Efficacy Of PARP Inhibitors Research Articles

Discovery of 6-Fluoro-5-{4-[(5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide (AZD9574): A CNS-Penetrant, PARP1-Selective Inhibitor.

PARP inhibitors have attracted considerable interest in drug discovery due to the clinical success of first-generation agents such as olaparib, niraparib, rucaparib, and talazoparib. Their success lies in their ability to trap PARP to DNA; however, first-generation PARP inhibitors were not strictly optimized for trapping nor for selectivity among the PARP enzyme family. Previously we described the discovery of the second-generation PARP inhibitor AZD5305, a selective PARP1-DNA trapper. AZD5305 maintained the antitumor efficacy of first-generation PARP inhibitors while exhibiting lower hematological toxicity. Recently, there has been interest in central nervous system (CNS)-penetrant PARP inhibitors for CNS malignancies and other neurological conditions; however, AZD5305 is not CNS penetrant. Herein we describe the discovery and optimization of a series of CNS-penetrant, PARP1-selective inhibitors and PARP1-DNA trappers, culminating in the discovery of AZD9574, a compound that maintains the PARP1 selectivity of AZD5305 with improved permeability, reduced efflux, and increased CNS penetration.

Combination strategies with PARP inhibitors in BRCA-mutated triple-negative breast cancer: overcoming resistance mechanisms.

Triple-negative breast cancer (TNBC) is a particularly aggressive breast cancer subtype, characterised by a higher incidence in younger women, rapid metastasis, and a generally poor prognosis. Patients with TNBC and BRCA mutations face additional therapeutic challenges due to the cancer's intrinsic resistance to conventional therapies. Poly (ADP-ribose) polymerase inhibitors (PARPis) have emerged as a promising targeted treatment for BRCA-mutated TNBC, exploiting vulnerabilities in the homologous recombination repair (HRR) pathway. However, despite initial success, the efficacy of PARPis is often compromised by the development of resistance mechanisms, including HRR restoration, stabilisation of replication forks, reduced PARP1 trapping, and drug efflux. This review explores latest breakthroughs in overcoming PARPi resistance through combination therapies. These strategies include the integration of PARPis with chemotherapy, immunotherapy, antibody-drug conjugates, and PI3K/AKT pathway inhibitors. These combinations aim to enhance the therapeutic efficacy of PARPis by targeting multiple cancer progression pathways. The review also discusses the evolving role of PARPis within the broader treatment paradigm for BRCA-mutated TNBC, emphasising the need for ongoing research and clinical trials to optimise combination strategies. By tackling the challenges associated with PARPi resistance and exploring novel combination therapies, this review sheds light on the future possibilities for improving outcomes for patients with BRCA-mutated TNBC.

Human HDAC6 senses valine abundancy to regulate DNA damage.

As an essential branched amino acid, valine is pivotal for protein synthesis, neurological behaviour, haematopoiesis and leukaemia progression1-3. However, the mechanism by which cellular valine abundancy is sensed for subsequent cellular functions remains undefined. Here we identify that human histone deacetylase 6 (HDAC6) serves as a valine sensor by directly binding valine through a primate-specific SE14 repeat domain. The nucleus and cytoplasm shuttling of human, but not mouse, HDAC6 is tightly controlled by the intracellular levels of valine. Valine deprivation leads to HDAC6 retention in the nucleus and induces DNA damage. Mechanistically, nuclear-localized HDAC6 binds and deacetylates ten-eleven translocation 2 (TET2) to initiate active DNA demethylation, which promotes DNA damage through thymine DNA glycosylase-driven excision. Dietary valine restriction inhibits tumour growth in xenograft and patient-derived xenograft models, and enhances the therapeutic efficacy of PARP inhibitors. Collectively, our study identifies human HDAC6 as a valine sensor that mediates active DNA demethylation and DNA damage in response to valine deprivation, and highlights the potential of dietary valine restriction for cancer treatment.

CDC7 Inhibition Potentiates Antitumor Efficacy of PARP Inhibitor in Advanced Ovarian Cancer.

Poly (ADP-ribose) Polymerase inhibitors (PARPi) have demonstrated remarkable clinical efficacy in treating ovarian cancer (OV) with BRCA1/2 mutations. However, drug resistance inevitably limits their clinical applications and there is an urgent need for improved therapeutic strategies to enhance the clinical utility of PARPi, such as Olaparib. Here, compelling evidence indicates that sensitivity of PARPi is associated with cell cycle dysfunction. Through high-throughput drug screening with a cell cycle kinase inhibitor library, XL413, a potent cell division cycle 7 (CDC7) inhibitor, is identified which can synergistically enhance the anti-tumor efficacy of Olaparib. Mechanistically, the combined administration of XL413 and Olaparib demonstrates considerable DNA damage and DNA replication stress, leading to increased sensitivity to Olaparib. Additionally, a robust type-I interferon response is triggered through the induction of thecGAS/STING signaling pathway. Using murine syngeneic tumor models, the combination treatment further demonstrates enhanced antitumor immunity, resulting in tumor regression. Collectively, this study presents an effective treatment strategy for patients with advanced OV by combining CDC7 inhibitors (CDC7i) and PARPi, offering a promising therapeutic approach for patients with limited response to PARPi.

BRCA promoter methylation in triple-negative breast cancer is preserved in xenograft models and represents a potential therapeutic marker for PARP inhibitors.

Most triple-negative breast cancers (TNBC) are sporadic in nature and often associated with dysfunction of the BRCA1 or BRCA2 genes. Since somatic BRCA mutations are rare in breast cancer (BC), this dysfunction frequently is the result of BRCA promoter methylation. Despite the phenotypic similarities of these tumors to those with germline or somatic BRCA mutation, the evidence of response to PARP inhibitors is unclear. We analyzed the prevalence of BRCA promoter methylation in 29 BC metastases through the well-established Illumina Infinium EPIC Human Methylation Bead Chip. In cases with BRCA methylation, the xenograft of the same tumor was tested. Additionally, we compared BC xenografts with an identified BRCA methylation to their matched primary tumors and subsequently investigated the efficacy of PARP inhibitors on tumor organoids from a BRCA2 promoter-methylated BC. BRCA2 promotor hypermethylation was identified in one pleural metastasis of a young patient as well as in the xenograft tissue. We also identified five more xenograft models with BRCA2 promotor hypermethylation. Analysis of one matched primary tumor confirmed the same BRCA2 methylation. PARP inhibitor treatment of tumor organoids derived from the BRCA2 methylated xenograft tumor tissue of the young patient showed a significant decline in cell viability, similar to organoids with somatic BRCA1 mutation, while having no effect on organoids with BRCA1 wildtype. BRCA promotor hypermethylation seems to be a rare event in metastatic BC but is preserved in subsequent xenograft models and might represent an attractive therapeutic marker for PARP inhibitors.

139 (PB127): ART6043: a first-in-class clinical DNA Polymerase Theta polymerase domain inhibitor for potentiating PARP inhibitor efficacy

139 (PB127): ART6043: a first-in-class clinical DNA Polymerase Theta polymerase domain inhibitor for potentiating PARP inhibitor efficacy

Efficacy and safety of PARP inhibitor maintenance therapy for ovarian cancer: a meta-analysis and trial sequential analysis of randomized controlled trials.

The landscape of poly (ADP-ribose) polymerase (PARP) inhibitor treatment for ovarian cancer (OC) is continually evolving. This research aimed to evaluate the efficacy and safety of PARP inhibitors compared to placebo as a maintenance therapy for OC patients. We conducted a search of PubMed, Embase, Web of Science, and the Cochrane Library databases for randomized controlled trials (RCTs) involving the use of PARP inhibitors as maintenance therapy in OC patients, up to 16 June 2024. Data regarding progression-free survival (PFS), overall survival (OS), chemotherapy-free interval (CFI), time to first subsequent therapy or death (TFST), time to second subsequent therapy or death (TSST), and treatment-emergent adverse events (TEAEs) were aggregated. Pooled hazard ratio (HR) and their corresponding 95% confidence intervals (CI) were calculated for PFS, OS, CFI, TFST, and TSST. Additionally, the relative risk (RR) and 95% CI for TEAEs were determined. This meta-analysis encompassed 20 RCTs involving 7,832 participants. The overall analysis demonstrated that maintenance therapy with PARP inhibitors led to significant improvements in PFS (HR: 0.398, 95% CI = 0.339-0.467, 95% PI = 0.219-0.724), OS (HR: 0.677, 95% CI = 0.582-0.788, 95% PI = 0.546-0.839), CFI (HR: 0.417, 95% CI = 0.368-0.472, 95% PI = 0.265-0.627), TFST (HR: 0.441, 95% CI = 0.391-0.498, 95% PI = 0.308-0.632), and TSST (HR: 0.574, 95% CI = 0.507-0.649, 95% PI = 0.488-0.674) compared with placebo. Subgroup analyses further indicated that PARP inhibitor maintenance treatment significantly improved PFS, regardless of homologous recombination status (all p < 0.05). However, the risks of any grade (RR = 1.046, 95% CI = 1.032-1.059, 95% PI = 1.028-1.055) and grade ≥3 TEAEs (RR = 2.931, 95% CI = 2.641-3.253, 95% PI = 2.128-3.792) were increased by PARP inhibitor maintenance therapy compared to placebo. Our research elucidated the benefits of maintenance therapy with PARP inhibitors in patients with OC, showing improvements in PFS, OS, CFI, TFST, and TSST. Vigilance regarding TEAEs is paramount for clinicians implementing PARP inhibitor maintenance therapy in clinical practice. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024560286.

CYP1B1 promotes PARPi-resistance via histone H1.4 interaction and increased chromatin accessibility in ovarian cancer

IntroductionOvarian cancer is the most lethal gynecological cancer and presents significant therapeutic challenges. The discovery of synthetic lethality between PARP inhibitors (PARPi) and homologous recombination deficiency marked a new era in treating BRCA1/2-mutated tumors. However, PARPi resistance remains a major clinical challenge. MethodsRNA sequencing was used to identify genes altered by PARPi treatment and LC-MS was used to detect proteins interacting with CYP1B1. Resistance mechanisms were explored through ATAC-seq and gene expression manipulation. Additional techniques, including micrococcal nuclease digestion assays, DAPI staining, and fluorescence microscopy, were used to assess changes in nuclear morphology and chromatin accessibility. ResultsThe gradual exposure of Olaparib has developed a PARPi-resistant cell line, A2780-OlaR, which exhibits significant upregulation of CYP1B1 at both RNA and protein levels. Down-regulating CYP1B1 expression or using specific inhibitors decreased the cellular response to Olaparib. Linker histone H1.4 was identified as associated with CYP1B1. ATAC-seq showed differential chromatin accessibility between A2780-OlaR and parental cells, indicating that the downregulation of H1.4 was associated with increased chromatin accessibility and higher cell viability after Olaparib treatment. ConclusionOur findings reveal a novel role for CYP1B1 in driving PARPi resistance through distinct molecular mechanisms in A2780-OlaR. This study highlights the importance of chromatin accessibility in PARPi efficacy and suggests the CYP1B1/H1.4 axis as a promising therapeutic target for overcoming drug resistance in ovarian cancer, offering potentially therapeutic benefits.

Efficacy of PARP inhibitors in advanced high-grade serous ovarian cancer according to BRCA domain mutations and mutation type.

Preclinical studies have emphasized the potential connection between BRCA specific domains defects and the activity of Poly ADP-ribose polymerase inhibitors (PARPi). Nevertheless, real-world evidence regarding the impact of BRCA domain defects and mutations on PARPi efficacy are limited. The aim of his study was to evaluate the efficacy of PARPi in terms of progression free survival (PFS) according to BRCA domains defects and mutation types. A retrospective analysis was performed among 79 BRCA mutated patients, diagnosed with advanced High-grade serous ovarian carcinoma (HGSOC) who received first- and second-line platinum- based chemotherapy followed by PARPi maintenance treatment. PFS was evaluated according to BRCA1 [Really Interesting Gene (RING), DNA Binding (DBD), Serine Cluster (SCD), BRCA1 C-terminal (BRCT)] and BRCA2 [RAD-51 Domain (RAD-51 BD), DBD] specific domain defects and mutation types [missense (MS), nonsense (NS), frameshift (FS), splicing (S), or large rearrangements (LR)]. After a median follow-up of 51 months, no significant difference in PFS was observed between the BRCA functional domains or mutation types in the BRCA1 and BRCA2 subgroups. Patients with BRCA2 DBD and RAD51-BD defects had the longest (39.8 months) and shortest (24.1 months) median PFS, respectively (p = 0.11). Additionally, patients with BRCA1 DBD defects had the greatest benefit (median PFS = 33.8 months) while those with BRCA1 RING domain mutations experienced the worst outcome (median PFS = 30.9 months (p = 0.43). The efficacy of maintenance treatment with PARPi is independent by BRCA domain defects or mutation types. Patients DBD domain defects experienced numerically longer median PFS compared to those with other BRCA1/2 alterations.

H3K27M diffuse midline glioma is homologous recombination defective and sensitized to radiotherapy and NK cell-mediated antitumor immunity by PARP inhibition.

Radiotherapy (RT) is the primary treatment for diffuse midline glioma (DMG), a lethal pediatric malignancy defined by histone H3 lysine 27-to-methionine (H3K27M) mutation. Based on the loss of H3K27 trimethylation producing broad epigenomic alterations, we hypothesized that H3K27M causes a functional double-strand break (DSB) repair defect that could be leveraged therapeutically with PARP inhibitor and RT for selective radiosensitization and antitumor immune responses. H3K27M isogenic DMG cells and orthotopic brainstem DMG tumors in immune deficient and syngeneic, immune competent mice were used to evaluate the efficacy and mechanisms of PARP1/2 inhibition by olaparib or PARP1 inhibition by AZD9574 with concurrent RT. H3K27M mutation caused an HRR defect characterized by impaired RT-induced K63-linked polyubiquitination of histone H1 and inhibition of HRR protein recruitment. H3K27M DMG cells were selectively radiosensitized by olaparib in comparison to isogenic controls, and this effect translated to efficacy in H3K27M orthotopic brainstem tumors. Olaparib and RT induced an innate immune response and induction of NK cell (NKG2D) activating ligands leading to increased NK cell-mediated lysis of DMG tumor cells. In immunocompetent syngeneic orthotopic DMG tumors, either olaparib or AZD9574 in combination with RT enhanced intratumoral NK cell infiltration and activity in association with NK cell-mediated therapeutic responses and favorable activity of AZD9574. The HRR deficiency in H3K27M DMG can be therapeutically leveraged with PARP inhibitors to radiosensitize and induce an NK cell-mediated antitumor immune response selectively in H3K27M DMG, supporting the clinical investigation of best-in-class PARP inhibitors with RT in DMG patients. H3K27M DMG are HRR defective and selectively radiosensitized by PARP inhibitor.PARP inhibitor with RT enhances NKG2D ligand expression and NK cell-mediated lysis.NK cells are required for the therapeutic efficacy of PARP inhibitor and RT. Radiotherapy is the cornerstone of H3K27M-mutant diffuse midline glioma treatment, but almost all patients succumb to tumor recurrence with poor overall survival, underscoring the need for RT-based precision combination therapy. Here, we reveal HRR deficiency as an H3K27M-mediated vulnerability and identify a novel mechanism linking impaired RT-induced histone H1 polyubiquitination and the subsequent RNF168/BRCA1/RAD51 recruitment in H3K27M DMG. This model is supported by selective radiosensitization of H3K27M DMG by PARP inhibitor. Notably, the combination treatment results in NKG2D ligand expression that confers susceptibility to NK cell killing in H3K27M DMG. We also show that the novel brain penetrant, PARP1-selective inhibitor AZD9574 compares favorably to olaparib when combined with RT, prolonging survival in a syngeneic orthotopic model of H3K27M DMG. This study highlights the ability of PARP1 inhibition to radiosensitize and induce an NK cell-mediated antitumor immunity in H3K27M DMG and supports future clinical investigation.

GPX4 Inhibition Enhances the Antitumor Effect of PARP Inhibitor on Homologous Recombination Proficient Ovarian Cancer Cells.

Poly (ADP-ribose) polymerase inhibitors (PARPi) are now widely used in BRCA1/2 mutation or homologous recombination (HR) deficiency ovarian cancer but have limited efficacy in HR-proficient patients. GPX4 is a key regulator of ferroptosis and has been proven to be associated with multiple drug sensitivities. As a molecule that regulates the sensitivity of multiple drugs, the relationship between GPX4 and the efficacy of PARPi in HR-proficient ovarian cancer has not been elucidated. In this study, siRNA transfection was used to regulate the expression of GPX4. The effect of GPX4 inhibition on HR-proficient ovarian cancer was determined by CCK-8 assay and flow cytometry. Immunofluorescence and comet assays were used to reflect DNA dam-age. ROS production was measured using DCFH-DA and flow cytometry. The combination index of PARP inhibitors and RSL3 was calculated using CompuSyn software based on Chou-Talalay methodology. GPX4 inhibition confers HR-proficient ovarian cancer cells sensitive to PARPi due to ROS generation and oxidative stress caused by DNA double-strand breakage. The combina-tion of olaparib and niraparib with GPX4 inhibitor RSL3 also showed a synergistic effect. Combining GPX4 inhibition with PARP inhibitors resulted in a notable increase in DNA damage, ultimately causing the death of cancer cells with proficient HR pathways. Our findings may provide new therapeutic options for HR-proficient patients to benefit from PARP inhibitors and improve outcomes.

Leveraging PARP-1/2 to Target Distant Metastasis.

Poly (ADP-Ribose) Polymerase (PARP) inhibitors have changed the outcomes and therapeutic strategy for several cancer types. As a targeted therapeutic mainly for patients with BRCA1/2 mutations, PARP inhibitors have commonly been exploited for their capacity to prevent DNA repair. In this review, we discuss the multifaceted roles of PARP-1 and PARP-2 beyond DNA repair, including the impact of PARP-1 on chemokine signalling, immune modulation, and transcriptional regulation of gene expression, particularly in the contexts of angiogenesis and epithelial-to-mesenchymal transition (EMT). We evaluate the pre-clinical role of PARP inhibitors, either as single-agent or combination therapies, to block the metastatic process. Efficacy of PARP inhibitors was demonstrated via DNA repair-dependent and independent mechanisms, including DNA damage, cell migration, invasion, initial colonization at the metastatic site, osteoclastogenesis, and micrometastasis formation. Finally, we summarize the recent clinical advancements of PARP inhibitors in the prevention and progression of distant metastases, with a particular focus on specific metastatic sites and PARP-1 selective inhibitors. Overall, PARP inhibitors have demonstrated great potential in inhibiting the metastatic process, pointing the way for greater use in early cancer settings.

Efficacy and Safety of PARP Inhibitor in Prostate Cancer: A Systematic Review

Efficacy and Safety of PARP Inhibitor in Prostate Cancer: A Systematic Review

Targeted Nanocarrier-Based Drug Delivery Strategies for Improving the Therapeutic Efficacy of PARP Inhibitors against Ovarian Cancer.

The current focus of ovarian cancer (OC) research is the improvement of treatment options through maximising drug effectiveness. OC remains the fifth leading cause of cancer-induced mortality in women worldwide. In recent years, nanotechnology has revolutionised drug delivery systems. Nanoparticles may be utilised as carriers in gene therapy or to overcome the problem of drug resistance in tumours by limiting the number of free drugs in circulation and thereby minimising undesired adverse effects. Cell surface receptors, such as human epidermal growth factor 2 (HER2), folic acid (FA) receptors, CD44 (also referred to as homing cell adhesion molecule, HCAM), and vascular endothelial growth factor (VEGF) are highly expressed in ovarian cancer cells. Generation of active targeting nanoparticles involves modification with ligands that recognise cell surface receptors and thereby promote internalisation by cancer cells. Several poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are currently used for the treatment of high-grade serous ovarian carcinomas (HGSOC) or platinum-sensitive relapsed OC. However, PARP resistance and poor drug bioavailability are common challenges, highlighting the urgent need to develop novel, effective strategies for ovarian cancer treatment. This review evaluates the utility of nanoparticles in ovarian cancer therapy, with a specific focus on targeted approaches and the use of PARPi nanocarriers to optimise treatment outcomes.

FANCI Inhibition Induces PARP1 Redistribution to Enhance the Efficacy of PARP Inhibitors in Breast Cancer.

Breast cancer is a global public health concern with high mortality rates, necessitating the development of innovative treatment strategies. PARP inhibitors have shown efficacy in certain patient populations, but their application is largely limited to cancers with homologous recombination deficiency. Here, we identified the suppression of FANCI as a therapeutic strategy to enhance the efficacy of PARP inhibitors in breast cancer. Elevated FANCI expression in breast cancer was associated with poor prognosis and increased cell proliferation and migration. FANCI interacted with PARP1, and suppressing FANCI limited the nuclear localization and functionality of PARP1. Importantly, FANCI inhibition sensitized breast cancer cells to the PARP inhibitor talazoparib in the absence of BRCA mutations. Additionally, the CDK4/6 inhibitor palbociclib enhanced the sensitivity of breast cancer cells to talazoparib through FANCI inhibition. These findings highlight the potential of targeting FANCI to enhance the efficacy of PARP inhibitors in treating breast cancer. Significance: Targeting FANCI is a promising therapeutic strategy for enhancing PARP inhibitor sensitivity in breast cancer that holds potential for broader therapeutic applications beyond cancers harboring BRCA mutations.

Expanding the Perspective on PARP1 and Its Inhibitors in Cancer Therapy: From DNA Damage Repair to Immunomodulation.

The emergence of PARP inhibitors as a therapeutic strategy for tumors with high genomic instability, particularly those harboring BRCA mutations, has advanced cancer treatment. However, recent advances have illuminated a multifaceted role of PARP1 beyond its canonical function in DNA damage repair. This review explores the expanding roles of PARP1, highlighting its crucial interplay with the immune system during tumorigenesis. We discuss PARP1's immunomodulatory effects in macrophages and T cells, with a particular focus on cytokine expression. Understanding these immunomodulatory roles of PARP1 not only holds promise for enhancing the efficacy of PARP inhibitors in cancer therapy but also paves the way for novel treatment regimens targeting immune-mediated inflammatory diseases.

PARP inhibitor boost the efficacy of photothermal therapy to TNBC through enhanced DNA damage and inhibited homologous recombination repair.

Triple-negative breast cancer (TNBC) could benefit from PARP inhibitors (PARPi) for their frequent defective homologous recombination repair (HR). However, the efficacy of PARPi is limited by their lower bioavailability and high susceptibility to drug resistance, so it often needs to be combined with other treatments. Herein, polydopamine nanoparticles (PDMN) were constructed to load Olaparib (AZD) as two-channel therapeutic nanoplatforms. The PDMN has a homogeneous spherical structure around 100nm and exhibits a good photothermal conversion efficiency of 62.4%. The obtained AZD-loaded nanoplatform (PDMN-AZD) showed enhanced antitumor effects through the combination of photothermal therapy (PTT) and PARPi. By western blot and flow cytometry, we found that PTT and PARPi could exert synergistic antitumor effects by further increasing DNA double-strand damage (DSBs) and enhancing HR defects. The strongest therapeutic effect of PDMN-AZD was observed in a BRCA-deficient mouse tumor model. In conclusion, the PDMN-AZD nanoplatform designed in this study demonstrated the effectiveness of PTT and PARPi for synergistic treatment of TNBC and preliminarily explained the mechanism.

Tailored Treatment Strategies in First Line Therapy for Ovarian Cancer Patients: A Critical Review of the Literature.

Ovarian cancer (OC) is a significant cause of cancer-related mortality in women globally, with a five-year survival rate of approximately 49%. Standard therapy involves cytoreductive surgery followed by chemotherapy. Its poor prognosis has driven interest in alternative therapies such as targeted molecular agents like bevacizumab and poly (ADP-ribose) polymerase inhibitors (PARPi). This review systematically searched PubMed from January 2018 to December 2023 for studies on PARPi in OC. Emphasis was on identifying relevant Phase III trials, extracting data on study design, patient demographics, and outcomes. Special focus was on assessing PARPi efficacy, safety, impact on quality of life, and ongoing trials, including those on Clinicaltrials.gov. The efficacy of PARPi in first-line therapy for OC has been extensively studied. Trials like SOLO-1, PRIMA, and ATHENA-MONO have demonstrated significant improvements in progression-free survival (PFS) and overall survival (OS), particularly in patients with BRCA mutations. Additionally, the combination of PARPi with other agents like bevacizumab has shown promising results in extending PFS. However, PARPi treatment is associated with various adverse effects, including hematologic toxicities like anemia, thrombocytopenia, and neutropenia. While most adverse events are manageable, some patients may require dose adjustments or discontinuation of treatment. Importantly, PARPi maintenance therapy has not adversely affected health-related quality of life (HRQoL), with studies reporting similar HRQoL scores between PARPi-treated and placebo-treated patients. PARPi offer effective treatment with manageable side effects, suitable even for medically fragile patients. Individualized dosing can optimize benefits while minimizing adverse events. Exploring diverse treatment approaches, particularly in patients with limited life expectancy or high disease burden, could improve outcomes. Ongoing research is investigating alternative therapies and combinations to broaden treatment options. Combining bevacizumab with PARPi may be justified for first-line and recurrent maintenance therapy. Regardless of mutational status, PARPi should be considered for maintenance therapy in newly diagnosed advanced OC. Platinum sensitivity remains crucial for treatment decisions and predicting survival outcomes.

Efficacy and safety of PARP inhibitors (PARPi) with immune checkpoint inhibitors (ICI) in metastatic castration-resistant prostate cancer (mCRPC): A systematic review and single-arm meta-analysis.

e17053 Background: Recent therapeutic advances in prostate cancer have allowed patients with metastatic disease to live longer and better, especially in the castration sensitive setting. Although improvements have been observed in the castration resistant space, survival in this setting remains suboptimal. Early-phase clinical trials suggest the combination of PARP inhibitors (PARPi) and immune checkpoint inhibitors (ICI) have synergistic effect by modulating the tumor microenvironment. In this systematic review and meta-analysis, we assessed the efficacy and safety of PARPi and ICI in the metastatic castration-resistant prostate cancer (mCRCP) setting. Methods: Pubmed, Cochrane and EMBASE were systematically searched from inception through December 10, 2023. Randomized and non-randomized clinical trials evaluating PARPi + ICI in mCRPC were included. PSA response rate (PSArr), radiographic progression-free survival (rPFS), objective response rate (ORR) and overall survival (OS) were analyzed. Subgroups according to (HRR) were assessed. We also pooled the prevalence of immune-related adverse events (irAE) and their corresponding 95% confidence intervals (95% CI). Statistical analysis was performed using R software version 4.3.2 and heterogeneity was evaluated through I2 statistics. Results: We screened 1070 reports, and six trials met the inclusion criteria (one phase III RCT and 5 phase I/II non-RCT), involving 799 participants. The overall ORR was 8.48% (95% CI 6.48-10.86 I2 0%). About 19% of patients achieved an PSArr (95% CI 9.51-32.50 I2 75%). Median OS was 15.8 months (95% IC 13.9-15.8), and rFPS was 4.5 months (95% IC 4.4-4.9). In patients harboring HRR mutations, PSArr was 17.53% (95% CI 10.43-27.95 I2 75), while in HRR non-mutated it was 10.49% (95% CI 5.89-17.99 I2 0%). The frequency of any-grade irAEs was 21.12% (95% CI 12.34-33.74 I2 85%), with 6.70% of grade 3-4 irAEs (95% CI 3.09-13.91 I2 80%). Hypothyroidism rate was 8.53% (95% CI 5.86-12.27 I2 29%) and adrenal insufficiency was 2.80% (95% CI 1.81-4.30 I2 0%). Conclusions: This meta-analysis results suggest that the combination of PARPi plus ICI in patients with mCRPC is safe and may benefit mainly patients with HRR mutations. Further studies in biomarker selected patients are needed. [Table: see text]

The efficacy of PARP inhibitors in the treatment of patients with synchronous breast cancer.

e13041 Background: Currently, the role of BRCA1/2 in the development of primary and multiple malignant breast tumors is under discussion, along with the effectiveness of targeted therapy for this oncopathology. At the same time, there is a lack of sufficient research dedicated to the treatment of patients with synchronous breast cancer (BC) concurrent with ovarian cancer (OC) and the outcomes of using PARP inhibitors in this patient population. Methods: A retrospective analysis of treatment outcomes based on long-term survival indicators was conducted for 23 patients with synchronous BC, where the second tumor was OC. These patients underwent evaluation and treatment between 2017 and 2022. The average age of the patients was 45.3±5.6 years, with a prevalence of patients in stages IIb-IIIa of BC and IIb-IIIc of OC. Germline mutations in the BRCA1/2 genes were detected in 8 patients, among whom 5 exhibited the triple-negative phenotype of BC. The 1st group included 11 (47.8%) patients without BRCA1/2 mutations, who received neoadjuvant chemotherapy with paclitaxel 175 mg/m2 + carboplatin AUC 6 once every 3 weeks. In the 2nd group, consisting of 12 (52.2%) patients, olaparib 800 mg was added to this chemotherapy regimen. This group also included 8 patients with BRCA1/2 mutations. Results: In the majority of patients in both groups, a significant elevation in CA125 levels in serum was observed, averaging 563 U/mL, with practically normal CA153 levels at 32 U/mL. Identified mutations included 5382insC and 4154delA mutations in the BRCA1 gene, as well as the 6174delT mutation in the BRCA2 gene. Patients underwent three courses of treatment, and four weeks after completing the last course, surgical intervention was performed in the form of radical mastectomy, hysterectomy, bilateral salpingo-oophorectomy, and omentectomy. Following surgical treatment, patients received adjuvant chemotherapy following the same regimens. In the 2nd group, patients continued to receive olaparib for one year, and no signs of unacceptable toxicity were reported. The median overall survival in the first group of patients was 34.2 months (95% CI: 28.6-37.5), while in the second group, it was 36.8 months (95% CI: 31.4-41.1). The addition of bevacizumab significantly increased the median time to progression from 13.8 months (95% CI: 11.8-14.5) to 15.2 months (95% CI: 12.4-15.8), p=0.042. Lethal outcomes primarily occurred due to the progression of ovarian cancer. Conclusions: Thus, the addition of the PARP inhibitor olaparib to a platinum-based chemotherapy regimen in patients with synchronous breast cancer, associated with germline mutations in BRCA1/2 genes and the presence of ovarian cancer as a second tumor, has a positive impact on treatment outcomes. This contributes to the resectability of patients and significantly increases the median time to progression.