Maintenance Therapy In Ovarian Cancer Research Articles

Usefulness of Nutritional Assessment Indicators in Predicting Treatment Discontinuation Due to Adverse Events from PARP Inhibitors in Ovarian Cancer Patients.

Nutritional status is an important factor influencing toxicity of treatment. Nutritional assessment indicators such as the Prognostic Nutritional Index (PNI), Controlling Nutritional Status (CONUT) score and modified Glasgow Prognostic Score (mGPS) have been reported to be associated with treatment-related adverse events (AEs) for various malignancies. However, there are no reports investigating the relationship between nutritional status and AEs from poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPi), which are widely used in recent years as maintenance therapy for ovarian cancer. The primary objective was to investigate the usefulness of nutritional assessment indicators in predicting treatment discontinuation due to AEs from PARPi. This multicenter retrospective study included patients diagnosed with ovarian cancer who received maintenance therapy with PARPi from January 2018 to December 2023. PNI, CONUT score, and mGPS were calculated based on hematological parameters measured within 7 days before the start of PARPi therapy. A total of 272 patients received maintenance therapy with PARPi during the period, but due to the absence of the blood collection of albumin levels within one week or other exclusion criteria, 71 patients were finally included in this analysis. AEs were seen in 59 patients (83.1%), including 25 (35.2%) severe events (grade ≥3 in Common Terminology Criteria for Adverse Events v5.0). Eighteen patients (25.4%) discontinued treatment due to PARPi-related AEs. Low PNI (<48.44) and high mGPS (≥1) were predictors of treatment discontinuation in both univariate and multivariate analyses. CONUT was not a significant predictor in this study. Our study suggested that PNI and mGPS can predict the risk of treatment discontinuation due to PARPi-related AEs before starting maintenance therapy. This insight opens avenues for more personalized treatment plans, potentially improving patient outcomes.

Micellar curcumol for maintenance therapy of ovarian cancer by activating the FOXO3a

Maintenance therapy (MT) for ovarian cancer (OC) is crucial for preventing disease relapse. Curcumol shows effective anti-OC ability and low-toxicity to the normal ovarian epithelial cells, however, its bioavailability is low. Herein, micellar loaded curcumol (MC) was prepared and the anti-tumor ability of MC were performed on OC cells. The results indicated that the IC50 values of MC in two kinds of OC cells were 37.69 ± 2.43 and 28.54 ± 1.58 μg/mL, respectively. Mechanistically, curcumol could interact with the AKTThr308 site, inhibiting the phosphorylation of FOXO3a, which promoted FOXO3a nuclear locating and recruited it to the PERK promoter, activating the ERS induced apoptosis pathway. Moreover, MC inhibited the growth of SKOV3 cells on tumor-bearing nude mice and the DiR-labeled MC could quickly accumulate in the tumor region. MC provides great feasibility to achieve efficient MT for OC based on the nanoplatforms of active ingredients from natural products.

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.

Blockade of the lncRNA-PART1-PHB2 axis confers resistance to PARP inhibitor and promotes cellular senescence in ovarian cancer

PARPi is currently the most important breakthrough in the treatment of ovarian cancer in decades, and it has been integrated into the initial maintenance therapy for ovarian cancer. However, the mechanism leading to PARPi resistance remains unelucidated. Our study aims to screen novel targets to better predict and reverse resistance to PARPi and explore the potential mechanism. Here, we conducted a comparative analysis of differentially expressed genes between platinum-sensitive and platinum-resistant groups within the TCGA ovarian cancer cohort. The analysis indicated that lncRNA PART1 was significantly highly expressed in platinum-sensitive patients compared to platinum-resistant individuals in TCGA-OV cohort and further validated in the GEO dataset and Qilu hospital cohort. Moreover, the upregulation of PART1 was positively correlated with a favorable prognosis in ovarian cancer. Furthermore, in vitro and in vivo experiments showed that inhibition of PART1 conferred resistance to both cisplatin and PARP inhibitor and promoted cellular senescence. Senescent cells are more resistant to chemotherapeutics. RNA antisense purification and RNA immunoprecipitation assays revealed an interaction between PART1 and PHB2, a crucial mitophagy receptor. Knockdown of PART1 could promote the degradation of PHB2, impairing mitophagy and leading to cellular senescence. Rescue assays indicated that overexpression of PHB2 remarkably diminished the resistance to PARPi and cellular senescence caused by PART1 knockdown. PDX models were utilized to further confirm the findings. Altogether, our study demonstrated that lncRNA PART1 has the potential to serve as a novel promising target to reverse resistance to PARPi and improve prognosis in ovarian cancer.

EHMT1/2 inhibition promotes regression of therapy-resistant ovarian cancer tumors in a CD8 T cell-dependent manner.

Poly ADP-ribose polymerase inhibitors (PARPi) are first-line maintenance therapy for ovarian cancer and an alternative therapy for several other cancer types. However, PARPi-resistance is rising and there is currently an unmet need to combat PARPi-resistant tumors. Here, we created an immunocompetent, PARPi-resistant mouse model to test the efficacy of combinatory PARPi and euchromatic histone methyltransferase 1/2 inhibitor (EHMTi) in the treatment of PARPi-resistant ovarian cancer. We discovered that inhibition of EHMT1/2 resensitizes cells to PARPi. Markedly, we show that single EHMTi and combinatory EHMTi/PARPi significantly reduced PARPi-resistant tumor burden and that this reduction is partially dependent on CD8 T cells. Altogether, our results show a low-toxicity drug that effectively treats PARPi-resistant ovarian cancer in an immune-dependent manner, supporting its entry into clinical development and potential incorporation of immunotherapy. Implications: Targeting the epigenome of therapy-resistant ovarian cancer induces an anti-tumor response mediated in part through an anti-tumor immune response.

Effectiveness of PARP Inhibitor Maintenance Therapy in Ovarian Cancer by BRCA1/2 and a Scar-Based HRD Signature in Real-World Practice.

The purpose of the study was to compare the effectiveness of PARP inhibitor maintenance therapy (mPARPi) in real-world practice by biomarker status [BRCA1/2 alterations (BRCAalt) and a homologous recombination deficiency signature (HRDsig)] in advanced ovarian cancer. Patients with ovarian cancer receiving first-line platinum-based chemotherapy and either mPARPi or no maintenance were included. Patient data were obtained by a US-based de-identified ovarian cancer Clinico-Genomic Database, from ∼280 US cancer clinics (01/2015-03/2023). Real-world progression-free survival (rwPFS) and overall survival (rwOS) were compared by biomarker status using Cox models, weighted by propensity scores. Of 673 patients, 160 received mPARPi [31.2% BRCAalt and 51.9% HRDsig(+)] and 513 no maintenance [15.6% BRCAalt and 34.1% HRDsig(+)]. BRCAalt patients receiving mPARPi versus no maintenance had favorable rwPFS [HR, 0.48; 95% confidence interval (CI), 0.26-0.87; P = 0.0154], as did BRCA wild-type (WT; HR, 0.76; 95% CI, 0.57-1.01; P = 0.0595). Favorable rwOS was not observed with mPARPi for BRCAalt or BRCA-WT. HRDsig(+) patients receiving mPARPi versus no maintenance had favorable rwPFS (HR, 0.36; 95% CI, 0.24-0.55; P < 0.001) and numerically favorable rwOS (HR, 0.46; 95% CI, 0.21-1.02; P = 0.0561). No differences were observed for HRDsig(-). mPARPi treatment interaction was observed for HRDsig(+) versus HRDsig(-) (rwPFS P < 0.001/rwOS P = 0.016) but not for BRCAalt versus BRCA-WT. Patients with BRCA-WT/HRDsig(+) receiving mPARPi had favorable rwPFS (HR, 0.40; 95% CI, 0.22-0.72; P = 0.003), whereas no difference was observed for BRCA-WT/HRDsig(-). HRDsig predicted benefit of mPARPi better than BRCAalt. Patients with HRDsig(+) status experienced favorable outcomes, even if they had BRCA-WT status. In contrast, patients with HRDsig(-) status did not show significant benefit from mPARPi treatment. HRDsig might predict benefit from mPARPi regardless of BRCAalt status.

Age Is a Risk Factor for Olaparib Dose Modification and Discontinuation in Patients With Ovarian Cancer.

Olaparib, a poly (ADP-ribose) polymerase inhibitor, is widely used as maintenance therapy for ovarian cancer. Dose modification, such as dose reduction and treatment interruption, are frequently performed to manage adverse events (AEs) of olaparib. By identifying patients at high risk for dose modification before administration, interventions related to appropriate control of AEs can be implemented. This study aimed to evaluate risk factors of olaparib dose modification and its clinical usefulness. Sixty patients with ovarian cancer who received olaparib were included in this retrospective cohort study. Associations between patients' characteristics and dose modification were evaluated by multivariate logistic regression analysis. We also examined whether risk factors of dose modification were associated with treatment discontinuation due to AEs. Twenty-five (41.7%) patients required dose modification. Patients who required dose modification were significantly older (p=0.018) and tended to be more underweight (p=0.078) than those who did not require dose modification. In multivariate analysis, increasing age was significantly associated with dose modification (odds ratio=1.056; 95% confidence interval=1.002-1.112; p=0.034). The optimal cutoff of age as a risk factor for dose modification, calculated from receiver operating characteristic curves, was 65.0 years. Patients aged 65.0 years and older were significantly more likely to discontinue olaparib owing to AEs (p=0.0437). Age is a risk factor of olaparib dose modification due to AEs. Older patients, who frequently require dose modification, are more likely to discontinue olaparib, suggesting that strict management of AEs is particularly necessary in this patient group.

Effects of niraparib dose reduction on short-term outcomes in ovarian cancer patients

ObjectivesDespite the individualized starting dose for maintenance therapy in ovarian cancer, the niraparib dose reduction rate remains high. The aim of this study was to evaluate the impact of niraparib...

Budget Impact Analysis of Olaparib in Combination with Bevacizumab for Maintenance Therapy for Ovarian Cancer in Argentina.

To perform a budget impact analysis (BIA) of introducing olaparib as maintenance therapy in women who have BRCA mutations (BRCAm) with platinum-sensitive recurrent ovarian cancer (PSROC) in combination with bevacizumab in Argentina. A BIA model was used to analyse over a 5-year time horizon the change in the health system's budget following the adoption of olaparib as maintenance therapy in BRCAm patients with PSROC. The BIA for each year was estimated by comparing the cost difference between the current scenario (treatment with bevacizumab) and the new scenario (the addition of olaparib) for a third-party payer. The BIA is estimated at the national health system level, and by healthcare sectors in Argentina (public sector, social security and private sector). International and national epidemiological data were used to determine the target patient population. Clinical efficacy, safety outcomes and duration of treatments were obtained from the pivotal clinical study report. Relevant direct medical costs were obtained from public data in Argentina and expert consultation. All the costs are reported in US dollars as of October 2022 ($1 = 152.59 Argentine pesos). A scenario analysis assessed the full coverage of the homologous recombination deficiency (HRD) test in Argentina. In addition, one-way sensitivity analysis was conducted to evaluate the model robustness. For a third-party payer with a cohort of 1,000,000 women covered, the estimated target population was 2 individuals in year 1 and 6 individuals in year 5. The incorporation of olaparib, with a wholesale price per pack of $3176.32, was associated with a weighted average of the budget impact per member per month (PMPM) of $0.062 for the national health system, being above the estimated health system budget impact threshold ($0.0153). By healthcare sector, the results of budget impact PMPM for year 5 ranged between $0.08 (public sector) and $0.114 (private sector). For all perspectives, the variables that most influenced the budget impact was the incidence of ovarian cancer, the drug acquisition cost and the treatment duration. The introduction of olaparib for the treatment of BRCAm women with PSROC has a high budget impact for all three health systems in Argentina.

Homologous recombination deficiency score for predicting efficacy of platinum-based chemotherapy and PARPi maintenance therapy in ovarian cancer.

e17543 Background: Currently, homologous recombination deficiency (HRD) has been confirmed to be a predictive biomarker for poly-ADP-ribose-polymerase inhibitors (PARPi) in ovarian cancer, while its effects on the clinical outcomes of platinum-based chemotherapy and PARPi maintenance therapy are not assessed rigorously in ovarian cancer. We developed an HRD assay to evaluate the effect of HRD scores on the platinum-based chemotherapy and PARPi maintenance therapy in Chinese patients with ovarian cancer. Methods: HRD testing was performed on the samples obtained at primary cytoreductive surgery. The progression-free survival (PFS) was observed among the BRCA-mutated/HRD-positive and BRCA wild-type/HRD-negative patients. Univariate and multivariate COX analyses were performed to test the association of PFS with different variables, and hazards ratios (HR) and 95% confidence interval (CI) were calculated. The two-tailed p value less than 0.05 was considered statistically significant. Results: Totally 74 patients who received platinum-based chemotherapy were eligible for the study, among whom 81.1% responded to the initial platinum-based chemotherapy, 33.8% harbored BRCA1/2 mutations and 74.3% were HRD-positive. The median HRD score of platinum-sensitive patients (n=60) was 48.5, significantly higher than the 31 of platinum-resistant patients (n=14, p=0.0035). Analysis of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI) and large-scale state transitions (LST) between platinum-sensitive and platinum-resistant patients showed significant differences in TAI ( p=0.0012) and LST ( p=0.004). Compared with HRD-negative patients, HRD-positive patients had a significantly longer median PFS (10 vs. 15 months, p=0.017), and multivariate analysis further indicated that HRD-positive status (HR, 0.423, 95%CI: 0.191-0.939, p=0.035) was a significant predictor for the improvement of PFS. Conclusions: The HRD assay developed in our study can accurately predict the response to platinum-based chemotherapy and PARPi efficacy in patients with ovarian cancer, providing powerful evidence for implementation of genetic testing and guidance of clinical treatment in ovarian cancer.

To modulate or to skip: De-escalating PARP inhibitor maintenance therapy in ovarian cancer using adaptive therapy

Toxicity and emerging drug resistance pose important challenges in poly-adenosine ribose polymerase inhibitor (PARPi) maintenance therapy of ovarian cancer. We propose that adaptive therapy, which dynamically reduces treatment based on the tumor dynamics, might alleviate both issues. Utilizing invitro time-lapse microscopy and stepwise model selection, we calibrate and validate a differential equation mathematical model, which we leverage to test different plausible adaptive treatment schedules. Our model indicates that adjusting the dosage, rather than skipping treatments, is more effective at reducing drug use while maintaining efficacy due to a delay in cell kill and a diminishing dose-response relationship. Invivo pilot experiments confirm this conclusion. Although our focus is toxicity mitigation, reducing drug use may also delay resistance. This study enhances our understanding of PARPi treatment scheduling and illustrates the first steps in developing adaptive therapies for new treatment settings. A record of this paper's transparent peer review process is included in the supplemental information.

“Having cancer is very expensive”: A qualitative study of patients with ovarian cancer and PARP inhibitor treatment

ObjectiveTo examine patient barriers and facilitators to PARP inhibitor (PARP-I) maintenance therapy in ovarian cancer. PARP-I improves survival in ovarian cancer, but these multi-year therapies cost around $100,000 annually and are under-prescribed. MethodsWe recruited patients with ovarian cancer treated with PARP-I maintenance therapy at an academic health system for a semi-structured interview. Patient demographics, including genetics and PARP-I cost, were self-reported. We assessed patient experiences with barriers and facilitators of PARP-I usage. Two team members used a thematic approach to analyze and identify key themes. ResultsIn May 2022, we interviewed 10 patients (mean age = 65 years; 80% White; 60% with a germline genetic mutation). Patients paid on average $227.50 monthly for PARP-I, straining resources for some participants. While sampled patients were insured, all patients identified having no or inadequate insurance as a major barrier to PARP-I. At the same time, all participants prioritized clinical effectiveness over costs of care. Patients identified PARP-I delivery from specialty pharmacies, separate and different from other medications, as a potential barrier, but each had been able to navigate delivery. Patients expressed significant initial side effects of PARP-I as a potential barrier yet reported clinician communication and prompt dose reduction as facilitating continuation. ConclusionsPatients identified cost, restrictive pharmacy benefits, and initial side effects as barriers to PARP-I usage. Having insurance and a supportive care team were identified as facilitators. Enhancing communication about PARP-I cost and side effects could improve patient experience and receipt of evidence-based maintenance therapy in ovarian cancer.

Olaparib and niraparib as maintenance therapy in patients with newly diagnosed and platinum-sensitive recurrent ovarian cancer: A single-center study in China.

Poly adenosine-diphosphate-ribose polymerase (PARP) inhibitors (PARPi) have been approved to act as first-line maintenance (FL-M) therapy and as platinum-sensitive recurrent maintenance (PSR-M) therapy for ovarian cancer in China for >5 years. Herein, we have analyzed the clinical-application characteristics of olaparib and niraparib in ovarian cancer-maintenance therapy in a real-world setting to strengthen our understanding and promote their rational usage. A retrospective chart review identified patients with newly diagnosed or platinum-sensitive recurrent ovarian cancer, who received olaparib or niraparib as maintenance therapy at Sichuan Cancer Hospital between August 1, 2018, and December 31, 2021. Patient medical records were reviewed. We grouped and analyzed patients based on the type of PARPi they used (the olaparib group and the niraparib group) and the line of PARPi maintenance therapy (the FL-M setting and the PSR-M setting). The primary endpoint was the 24-month progression-free survival (PFS) rate. In total, 131 patients (olaparib: n=67, 51.1%; niraparib: n=64, 48.9%) were enrolled. Breast cancer susceptibility genes (BRCA) mutations (BRCAm) were significantly less common in the niraparib group than in the olaparib group [9.4% (6/64) vs. 62.7% (42/67), P<0.001], especially in the FL-M setting [10.4% (5/48) vs. 91.4% (32/35), P<0.001]. The 24-month PFS rates in the FL-M and PSR-M settings were 60.4% and 45.7%, respectively. In patients with BRCAm, the 24-month PFS rates in the FL-M and PSR-M settings were 62.2% and 72.7%, respectively. Olaparib and niraparib were effective in patients with ovarian cancer without any new safety signals except for skin pigmentation. In patients with BRCAm, the 24-month PFS of the PARPi used in the PSR-M setting was even higher than that used in the FL-M setting.

RAD51 as an immunohistochemistry-based marker of poly(ADP-ribose) polymerase inhibitor resistance in ovarian cancer.

Effective functional biomarkers that can be readily used in clinical practice to predict poly(ADP-ribose) polymerase inhibitor (PARPi) sensitivity are lacking. With the widespread adoption of PARPi maintenance therapy in ovarian cancer, particularly in patients with BRCA mutation or HR deficiencies, accurately identifying de novo or acquired resistance to PARPi has become critical in clinical practice. We investigated RAD51 immunohistochemistry (IHC) as a functional biomarker for predicting PARPi sensitivity in ovarian cancer. Ovarian cancer patients who had received PARPi and had archival tissue samples prior to PARPi exposure ("pre-PARPi") and/or after progression on PARPi ("post-PARPi") were selected. RAD51 IHC expression was semi-quantitatively evaluated using the H-score in geminin (a G2/S phase marker)- and γH2AX (a DNA damage marker)-positive tissues. A RAD51 H-score of 20 was used as the cutoff value. In total, 72 samples from 56 patients were analyzed. The median RAD51 H-score was 20 (range: 0-90) overall, 10 (0-190) in pre-PARPi samples (n = 34), and 25 (1-170) in post-PARPi samples (n = 19). Among patients with BRCA mutations, RAD51-low patients had better progression-free survival (PFS) after PARPi treatment than RAD51-high patients (P = 0.029). No difference was found in PFS with respect to the genomic scar score (P = 0.930). Analysis of matched pre- and post-PARPi samples collected from 15 patients indicated an increase in the RAD51 H-score upon progression on PARPi, particularly among pre-PARPi low-RAD51-expressing patients. RAD51 is a potential functional IHC biomarker of de novo and acquired PARPi resistance in BRCA-mutated ovarian cancer and can be used to fine-tune ovarian cancer treatment.

Trends and frontiers of maintenance therapy for ovarian cancer over the past 20years: a bibliometric analysis.

Aim: To summarize and analyze the research trends and frontiers in maintenance therapy for ovarian cancer over the past 20years.Methods: Relevant articles were identified in Web of Science, and analyzed using CiteSpace and Excel.Results: 1204 articles from 61 countries led by theUSA and England were included. 6821 authors, 2345 institutions and292 journals have participated in the publication of papers, but the collaboration between them was not very close. The annual publication volume has increased significantly since 2015. Drug combination therapy, genetic testing, management of adverse reaction andprognostic factors are research trends and frontiers of this field.Conclusion: This is the first bibliometric research in this field, which can provide some references for researchers.

PARP inhibitors in newly diagnosed or recurrent ovarian cancer maintenance therapy: evidence of efficacy and safety from randomized controlled trials

PARP inhibitors in newly diagnosed or recurrent ovarian cancer maintenance therapy: evidence of efficacy and safety from randomized controlled trials

Increase in creatinine levels associated with niraparib maintenance therapy in ovarian cancer.

In Japan, Niraparib maintenance therapy for primary and recurrent ovarian cancer was approved in September 2020 and is expected to improve the prognosis of ovarian cancer. However, the safety of niraparib maintenance therapy in Japanese patients has not been fully evaluated. Patients with ovarian cancer (including fallopian tube and peritoneal cancer) treated with niraparib at Jichi Medical University Hospital from September 2020 to August 2022 were enrolled in this study. Patient background, starting dose, rates of interruption, reduction, or discontinuation, adverse events (AEs) during treatment, and estimated glomerular filtration rate (eGFR) trends were retrospectively analyzed. Twenty-nine patients received niraparib maintenance therapy during the study period, including 21 with primary cancer and 8 patients with recurrent cancer. Seventeen patients (58.6%) required dose interruptions and 16 patients (55.2%) required dose reductions. Only two patients (6.9%) discontinued treatment due to fatigue and nausea. The most frequent AE was creatinine increases in 18 patients (62.1%, all grades). Although eGFR levels decreased significantly after niraparib therapy compared to before niraparib therapy (59.3 vs. 50.3 mL/min/1.73 m2 , p < 0.001), the levels returned to pre-niraparib initiation levels after discontinuation of niraparib (64.6 vs. 64.6 mL/min/1.73 m2 , p = 0.96). Multivariate regression analysis showed that diabetes was independently associated with decreased eGFR (p = 0.013). Niraparib maintenance therapy frequently increased serum creatinine, but the change was reversible. Further studies are needed to determine the effects of niraparib on renal function in Japanese patients.

Targeting Metastases in Optimizing Ovarian Cancer Maintenance Therapy

Targeting Metastases in Optimizing Ovarian Cancer Maintenance Therapy

Trends in the use of maintenance therapy in ovarian cancer.

6585 Background: Emerging maintenance therapies in advanced ovarian cancer (OC) remain of high interest since 70% of patients (pts) will relapse and ultimately succumb to OC. This study analyzes nonclinical factors associated with maintenance therapy (MT) in OC. We define MT in OC as the use of polyADP-ribose polymerase inhibitors (PARPi) and/or bevacizumab (bev) following platinum-based chemotherapy. Methods: We used data from Optum’s de-identified Clinformatics Data Mart Database F to conduct an analysis of OC pts with Medicare or commercial health insurance. Pts were included if they had 1 inpatient or 2 outpatient diagnosis codes for OC from 01/2017 to 12/2020 and received platinum-based chemotherapy after diagnosis. Pts were excluded if they did not have continuous coverage from diagnosis until 6 months after completion of platinum-based chemotherapy or death. MT was identified by insurance claims for PARPi or bev received within 6 months after completion of platinum-based chemotherapy. Descriptive statistics were used to summarize patient characteristics. Multivariable logistic regression was used to evaluate associations between pts’ nonclinical characteristics and MT use. Trends in MT use were reviewed by year. Subgroup analysis comparing trends in PARPi use to bev use was also performed. The median time from last chemotherapy until initiation of MT was 22 days. Results: 5,652 pts were included in the study with a median age of 70 years. The majority were white (70.7%), Medicare-insured (71.8%), and treated in the South (42.8%). 33.6% of pts received MT and 66.4% of pts received neither PARPi nor bev. More pts received bev alone (19.6%) compared to PARPi alone (10.3%) or combination MT (3.7%). Olaparib was the most commonly prescribed PARPi. After adjusting for insurance type, both PARPi and bev use increased significantly over time from 2017 to 2021. Pts with more comorbidity burdens (i.e. higher Elixhauser comorbidity index) were more likely to receive MT compared to pts with less comorbidity [OR (95% CI): 1.44 (1.26-1.65)]. MT use was significantly associated with treatment in the South compared to the Northeast [1.22(1.01-1.46)] and younger age, pts &gt; 76 years were less likely to use MT compared to pts &lt; 56 years old [0.78 (0.62-0.98)]. In the subgroup analysis, PARPi use was significantly associated with age, race and region compared with no MT use, while bev use was not associated with these factors. Conclusions: Age, comorbidity status, and geographic location of treatment were associated with MT use. The increasing use of MT over time is consistent with published data since both agents have demonstrated a progression free survival advantage and have tolerable toxicity profiles. With increasing focus on MT in OC, a better understanding of nonclinical factors associated with MT use is imperative to eliminating potential disparities in OC outcomes.

Resistance mechanism and microenvironment changes after PARPi treatment: Paired analysis of ovarian cancer samples pre and post treatment.

e17586 Background: PARP inhibitors (PARPi) have been widely used in the maintenance therapy of ovarian cancer (OC) and have shown strong anti-tumor effect in tumors with homologous recombination defects (HRD). However, there is still a lack of systematic clinical data on drug resistance mechanisms and tumor microenvironment changes. Methods: 13 OC patients who were treated with PARPi at West China Second University Hospital were enrolled. PARPi treatment-naive samples (PNS, n = 11) and post-PARPi progression samples (PPS, n = 13) were acquired. Two next-generation sequencing (NGS) panels (Master panel, 563 genes for exons of DNA plus 1831 genes for RNA; HRD panel, 70,000 SNPs for HRD score evaluation, AmoyDx) were used to analyze gene variation, expression, and HRD score changes in tumors. Results: Median duration of treatment for PARPi was 17 months (9-36), and the median lines of chemotherapy before PARPi was 2 (1-3). 38.5% (5/13) patients achieved R0 resection. BRCA reversion mutations were observed in 30.0% (3/10) of the g BRCA+ PPS, including 1 splicing variant and 2 frameshift mutations. High-frequency variants also included MYC amplification (30.8%, 4/13) and ZFHX4 mutations (23.1%, 3/13); Amplification of ch11 q13 were observed in two patients (15.4%). HRD scores and tumor mutation burden (TMB) were significantly increased in PPS. RNA expression profiling showed that the expression of NGFR, CCL18, C7 and other 85 genes in PPS was up regulated. GO/KEGG analysis showed that NF-κb pathway, immune response related cell activation, cytokine - cytokine receptor interaction, B cell receptor signaling pathway, NK cytotoxicity pathways, and etc., were significantly upregulated in PPS, suggesting that PARPi may activated immune-related pathways of the tumor microenvironment (TME). Downregulated pathways in PPS include JAK-STAT signaling pathway, Wnt signaling pathway, and etc. In PPS, the level of memory B cells and neutrophils were significantly up-regulated, while the levels of immune suppression by myeloid cells were significantly down-regulated. Conclusions: Our small-scale study confirmed that BRCA reversion mutation is one of the important resistance mechanisms of PARPi, and the reversion mutation is located near the germline pathogenic mutation to counteract the reading frame change caused by the frameshift mutation. The up-regulation of B-cell receptor, NK cytotoxic cytokine receptor interaction and other related pathways suggested that PARPi may activate immune response, and the changes in the levels of memory B cells, C7 and neutrophils also confirmed the results above. Epithelial mesenchymal transition induced by CCL18 may also lead to PARPi resistance and activate the NF-κb pathway simultaneously, increasing the inflammatory characteristics of TME. These findings can provide ideas for future treatment, and larger samples are needed to verify later.