Use Of PARP Inhibitors Research Articles

Oxaliplatin prior to PARP inhibitor in BRCA-mutated ovarian cancer.

The use of PARP inhibitor (PARPi) has shown a considerable benefit in progression-free survival (PFS) in relapsed, platinum-sensitive epithelial ovarian cancer (OC). Our study aimed to investigate the impact of the last platinum-based chemotherapy treatment in response to PARPi. Retrospective cohort study. The study involved 96 consecutive, pretreated, platinum-sensitive advanced OC patients. Demographics and clinical data were retrieved from clinical records. PFS and overall survival (OS) were calculated from the start of PARPi. Germline BRCA mutation was investigated in all cases. Platinum-based chemotherapy before PARPi maintenance therapy included pegylated liposomal doxorubicin-oxaliplatin (PLD-Ox) in 46 patients (48%) and other platinum-based chemotherapy in 50 patients (52%). During a median follow-up of 22 months from the beginning of PARPi therapy, 57 patients relapsed (median PFS: 12 months) and 64 patients died (median OS: 23 months). During multivariable analysis, receiving PLD-Ox before PARPi was associated with improved PFS [hazard ratio (HR): 0.46, 95% CI: 0.26-0.82] and OS (HR: 0.48, 95% CI: 0.27-0.83). In 36 BRCA-mutated patients, PLD-Ox was associated with improved PFS (2-year PFS: 70.0% versus 25.0%, p = 0.02). Receiving PLD-Ox before PARPi may improve prognosis in platinum-sensitive advanced OC patients and may provide advantages in the BRCA-mutated subgroup.

BRCA1/2 Reversion Mutations in Patients Treated with Poly ADP-Ribose Polymerase (PARP) Inhibitors or Platinum Agents.

Background: Reversion mutations in BRCA1/2, resulting in restoration of the open reading frame, have been identified as a mechanism of resistance to platinum-based chemotherapy or PARP inhibition. We sought to explore the incidence of BRCA1/2 reversion mutations in different tumor types. Methods: We retrospectively analyzed molecular profiling results from primary and/or metastatic tumor samples submitted by multiple institutions. The samples underwent DNA and RNA sequencing at a CLIA/CAP-certified clinical lab. Reversion mutations were called only in patients whose available clinical records showed the use of PARP inhibitors or platinum agents prior to tumor profiling. Results: Reversion mutations were identified in 75 of 247,926 samples profiled across all tumor types. Among patients carrying pathogenic or likely pathogenic BRCA1/2 mutations, reversion mutations in BRCA1/2 genes were seen in ovarian cancer (OC) (30/3424), breast cancer (BC) (27/1460), endometrial cancer (4/564), pancreatic cancer (2/340), cholangiocarcinoma (2/178), prostate cancer (5/461), cervical cancer (1/117), cancer of unknown primary (1/244), bladder cancer (1/300), malignant pleural mesothelioma (1/10), and a neuroendocrine tumor of the prostate. We identified 22 reversion mutations in BRCA1 and 8 in BRCA2 in OC. In BC, we detected 6 reversion mutations in BRCA1 and 21 in BRCA2. We compared molecular profile results of 14 high-grade serous ovarian cancers (HGSOC) with reversion mutations against 87 control HGSOC with pathogenic BRCA1/2 mutations without reversion mutations. Tumors with reversion mutations trended to have had lower ER expression (25% vs. 64%, p = 0.024, q = 0.82) and higher KDM6A mutation rate (15% vs. 0, p = 0.016, q = 0.82). Conclusions: We present one of the largest datasets reporting reversion mutations in BRCA1/2 genes across various tumor types. These reversion mutations were rare; this may be because some patients may not have had repeat profiling post-treatment. Repeat tumor profiling at times of treatment resistance can help inform therapy selection in the refractory disease setting.

Natural phytochemicals prevent side effects in BRCA-mutated ovarian cancer and PARP inhibitor treatment.

Ovarian cancer is among the most common malignant tumors in gynecology and is characterized by insidious onset, poor differentiation, high malignancy, and a high recurrence rate. Numerous studies have shown that poly ADP-ribose polymerase (PARP) inhibitors can improve progression-free survival (PFS) in patients with BRCA-mutated ovarian cancer. With the widespread use of BRCA mutation and PARP inhibitor (PARPi) combination therapy, the side effects associated with BRCA mutation and PARPi have garnered attention worldwide. Mutations in the BRCA gene increase KEAP1-NRF2 ubiquitination and reduce Nrf2 content and cellular antioxidant capacity, which subsequently produces side effects such as cardiovascular endothelial damage and atherosclerosis. PARPi has hematologic toxicity, producing thrombocytopenia, fatigue, nausea, and vomiting. These side effects not only reduce patients' quality of life, but also affect their survival. Studies have shown that natural phytochemicals, a class of compounds with antitumor potential, can effectively prevent and treat the side effects of chemotherapy. Herein, we reviewed the role of natural phytochemicals in disease prevention and treatment in recent years, including sulforaphane, lycopene, catechin, and curcumin, and found that these phytochemicals have significant alleviating effects on atherosclerosis, nausea, and vomiting. Moreover, these mechanisms of action significantly correlated with the side-effect-producing mechanisms of BRCA mutations and PARPi. In conclusion, natural phytochemicals may be effective in alleviating the side effects of BRCA mutant ovarian cancer cells and PARP inhibitors.

TRAIL Receptor Targeting Agents Potentiate PARP Inhibitor Efficacy in Pancreatic Cancer Independently of BRCA2 Mutation Status.

Chemotherapy, the standard treatment for pancreatic ductal adenocarcinoma (PDAC), has only a modest effect on the outcome of patients with late-stage disease. Investigations of the genetic features of PDAC have demonstrated a frequent occurrence of mutations in genes involved in homologous recombination (HR), especially in the breast cancer susceptibility gene 2 (BRCA2). Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, is approved as a maintenance treatment for patients with advanced PDAC with germline BRCA1/2 mutations following a platinum-containing first-line regimen. Limitations to the use of PARP inhibitors are represented by the relatively small proportion of patients with mutations in BRCA1/2 genes and the modest capability of these substances of inducing objective response. We have previously shown that pancreatic cancer with BRCA2 mutations exhibits a remarkably enhanced sensitivity towards tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) receptor-stimulating agents. We thus aimed to investigate the effect of combined treatment with PARP inhibitors and TRAIL receptor-stimulating agents in pancreatic cancer and its dependency on the BRCA2 gene status. The respective effects of TRAIL-targeting agents and the PARP inhibitor olaparib or of their combination were assessed in pancreatic cancer cell lines and patient-derived organoids. In addition, BRCA2-knockout and -complementation models were investigated. The effects of these agents on apoptosis, DNA damage, cell cycle, and receptor surface expression were assessed by immunofluorescence, Western blot, and flow cytometry. PARP inhibition and TRAIL synergized to cause cell death in pancreatic cancer cell lines and PDAC organoids. This effect proved independent of BRCA2 gene status in three independent models. Olaparib and TRAIL in combination caused a detectable increase in DNA damage and a concentration-dependent cell cycle arrest in the G2/M and S cell cycle phases. Olaparib also significantly increased the proportion of membrane-bound death receptor 5. Our results provide a preclinical rationale for the combination of PARP inhibitors and TRAIL receptor agonists for the treatment of pancreatic cancer and suggest that the use of PARP inhibitors could be extended to patients without BRCA2 mutations if used in combination with TRAIL agonists.

The Role of PARP Inhibitors in Patients with Primary Malignant Central Nervous System Tumors.

Primary malignant central nervous (CNS) tumors are a devastating group of diseases with urgent need for improved treatment options. Surgery, radiation, and cytotoxic chemotherapy remain the primary standard treatment modalities, with molecularly targeted therapies having proven efficacy in only small subsets of cases. Poly(ADP-ribose) polymerase (PARP) inhibitors, which have had immense success in the treatment of extracranial cancers with homologous recombination deficiency (HRD), are emerging as a potential targeted treatment for various CNS tumors. Although few primary CNS tumors display canonical BRCA gene defects, preclinical evidence suggests that PARP inhibitors may benefit certain CNS tumors with functional HRD or elevated replication stress. In addition, other preclinical studies indicate that PARP inhibitors may synergize with standard therapies used for CNS tumors including radiation and alkylating agents and may prevent or overcome drug resistance. Thus far, initial clinical trials with early-generation PARP inhibitors, typically as monotherapy or in the absence of selective biomarkers, have shown limited efficacy. However, the scientific rationale remains promising, and many clinical trials are ongoing, including investigations of more CNS penetrant or more potent inhibitors and of combination therapy with immune checkpoint inhibitors. Early phase trials are also critically focusing on determining active drug CNS penetration and identifying biomarkers of therapy response. In this review, we will discuss the preclinical evidence supporting use of PARP inhibitors in primary CNS tumors and clinical trial results to date, highlighting ongoing trials and future directions in the field that may yield important findings and potentially impact the treatment of these devastating malignancies in the coming years.

Correlation between molar activity, injection mass and uptake of the PARP targeting radiotracer [18F]olaparib in mouse models of glioma

PurposeRadiopharmaceuticals targeting poly(ADP-ribose) polymerase (PARP) have emerged as promising agents for cancer diagnosis and therapy. PARP enzymes are expressed in both cancerous and normal tissue. Hence, the injected mass, molar activity and potential pharmacological effects are important considerations for the use of radiolabelled PARP inhibitors for diagnostic and radionuclide therapeutic applications. Here, we performed a systematic evaluation by varying the molar activity of [18F]olaparib and the injected mass of [TotalF]olaparib to investigate the effects on tumour and normal tissue uptake in two subcutaneous human glioblastoma xenograft models.Methods[18F]Olaparib uptake was evaluated in the human glioblastoma models: in vitro on U251MG and U87MG cell lines, and in vivo on tumour xenograft-bearing mice, after administration of [TotalF]olaparib (varying injected mass: 0.04–8.0 µg, and molar activity: 1–320 GBq/μmol).ResultsSelective uptake of [18F]olaparib was demonstrated in both models. Tumour uptake was found to be dependent on the injected mass of [TotalF]olaparib (µg) but not the molar activity. An injected mass of 1 μg resulted in the highest tumour uptake (up to 6.9 ± 1.3%ID/g), independent of the molar activity. In comparison, both the lower and higher injected masses of [TotalF]olaparib resulted in lower relative tumour uptake (%ID/g; P < 0.05). Ex vivo analysis of U87MG xenograft sections showed that the heterogeneity in [18F]olaparib intratumoural uptake correlated with PARP1 expression. Substantial upregulation of PARP1-3 expression was observed after administration of [TotalF]olaparib (> 0.5 µg).ConclusionOur findings show that the injected mass of [TotalF]olaparib has significant effects on tumour uptake. Moderate injected masses of PARP inhibitor-derived radiopharmaceuticals may lead to improved relative tumour uptake and tumour-to-background ratio for cancer diagnosis and radionuclide therapy.

PARP INHIBITION INDUCES PHILADEPHIA P190 POSITIVE ACUTE LYMPHOID LEUKEMIA CELL DEATH IN LEVELS SIMILAR TO IMATINIB TREATMENT

Acute Lymphoid Leukemia (ALL) is the most common leukemic subtype among pediatric populations. The prognosis is worse among patients which are Philadelphia chromosome positive (Ph+), detected with BCR-ABL1 p190 translocation, and, although treatments strategies utilizing tyrosine-kinase inhibitors improved Ph+ patient's outcomes, the development of new therapeutic approaches is of utmost importance in the oncologic practice when facing the inevitable cases of resistance emergence. This study aims to evaluate the cytotoxic effect of inhibiting poly-ADP-ribose 1 (PARP1), a signaling pathway for DNA repair machinery, in an ALL Ph+ cell model. Cytotoxicity analyses of the compounds AZD2461, Imatinib and Doxorubicin were performed by Alamar Blue assay in three cell lines: SUP-B15 – B-lymphoblast Ph p190+ ALL –, Raji and Namalwa – both B-lymphocyte Burkitt's lymphoma. Drug cytotoxicity was determined through serial dilutions resulting in final concentrations of 10 μM, 2 μM, 0.4 μM, 0.08 μM, 0.016 μM and 0.0032 μM for every drug. All concentrations were analyzed in triplicates for each cell line after a period of 72 hours of treatment, except for SUP-B15, which was also analyzed with all the drugs in periods of 24 and 48 hours. After the treatment period, Alamar Blue was added to each well, plates were incubated and then read for fluorescence. Viability results were analyzed through non-linear regression using GraphPad Prism (v. 5.01). AZD2461 showed cytotoxic activity comparable to that of Imatinib in Ph+ SUP-B15, represented by an IC 50 at 72 hours of treatment of 344.3 nM and 329.2 nM, respectively. The use of PARP inhibitors showed little to no efficacy when treating either of the remaining cell lines, with an IC 50 that was not reached in treatment of Raji and a high IC 50 of 20.9 μM in the treatment of Namalwa. Doxorubicin showed high cytotoxic activity against all cell lines, with IC 50 values at 72 hours of low nanomolar levels; 20.32 nM, 85 nM and 75.93 nM for SUP-B15, Raji and Namalwa, respectively. Due to non-responsiveness of Raji and Namalwa to the targeted therapies, only SUP-B15 was evaluated at 24 and 48 hours and treatment. AZD2461 and Imatinib's IC 50 remained comparable at 1421 nM and 1230 nM at 48 hours, respectively, and 3295 nM and 3966 nM at 24 hours, respectively. The use of PARP inhibitors (PARPi) shows great clinical efficiency in the treatment of BRCA1/ 2-mutated tumors and other malignancies that harbor defects in double-strand-breaks repair through homologous recombination. Although Raji and Namalwa have been previously shown to considerably overexpress PARP1 in relation to SUP-B15, the presence of BCR-ABL1 translocation is highly associated with increased chromosomal instability through intracellular accumulation of reactive oxygen species and promotion of non-conservative repair pathways. The major cytotoxic effect of AZD2461 over SUP-B15, in levels comparable to those of Imatinib, shows that ALL Ph+ models seem to be over reliant on pathways that regulate genomic damage and minimize the instability brought by BCR-ABL1 , specifically PARP1. The use of PARPis shows great effect over the viability of ALL Ph+ models and PARP1 represents a potential new target for investigation in BCR-ABL1 positive tumors. However, studies are being conducted to confirm cell death through on-target effects of AZD2461 and the possible effects of PARPi in the expression levels of BCR-ABL1.

A clinical case of repeat use of PARP inhibitors in a patient with &lt;i&gt;mBRCA&lt;/i&gt;-associated ovarian cancer

Backgraound. High-grade serous ovarian carcinoma (HGSOC) is the most common type of ovarian cancer. The prevalence of BRCA1/2 germline mutations is the highest in HGSOC. patients with germline BRCA gene mutations are more likely to respond to platinum-based chemotherapy. Clinical trials demonstrate the effectiveness of PARP inhibitors in the treatment of BRCA-associated ovarian cancer. Re-administration of PARP inhibitors after response to platinum-based chemotherapy demonstrates an increase in progression-free survival rates regardless of BRCA status. it is important for understanding the development of molecular mechanisms of resistance to platinum drugs and PARP inhibitors, as well as for developing new treatment strategies and tools to overcome resistance. Case description. This clinical case of BRCA-associated hereditary ovarian cancer demonstrates the efficacy and good tolerability of PARP inhibitor maintenance therapy following the treatment of the first relapse, as well as the efficacy of re-administration of PARP inhibitors following the treatment of the second relapse. The short-course of re-treatment with PARP inhibitors was accompanied by the development of multidrug resistance. the overall survival time was 112 months. Conclusion. The presence of mutations in BRCA1/2 genes is a promising justification for the administration of maintenance therapy with PARP inhibitors. Re-administration of PARP inhibitor maintenance therapy for relapsed ovarian cancer is currently being considered as a possible therapeutic option. deciphering the molecular mechanisms of resistance to PARP inhibitors is of paramount importance for the development of new treatment strategies and tools to overcome chemoresistance, re-sensitization of the tumor to platinum-based drugs or PARP inhibitors.

1577P Optimizing the management of PARP inhibitors in clinical practice: Results of a DELPHI French consensus

PARP inhibitors (PARPi) have brought considerable progress in the management of ovarian cancer and are now one of the therapeutic options for patients with breast, prostate, and pancreatic cancers. Despite the increasing number of therapeutic indications, the practical use of PARPi remains suboptimal in terms of adequate management of adverse events and adherence - both of which would maximize patient benefit. Therefore, specific recommendations are needed. A Delphi consensus was conducted to suggest statements for improved use of PARPi. A multidisciplinary steering committee of 17 experts (oncologists, nurses, pharmacist, and patient association representative) drafted statements which were submitted to the independent and anonymous vote of clinicians and health care professionals with clinical experience of PARPi (panelists). Statements were divided into the following topics: Initiation and Treatment; Management of adverse events (including hematological, gastrointestinal, insomnia, fatigue, dizziness); Specific populations and situations; Communication with the patient; Adherence. After three voting rounds of the 61 panelists, 49/52 (94%) assertions obtained a consensus. We report here 21 statements specifically related to supportive care (19/21 obtained a consensus). It includes recommendations not to use erythropoiesis-stimulating agents (ESAs) or hematopoietic granulocyte-colony stimulating factors (G-CSFs) to treat PARPi related anemia and neutropenia, given the lack of efficacy data in this setting. Symptomatic antiemetic/anti-nausea treatments can be used to relieve grade 1 gastrointestinal adverse events, while grade ≥2 gastrointestinal adverse events should be managed with treatment interruption/dose reduction. The consensus also recommends to systematically prescribe antidopaminergics when resuming PARPi treatment after interruption due to emesis. The 21 statements will be fully presented and discussed in the communication. This work is the first Delphi consensus on the practical use of PARPi. The pragmatic guidance resulting from this work should help in the management of PARPi adverse events thus improving adherence by preserving patient quality of life.

Poly(ADP-Ribose) Polymerase Inhibition as a Promising Approach for Hepatocellular Carcinoma Therapy.

Simple SummaryLiver cancer has very high incidence and mortality rates, making it a major public health problem. Indeed, the available treatments are not numerous, and few strategies exist for patients with advanced cancers. Thus, there is an urgent need to search for new treatment targets. This review provides an overview of one potential target, poly(ADP)ribose polymerase 1, a protein involved in DNA repair pathways and its expression profiles in liver cancer. Inhibition of this protein could potentiate the effects of current treatments and improve therapeutic outcomes for patients.Primary liver cancer is the sixth most common cancer in men and seventh in women, with hepatocellular carcinoma (HCC) being the most common form (75–85% of primary liver cancer cases) and the most frequent etiology being viral infections (HBV and HCV). In 2020, mortality represented 92% of the incidence—830,180 deaths for 905,677 new cases. Few treatment options exist for advanced or terminal-stage HCC, which will receive systemic therapy or palliative care. Although radiotherapy is used in the treatment of many cancers, it is currently not the treatment of choice for HCC, except in the palliative setting. However, as radiosensitizing drugs, such as inhibitors of DNA repair enzymes, could potentiate the effects of RT in HCC by exploiting the modulation of DNA repair processes found in this tumour type, RT and such drugs could provide a treatment option for HCC. In this review, we provide an overview of PARP1 involvement in DNA damage repair pathway and discuss its potential implication in HCC. In addition, the use of PARP inhibitors and PARP decoys is described for the treatment of HCC and, in particular, in HBV-related HCC.

Patient-reported quality of life during PARP-inhibitor treatment for high-grade serous ovarian cancer (468)

<b>Objectives:</b> To determine the impact of PARP inhibitor maintenance treatment on the health-care quality of life (QOL) of women with high-grade serous ovarian cancer after cytoreductive surgery. <b>Methods:</b> Patient-reported outcome (PRO) collection was implemented at our gynecologic oncology clinic in January 2018. At serial visits, patients were administered general oncology and diseasespecific PRO measures (PROMs) based on the patient disease site. All patients with ovarian cancer (OC) were then identified, and data on PARP inhibitor use was collected from the electronic health records. The date of cytoreductive surgery, as well as initiation of PARP inhibitor therapy, were noted. Specific PROM questions reflecting the quality of life were selected a priori from questionnaires for analysis, and health-related quality of life was compared pre- and post- PARP inhibitor therapy and between patients who were and were not treated with PARP inhibitors. <b>Results:</b> Between January 2018 and July 2020, 285 patients with ovarian cancer were identified who had both undergone cytoreductive surgery and completed PROMs. From these 285 patients, 1275 individual PROMs responses were available for analysis. Seventy- three patients from the cohort had been started on PARP inhibitor maintenance therapy postoperatively. Utilizing the quality-of-life items within the EORTC-QLQ C-30, patients reported an initial drop in quality of life after initiation of PARP inhibitor therapy (Figure 1 A). However, with increasing duration of PARP inhibitor use, patients reported an improvement in their quality of life which surpassed pre-treatment levels at 180 days post-initiation (Figure 1A). When patients who received PARPs were compared to those who did not, the quality of life in the PARP-inhibitor group was worse during the first six postoperative months (Figure 1B). However, at one year post- operatively, the quality of life in the two groups was equal (Figure 1B). <b>Conclusions:</b> PARP inhibitor use is associated with an initial reduction in healthcare quality of life in patients with high-grade serous ovarian cancer. However, with increasing duration of use, quality of life surpasses pre-treatment levels and is equal to that of patients who are not receiving PARP inhibitor therapy by one year postopera- tively. This study confirms the tolerability of PARP inhibitor maintenance therapy in women with high-risk ovarian cancer.

Efficacy of combining tumor treating fields (TTFields) with a PARP inhibitor in ovarian cell lines (300.5)

Objectives: PARP inhibition demonstrates clinical effectiveness in patients with solid tumors and deleterious BRCA mutations. The use of PARP inhibitors is specifically relevant in ovarian cancer, as one of three women with this malignancy harbor BRCA mutations. Tumor Treating Fields (TTFields) are alternating electric fields with antimitotic effects on cancerous cells, which are approved to treat patients with glioblastoma and malignant pleural mesothelioma. TTFields were shown to induce a state of BRCAness in several cancerous cell lines. The objective of this study was to explore the potential of combining TTFields with PARP inhibition for the treatment of ovarian cancer based on in vitro work. Methods: Ovarian carcinoma cells, A2780 (BRCA1/2 wild type) and OVCAR3 (BRCA1 wild type, BRCA2 mutated), were treated for 72 h with TTFields (at an intensity of 1.2 V/cm RMS and frequency of 200 kHz) using the in vitro system. The effectiveness of TTFields in combination with the PARP inhibitor niraparib was examined by measuring cell counts, clonogenic potential, overall effect (multiplicity product of cytotoxicity and clonogenicity), and apoptosis induction. Results: The application of TTFields to A2780 or OVCAR3 cells resulted in about 50% reduction in cell counts. Niraparib displayed a dose-dependent cytotoxic effect on both cell lines. Co-application of niraparib and TTFields resulted in enhanced cytotoxicity compared to the effect of niraparib or TTFields alone. TTFields also elevated the effects of niraparib on the colony-forming ability of the cells, the overall effect, and apoptosis. Conclusions: These results suggest a potential benefit for concomitant treatment of TTFields with niraparib in ovarian cancer. Additional experiments will examine the effect on the BRCA-FANC pathway in ovarian cancer. Objectives: PARP inhibition demonstrates clinical effectiveness in patients with solid tumors and deleterious BRCA mutations. The use of PARP inhibitors is specifically relevant in ovarian cancer, as one of three women with this malignancy harbor BRCA mutations. Tumor Treating Fields (TTFields) are alternating electric fields with antimitotic effects on cancerous cells, which are approved to treat patients with glioblastoma and malignant pleural mesothelioma. TTFields were shown to induce a state of BRCAness in several cancerous cell lines. The objective of this study was to explore the potential of combining TTFields with PARP inhibition for the treatment of ovarian cancer based on in vitro work. Methods: Ovarian carcinoma cells, A2780 (BRCA1/2 wild type) and OVCAR3 (BRCA1 wild type, BRCA2 mutated), were treated for 72 h with TTFields (at an intensity of 1.2 V/cm RMS and frequency of 200 kHz) using the in vitro system. The effectiveness of TTFields in combination with the PARP inhibitor niraparib was examined by measuring cell counts, clonogenic potential, overall effect (multiplicity product of cytotoxicity and clonogenicity), and apoptosis induction. Results: The application of TTFields to A2780 or OVCAR3 cells resulted in about 50% reduction in cell counts. Niraparib displayed a dose-dependent cytotoxic effect on both cell lines. Co-application of niraparib and TTFields resulted in enhanced cytotoxicity compared to the effect of niraparib or TTFields alone. TTFields also elevated the effects of niraparib on the colony-forming ability of the cells, the overall effect, and apoptosis. Conclusions: These results suggest a potential benefit for concomitant treatment of TTFields with niraparib in ovarian cancer. Additional experiments will examine the effect on the BRCA-FANC pathway in ovarian cancer.

BRCA/HRD genetic status does not increase toxicity to PARP inhibitors or next-line cytotoxic chemotherapy in women with epithelial ovarian cancer (479)

<b>Objectives:</b> Poly (ADP-ribose) polymerase inhibitors (PARPis) are often incorporated into epithelial ovarian cancer (EOC) treatment. PARPis are most effective for patients with a <i>BRCA</i> mutation (germline or somatic), followed by homologous recombination deficiency (HRD). We aimed to determine if genetic mutational status impacts toxicity to PARPis or next-line (NL) cytotoxic chemotherapy, as this could inform early interventions to support and maintain patients on treatment. <b>Methods:</b> A retrospective review was conducted of patients with EOC receiving PARPi from March 1, 2014, to May 31, 2021. Medical records were reviewed for clinical-pathologic, genetic, treatment and toxicity data. Toxicities were graded using Common Terminology Criteria for Adverse Events Version 5.0 and coded by organ system. Statistics included descriptive, Chi-square, and Fisher's exact. <b>Results:</b> A total of 230 patients were identified. The mean age at diagnosis was 60.9 years (27-93). Most patients had high-grade serous histology (89.1%) and advanced stage (III 63.0%; IV 23.0%). PARPi indications included frontline maintenance (FM) (18.7%), platinum-sensitive recurrent maintenance (PSRM) (43.9%) and active therapy (AT) (37.4%). Genetic variants included 27.8% germline <i>BRCA</i> (g<i>BRCA</i>+), 5.2% somatic <i>BRCA</i> (s<i>BRCA</i>+), 4.8% HRD, 55.7% wild type and 6.5% not tested. PARPi toxicity was common (overall 94.4%); gastrointestinal (GI) (67.8%), constitutional (64.8%) and hematologic (59.1%) were most prevalent. The myelodysplastic syndrome was rare (0.87%). <i>gBRCA+</i> was not associated with increased PARPi overall (p=0.13), Gr 3/4 (p=0.40), or any specific category of toxicity (Table 1). Stratifying by PARPi indication, <i>gBRCA+</i> was only predictive of higher neurologic toxicity with PARPi used as PSRM (57.1% vs 26.3%, p=0.01). Total 117 patients (50.9%) received NL chemotherapy after PARPi. Toxicity was common (overall 95.7%), with 71.8% hematologic, 63.2% GI and 57.3% constitutional. <i>gBRCA+</i> did not predict worse NL chemotherapy overall (p=0.25), Gr 3/4 (p=0.43), or any category of toxicity (Table 1). Stratifying by the first PARPi (PARPi-1) indication, <i>gBRCA+</i> did not predict worse NL chemotherapy toxicity (overall, Gr 3/4, or any specific category). Broadening the above analyses to incorporate patients with <i>sBRCA</i> mutations +/- HRD did not significantly impact the aforementioned PARPi-1 or NL chemotherapy toxicity (Table 1). Nineteen patients (8.3%) received a second PARPi (PARPi-2); six (2.6% cohort / 31.6% PARP-2) changed agents due to PARPi-1 toxicity and 13 (5.7% cohort / 68.4% PARP-2) used as a new treatment line. PARPi-2 toxicity occurred often (overall 89.5%; Gr 3/4 15.8%); GI (68.4%), constitutional (42.1%) and hematologic (42.1%) were most common. <i>gBRCA+</i> did not predict PARPi-2 overall (87.5% vs 90.9%, p=0.68), Gr 3/4 (25.0% vs 9.1%, p=0.38) or any specific category of toxicity; this held true when analyzed as <i>gsBRCA+</i> (overall 88.9% vs 90.0%, p=0.74; Gr 3/4 22.2% vs 10.0%, p=0.46) and gs<i>BRCA</i>+HRD+ (overall 81.8% vs 100%, p=0.32; Gr 3/4 18.2% vs 12.5%, p=0.62). <b>Conclusions:</b> In this cohort, genetic variant status did not predict worse toxicity to PARPi-1, PARPi-2, or NL chemotherapy. Overall, this data supports the continued use of PARPis across indications and genetic mutational status with low concern for treatment-limiting toxicities.

DNA repair as a shared hallmark in cancer and ageing.

Increasing evidence demonstrates that DNA damage and genome instability play a crucial role in ageing. Mammalian cells have developed a wide range of complex and well‐orchestrated DNA repair pathways to respond to and resolve many different types of DNA lesions that occur from exogenous and endogenous sources. Defects in these repair pathways lead to accelerated or premature ageing syndromes and increase the likelihood of cancer development. Understanding the fundamental mechanisms of DNA repair will help develop novel strategies to treat ageing‐related diseases. Here, we revisit the processes involved in DNA damage repair and how these can contribute to diseases, including ageing and cancer. We also review recent mechanistic insights into DNA repair and discuss how these insights are being used to develop novel therapeutic strategies for treating human disease. We discuss the use of PARP inhibitors in the clinic for the treatment of breast and ovarian cancer and the challenges associated with acquired drug resistance. Finally, we discuss how DNA repair pathway‐targeted therapeutics are moving beyond PARP inhibition in the search for ever more innovative and efficacious cancer therapies.

Survey on implementation of molecular testing in ovarian cancer and PARP inhibitor: a national North-Eastern German Society of Gynecologic Oncology/Young Academy of Gynecologic Oncology/Arbeitsgemeinschaft Gynäkologische Onkologie intergroup analysis

BackgroundSince the introduction of poly (ADP-ribose) polymerase (PARP) inhibitors, BRCA testing has evolved as a standard management in epithelial ovarian cancer.ObjectiveTo analyze the implementation of molecular testing and PARP inhibitor...

Long‑term survival of a BRCA2 mutation carrier following second ovarian cancer relapse using PARPi therapy: A case report

BRCA1/2 mutation carriers have lifelong increased risks of developing breast and ovarian cancer. Due to the lack of efficient ovarian cancer screening, patients mainly present when the tumors are at an advanced stage, and the long-term survival is poor. The application of poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) has been used in personalized cancer treatment. Specific strategies to improve the outcome of patients are available and mainly include targeting of BRCA1 or BRCA2 mutations. The aim of the present study was to report the case of a 67-year old BRCA2 mutation carrier, who was enrolled in 2010 in one of the first PARPi studies (ICEBERG2). The patient exhibited second ovarian cancer (OC) relapse following a platinum-free interval of 5 months. The third-line treatment with olaparib monotherapy was initiated in January 2011, without prior surgery or chemotherapy, and achieved a persistent response. The patient demonstrated an unprecedented long-term survival of >9 years under PARPi monotherapy after the second relapse of OC. The data of the present case report support the use of PARPi as a well-tolerated and effective long-term treatment, even for patients with unfavourable prognostic characteristics, such as platinum resistance, without immediately preceding optimal cytoreduction. However, further studies are required to provide more insight into the selection of patients for favourable maintenance treatment.

Current and New Novel Combination Treatments for Metastatic Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) has a worse prognosis and remains the most challenging breast cancer subtype to treat. This is largely related to the heterogeneity of this disease and the lack of reliable oncological targets. In this review, we discuss the current standard-of-care treatment options for metastatic TNBC, including recent advances with the use of immunotherapy, PARP inhibitors and antibody-drug conjugates. This review also explores new agents and novel combinations arising in the field for the treatment of advanced TNBC.

Role of PARP Inhibitors in Glioblastoma and Perceiving Challenges as Well as Strategies for Successful Clinical Development.

Glioblastoma multiform is the most aggressive primary type of brain tumor, representing 54% of all gliomas. The average life span for glioblastoma multiform is around 14–15 months instead of treatment. The current treatment for glioblastoma multiform includes surgical removal of the tumor followed by radiation therapy and temozolomide chemotherapy for 6.5 months, followed by another 6 months of maintenance therapy with temozolomide chemotherapy (5 days every month). However, resistance to temozolomide is frequently one of the limiting factors in effective treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors have recently been investigated as sensitizing drugs to enhance temozolomide potency. However, clinical use of PARP inhibitors in glioblastoma multiform is difficult due to a number of factors such as limited blood–brain barrier penetration of PARP inhibitors, inducing resistance due to frequent use of PARP inhibitors, and overlapping hematologic toxicities of PARP inhibitors when co-administered with glioblastoma multiform standard treatment (radiation therapy and temozolomide). This review elucidates the role of PARP inhibitors in temozolomide resistance, multiple factors that make development of these PARP inhibitor drugs challenging, and the strategies such as the development of targeted drug therapies and combination therapy to combat the resistance of PARP inhibitors that can be adopted to overcome these challenges.

Crystal structures of the catalytic domain of human PARP15 in complex with small molecule inhibitors

PARP15, or ARTD7, is an enzyme carrying out mono-ADP-ribosylation and regulating activities of a range of cellular proteins. This enzyme belongs to the family of the poly(ADP-ribose) polymerases (PARPs), which comprises of proteins with various potential disease indications. Due to their involvement in a number of cellular processes and important role in DNA repair and regulation, PARPs have been considered attractive therapeutic targets over the past few years. The pursuit of small molecule PARP inhibitors has resulted in several FDA approved drugs for multiple cancers so far. As the use of PARP inhibitors as drug scaffolds is actively explored recently, there is increasing interest in the design of selective inhibitors based on the structural features of the PARP proteins. Here, we solved high-resolution crystal structures of the human PARP15 catalytic domain in complex with three marketed drugs of PARP inhibitors, which includes compounds 3-AB, iniparib and niraparib. The structures reported here contribute to our understanding of the ligand binding modes and structural features in the PARP15 catalytic domain, which can be employed to guide the rational design of selective inhibitors of PARPs.

Experience with olaparib in a patient with luminal HER2-positive metastatic breast cancer

Hereditary breast cancer (BC) accounts for about 5-10% of cases. BRCA-associated tumors have been identified as a separate group of malignant neoplasms with distinctive clinical manifestations and specific treatment features. Understanding of biological mechanisms leading to cancer in BRCA1/2 mutation carriers and discovery of potential molecular targets, such as poly (ADP-ribose) polymerase (PARP), involved in base excision repair mechanisms, led to the development of a new class of targeted drugs belonging to the PARP inhibitors group. PARP inhibition leads to the preservation of single-stranded DNA breaks, the arrest of the replication fork, and the realization of the “synthetic lethality” phenomenon due to the inability to repair double-stranded DNA breaks by homologous recombination in cells with mutations in the BRCA1/2 genes. Two randomized trials OlympiAD and EMBRACA evaluated and proved the effectiveness of PARP inhibitors in patients with metastatic BRCA-mutated HER2-negative breast cancer in comparison with standard chemotherapy. At the same time, data on the potential use of PARP inhibitors for the treatment of BRCA-mutated HER2-positive breast cancer patients are extremely limited. This article presents a clinical example of the use of olaparib in a patient with BRCA-mutated HER2-positive metastatic breast cancer.