Y, identified in patients, abolished the effects of RAD54B knockdown, indicating these RAD54B mutants probably malfunctioned in HR repair. Our investigations may offer insight into the contributions of RAD54B mutations to synthetic lethality with olaparib treatment in OvCas, enrich the gene list for "HR deficiency scoring," and expand the applications of PARPis.
| S-EPMC9463535 | biostudies-literature
Project description:Approximately a quarter of men with metastatic castrate resistant prostate cancer (mCRPC) have alterations in homologous recombination repair (HRR). These patients exhibit enhanced sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Leveraging the synthetic lethality between PARP inhibition and HRR deficiency, studies have established marked clinical benefit and a survival advantage from PARP inhibitors (PARPi) in mCRPC, most notably in cancers with BRCA1/2 alterations. The role of PARPi is evolving beyond patients with HRR alterations, with studies increasingly focused on exploiting synergistic effects from combination therapeutics. Strategies combining PARP inhibitors with androgen receptor pathway inhibitors, radiation, radioligand therapy, chemotherapy and immunotherapy demonstrate potential additional benefits in mCRPC and these approaches are rapidly moving into the metastatic hormone sensitive treatment paradigm. In this review we summarise the development and expanding role of PARPi in prostate cancer including biomarkers of response, the relationship between the androgen receptor and PARP, evidence for combination therapeutics and the future directions of PARPi in precision medicine for prostate cancer.
| S-EPMC9736565 | biostudies-literature
Project description:Genetic complexity and DNA damage repair defects are common in different cancer types and can induce tumor-specific vulnerabilities. Poly(ADP-ribose) polymerase (PARP) inhibitors exploit defects in the DNA repair pathway through synthetic lethality and have emerged as promising anticancer therapies, especially in tumors harboring deleterious germline or somatic breast cancer susceptibility gene (BRCA) mutations. However, the utility of PARP inhibitors could be expanded beyond germline BRCA1/2 mutated cancers by causing DNA damage with cytotoxic agents in the presence of a DNA repair inhibitor. US Food and Drug Administration (FDA)-approved PARP inhibitors include olaparib, rucaparib, and niraparib, while veliparib is in the late stage of clinical development. Talazoparib inhibits PARP catalytic activity, trapping PARP1/2 on damaged DNA, and it has been approved by the US FDA for the treatment of metastatic germline BRCA1/2 mutated breast cancers in October 2018. The talazoparib side effect profile more closely resembles traditional chemotherapeutics rather than other clinically approved PARP inhibitors. In this review, we discuss the scientific evidence that has emerged from both experimental and clinical studies in the development of talazoparib. Future directions will include optimizing combination therapy with chemotherapy, immunotherapies and targeted therapies, and in developing and validating biomarkers for patient selection and stratification, particularly in malignancies with 'BRCAness'.
| S-EPMC7221042 | biostudies-literature
Project description:Ovarian cancer is one of the most common reproductive system tumors. The incidence of ovarian cancer in China is on the rise. Poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) is a DNA repair enzyme associated with DNA damage repair. PARPi takes PARP as a target to kill tumor cells, especially for tumors with homologous recombination (HR) dysfunction. Currently, PARPi has been widely used in clinical practice, mainly for the maintenance of advanced ovarian epithelial cancer. The intrinsic or acquired drug resistance of PARPi has gradually become an important clinical problem with the wide application of PARPi. This review summarizes the mechanisms of PARPi resistance and the current progress on PARPi-based combination strategies.
| S-EPMC10326311 | biostudies-literature
Project description:Diffuse infiltrating gliomas are a clinically and molecularly heterogeneous group of tumors that are uniformly incurable. Despite our growing knowledge of genomic and epigenomic alterations in gliomas, standard treatments have not changed in the past 2 decades and remain limited to surgical resection, ionizing radiation, and alkylating chemotherapeutic agents. Development of novel therapeutics for diffuse gliomas has been challenging due to inter- and intra-tumoral heterogeneity, diffuse infiltrative nature of gliomas, inadequate tumor/drug concentration due to blood-brain barrier, and an immunosuppressive tumor microenvironment. Given the high frequency of DNA damage pathway alterations in gliomas, researchers have focused their efforts in targeting the DNA damage pathways for the treatment of gliomas. A growing body of data has shed light on the role of poly(ADP-ribose) polymerase (PARP) in combination with radiation and temozolomide in high-grade gliomas. Furthermore, a novel therapeutic strategy in low-grade glioma is the recent elucidation for a potential role of PARP inhibitors in gliomas with IDH1/2 mutations. This review highlights the concepts behind targeting PARP in gliomas with a focus on putative predictive biomarkers of response. We further discuss the challenges involved in the successful development of PARP inhibitors in gliomas, including the intracranial location of the tumor and overlapping toxicities with current standards of care, and promising strategies to overcome these hurdles.
| S-EPMC9165443 | biostudies-literature