PARP Inhibitors Research Articles

A quality initiative focused on BRCA and HRD testing and use of first line maintenance in advanced ovarian cancer.

286 Background: In May of 2020, the approval of two Poly (ADP-ribose) polymerase inhibitors (PARPi) changed the landscape for treatment among patients (pts) with advanced ovarian cancer (aOC). As such, National Comprehensive Cancer Network guidelines recommend BRCA testing for individuals with epithelial ovarian cancer and Homologous Recombination Repair Deficiency (HRD) testing for pts who are BRCA germline negative to guide the decision of maintenance therapy. Regional Cancer Care Associates (RCCA) conducted a quality initiative (QI) with Integra Connect PrecisionQ to assess the rates of BRCA testing, HRD testing, and use of first line maintenance (LOT 1M) therapy based on biomarker status. This QI focused on interventions to optimize testing and LOT 1M treatment in these pts. We aim to show the improvement in BRCA testing, HRD testing, and rates of LOT 1M therapy use after implementation of the QI, in pts with aOC at RCCA. Methods: Using the de-identified IC PrecisionQ database, 90 RCCA pts with aOC as defined by stage III and IV were selected for medical chart curation at baseline. Pts in the baseline group received first-line treatment between 1/1/2020 to 5/31/2022. The baseline data was reviewed with RCCA clinical leadership and findings were presented at a standing practice clinical meeting on 6/20/2024. Post-baseline, we evaluated 28 aOC pts who started a new first-line of therapy between 7/1/2023 to 4/30/2024 to assess BRCA and HRD testing rates and use of LOT 1M among maintenance eligible (ME) pts. ME was defined by a complete response, partial response, or for those where no response was known and had either received maintenance or had no subsequent treatment after 180 days of completing first line therapy. Maintenance therapies included PARPi(s) and bevacizumab. Descriptive analyses were performed and proportions were compared using a chi-squared test. Results: The baseline cohort had 90 pts of which 66% were stage III and 34% were stage IV. The post-baseline cohort had 28 pts of which 54% were stage III and 46% were stage IV. The rate of BRCA testing at baseline was 86% compared to 93% post-baseline. The rate of HRD testing at baseline was 41% compared to 71% post-baseline (p <0.01). The rate of LOT 1M use among maintenance eligible pts at baseline was 57% (N=76) compared to 78% (N=23) post-baseline. PARPi maintenance at baseline was 67% (N=43) compared to 67% (N=14) post-baseline. While rates of maintenance therapy use remained the same from baseline to post-baseline for BRCA mutated pts at 80%, the use of maintenance increased in HRD positive pts from 71% (N = 7) to 77% (N=13). Conclusions: The QI at RCCA that focused on BRCA and HRD testing and treatment with LOT 1M among aOC pts led to improvements against clinical guidelines. QI programs are critical to transforming cancer care and can be useful tools to drive improvement in testing and treatment.

Comprehensive Genomic Assessment of Advanced-Stage GI Stromal Tumors Using the Japanese National Center for Cancer Genomics and Advanced Therapeutics Database.

Clinical utility of comprehensive genomic profiling (CGP) for precision medicine has become evident. Although there are several reports on the genomic landscape of GI stromal tumors (GISTs), large-scale data specific to GIST are limited, especially in Asia. Additionally, the applicability of molecular-targeted agents identified using CGP has not been extensively examined. We investigated the status of genomic alterations in Japanese patients with advanced GISTs using the National Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database to identify novel treatment strategies and drug development. We retrospectively reviewed the clinical and CGP data of patients with advanced-stage GIST registered in the C-CAT database to assess the genomic landscape and potential actionable alterations. Data from 144 patients were reviewed. Oncogenic alterations were detected frequently in KIT (78%), CDKN2A (37%), CDKN2B (29%), RB1 (11%), STK11 (10%), TP53 (9%), PDGFRA (6%), and SDHB (6%). Loss of CDKN2A/CDKN2B was only observed in KIT/PDGFRA-mutated GISTs, while alterations in SDHA/SDHB were only detected in KIT/PDGFRA wild-type GISTs. Among 119 KIT/PDGFRA-mutated GISTs, 95 (80%) had oncogenic genomic alterations and 29 (24%) had actionable alterations, excluding KIT and PDGFRA. However, among 25 KIT/PDGFRA wild-type GISTs, 22 (88%) had oncogenic alterations and 11 (44%) had actionable alterations. Representative candidate drugs for genome-matched therapies in KIT/PDGFRA-mutated and wild-type GISTs were as follows: pembrolizumab for tumor mutation burden-high in one and two patients, respectively; poly-adenosine diphosphate ribose polymerase inhibitors for alterations related to homologous recombination deficiency in 12 and one patient, respectively; NTRK inhibitor for ETV6-NTRK3 fusion in one with KIT/PDGFRA wild-type GIST; and human epidermal growth factor receptor 2-antibody-drug conjugate in one with KIT/PDGFRA-mutated GIST. This study highlights the genomic landscape of advanced GISTs and the important role of CGP in identifying rational molecular-targeted therapeutic options.

Characterizing access for oral oncolytics used to treat breast cancer at an academic medical center.

116 Background: Everolimus, CDK 4/6, PIK3CA, Her2 tyrosine kinase, and PARP inhibitors are commonly used oral oncolytic agents for breast cancer patients. However, oral oncolytics are tiered differently for insurance cost coverage than IV therapies. We characterized the financial toxicity associated with breast cancer oral oncolytics, investigated the prevalence of financial assistance mechanisms utilized, and explored the association of these mechanisms with timing of treatment initiation in adult breast cancer patients. Methods: Patients 18 years or older with a primary breast cancer diagnosis who received care at the outpatient breast cancer clinic and were prescribed an oral oncolytic by a Michigan Medicine provider were included. Using the electronic medical record, we identified initial prescriptions for everolimus, CDK 4/6 inhibitors (palbociclib, ribociclib, abemaciclib), PIK3CA inhibitor (alpelisib), HER2 tyrosine kinase inhibitors (lapatinib, neratinib, tucatinib), and PARP inhibitors (olaparib, talazoparib) dated between January 1, 2014 and November 30, 2022. Patient demographics, adjuvant versus metastatic status, insurance coverage, monthly out-of-pocket costs, financial assistance obtained, prescribed date, planned medication start date, pill-to-mouth date, duration of treatment and reason for treatment discontinuation were collected. Results: There were 418 unique patients in our final cohort. Almost one third of all prescriptions were filled with financial assistance (n=126, 31.2%). The three most common assistance mechanisms were copay cards (n=55, 43.6%), grants (n=34, 26.9%) and patient assistance programs (n=31, 24.6%). For monthly out-of-pocket costs before any financial assistance was obtained, the three most common cost groups were $0-$15 (n=155, 36%), $15-$100 (n=101, 23.7%) and >$500 (n=91, 21%). Among the 48 prescriptions that were never filled, almost one third were due to prohibitive cost (n=15, 28.3%). For insurance coverage, the three most common types were commercial (n=224, 54%), Medicare Part D (n=108, 26%), and Medicaid (n=57, 14%). The median number of days treatment was delayed was 10 days (range 0-495 days). Insurance approval/denial delays accounted for 33.9% of delays (n=120). Conclusions: One third of breast cancer oral oncolytic prescriptions were filled with financial assistance. In the instances in which patients were not able to receive timely treatment for their cancer, one out of three times it was due to insurance delay.

Chitosan/siRNA nanoparticles targeting PARP-1 attenuate Neuroinflammation and apoptosis in hyperglycemia-induced oxidative stress in Neuro2a cells

Hyperglycemia induces an excessive production of superoxide by the mitochondria's electron-transport chain triggers several pathways of injury contributing to the development of diabetic complications. This increase in oxidative and nitrosative stress triggers the activation of PARP-1, a nuclear enzyme, through mechanisms such as DNA damage. siRNA-chitosan nanoparticles were formed based on electrostatic interaction, their particle size, zeta potential, STEM, and cellular uptake were characterized. Neuro2a cells were treated with low glucose (LG) and high glucose (HG) for 24 and 48 h. Neuro2a cells were pre-treated with negative siRNA, naked siRNA, siRNA-Lipofectamine™300, and ChNPs-5. qRT-PCR was used to analyze the expression of regulatory, inflammatory, and apoptotic biomarkers. The siRNA-chitosan complex at the weight ratio 1:3000 were approximately uniform spheres with particle size 150.5 nm and a positive zeta potential of about +41.5 mV. The uptake of FITC-labeled nanoparticles into Neuro2a cells was visualized using fluorescence microscopy with no significant cytotoxicity compared to the control cells. High glucose stimulation of Neuro2a cells increased PARP1 expression, and with siRNA-ChNP (1:3000) treatment, significant inhibition of PARP1 expression is observed that consequently reversed the expression of regulatory genes like SIRT1, FOXO1, FOXO3, and p53. PARP-1 inhibition reduced HG-induced inflammatory response, including NF-kB, IL6, IL1β, TNFα, iNOS, and TGF-β expression, and HG-induced apoptosis response, such as Cas-3, Cas-9, BAK, BAX, and AIF expression. This study highlights the crucial role of siRNA delivery via ChNPs and PARP-1 inhibition in hyperglycemia-induced oxidative stress in Neuro2a cells and PARP-1 inhibition may be a feasible strategy for the treatment of hyperglycemia-induced oxidative stress.

Temporal and Apparent Decrease of Creatinine-Derived eGFR in the Patients with Cancer Treated with Poly ADP-Ribose Polymerase Inhibitors

Temporal and Apparent Decrease of Creatinine-Derived eGFR in the Patients with Cancer Treated with Poly ADP-Ribose Polymerase Inhibitors

Enhancing therapeutic efficacy in homologous recombination-proficient pancreatic cancer via the combination of PARP1-PROTAC and a BRD4 inhibitor

Currently, poly (ADP-ribose) polymerase inhibitors (PARPi) have been approved by the U.S. Food and Drug Administration for BRCA-mutated pancreatic cancer therapy. However, limited indications hinder their further application. Bromodomain-containing protein 4 (BRD4) repression can block the homologous recombination (HR) repair pathway and has the potential to enhance the response to PARPi in HR-proficient pancreatic cancer therapy. In addition, proteolysis targeting chimeras (PROTACs) can hijack E3 ligase within the cell to ubiquitinate degradation-targeted proteins effectively and quickly, thus enhancing the therapeutic effect on tumors. In the present study, the LB23 compound (with the ability to induce PARP1 degradation) was employed in combination with the BRD4 inhibitor, JQ1, and their synergistic effect in HR-proficient pancreatic cancer was confirmed via various methods. Moreover, compared with the JQ1 and PARPi olaparib combination, it was revealed that PARP1-PROTAC and JQ1 had more notable synergistic effects. Further research into the synergistic mechanism demonstrated that combination therapy enhanced DNA damage and suppressed DNA repair by inducing cell cycle arrest and cell apoptosis. The present study therefore provides the experimental data for this type of combination therapy, which is expected to be an innovative approach for the treatment of HR-proficient pancreatic cancer.

Pharmacodynamic Activity of [18F]-Fluorthanatrace Poly(ADP-ribose) Polymerase Positron Emission Tomography in Patients With BRCA1/2-Mutated Breast Cancer Receiving Talazoparib.

We tested the ability of [18F] fluorthanatrace (FTT), a radiolabeled analog of poly(ADP-ribose) polymerase (PARP)-1 inhibitors, to demonstrate target engagement on positron emission tomography (PET) scans from patients with newly diagnosed primary breast cancer receiving the PARP inhibitor (PARPi) talazoparib. Seven patients with germline BRCA1/2 pathogenic variants underwent [18F]FTT PET-computed tomography scanning at baseline, and five underwent repeat scanning 14 days after talazoparib initiation. Maximum uptake on PET was quantified in the primary tumor, involved nodes, contralateral pectoralis muscle, and lumbar vertebra body level 3, and compared between the two time points. Blocking of [18F]FTT was observed on the second scan. Potentially strong but nonsignificant correlations were found between changes in tumor volume (on ultrasound at 1 month v baseline) and percentage changes in tumor-to-muscle uptake ratio at 14 days from baseline (Spearman rank correlation coefficient r = 1; P = .083); and between the highest-grade hematologic toxicity and baseline bone marrow-to-muscle (B/M) uptake ratio (r = 0.72; P = .068) and percentage change in B/M ratio at 14 days from baseline (r = 0.87; P = .058). We conclude that [18F]FTT can image target engagement by PARPi, but larger studies are needed to determine whether [18F]FTT uptake can predict response to PARPi and whether uptake of [18F]FTT in bone marrow may be an early predictor of hematologic toxicity.

In vitro characterization of beta-cyclodextrin liposomal formulation of cisplatin nanomedicine

This study aims to develop a nanomedicine-based approach to protect healthy tissue during cancer treatment, improve patient compliance, reduce adverse drug reactions, and enhance the quality of life. By utilizing hydroxypropyl-β-cyclodextrin (BPCP) to increase drug hydrophilicity and liposomes for controlled release of cisplatin (CP), the hydroxypropyl-β-cyclodextrin-cisplatin liposomal formulation (BCDCPLP) demonstrated improved stability, targeted delivery, and reduced toxicity. The study confirmed that the above formulation had the highest cytotoxicity against HeLa cells, with significantly lower IC50 and IC90 values than cisplatin alone. This is attributed to improved drug stability and cellular uptake. Caspase-3 and cleaved PARP assays confirmed that BCDCPLP and CP-loaded liposomes induced substantial apoptosis, with BCDCPLP showing the highest increase in caspase-3 activity and PARP cleavage at 85 kDa. The ability of BCDCPLP to enhance apoptosis was further demonstrated through Western blot analysis, where the density of PARP cleavage bands was highest in BCDCPLP-treated cells, followed by CPLP and CP-treated cells. The study highlights that the cumulative release of PARP from CP-nanocarrier complexes leads to more efficient apoptosis than free CP. These findings align with the synergistic effects observed when combining CP with PARP inhibitors, which induce mitochondrial membrane permeabilization and cytochrome C release, activating the intrinsic apoptosis pathway. The potential of these nanomedicines, especially BCDCPLP, is in reducing the required dosage while maintaining therapeutic efficacy offers promising advances in cancer therapy.

Olaparib as maintenance therapy in non resectable pancreatic adenocarcinoma associated with homologous recombination deficiency profile: A French retrospective multicentric AGEO real-world study

BackgroundPancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. The POLO trial showed that olaparib (PARP inhibitor) improved progression-free survival (PFS) but not overall survival (OS), when used as maintenance therapy after ≥ 16 weeks of disease control with first-line platinum-based chemotherapy in patients with germline (g) BRCA 1 or 2 pathogenic variants (PV) metastatic PDAC. However, real-world data on the effectiveness of olaparib are missing. MethodsPatients with unresectable PDAC associated with somatic (s) or (g)BRCA1/2 and (g)non-BRCA-HRD PV (i.e. other homologous recombination deficiency/HRD genes) who were treated with olaparib between 2020–2023 were included. The primary objective was to describe treatment patterns. Secondary exploratory objectives included OS and PFS in patients treated with olaparib according to the POLO trial or not, OS and PFS in patients with (g)HRD PV-associated PDAC versus (s)PVs, olaparib safety profile and factors associated with olaparib poor outcomes. ResultsAmong 85 patients, 45.9 % received olaparib as defined by the POLO trial. No difference in OS and PFS was observed between patients who received olaparib according to the POLO trial versus not. Patients with (g)HRD PV-associated PDAC had better OS compared to others (22.3 versus 10.5 months, p = 0.038). Factors associated with olaparib poor outcomes included a high neutrophil-to-lymphocyte ratio and the use of olaparib outside the recommendations of the POLO trial. Few grade ≥ 3 adverse events were reported (9.4 %). ConclusionPatients with (g)HRD PV-associated PDAC had longer OS than those with (s)HRD PV. Olaparib use beyond the scope of the POLO trial was associated with poor outcomes.

359 (PB347): Neoplastic small extracellular vesicles cause DNA damage and inhibit DNA damage repair in Barrett’s esophagus cells: A model for synthetic lethality by PARP inhibitors

359 (PB347): Neoplastic small extracellular vesicles cause DNA damage and inhibit DNA damage repair in Barrett’s esophagus cells: A model for synthetic lethality by PARP inhibitors

Real-World Evidence on Prescribing Patterns and Clinical Outcomes of Metastatic Breast Cancer Patients Treated with PARP Inhibitors: The Mayo Clinic Experience

Real-World Evidence on Prescribing Patterns and Clinical Outcomes of Metastatic Breast Cancer Patients Treated with PARP Inhibitors: The Mayo Clinic Experience

223 (PB211): PHI-101 synergizes with chemotherapy and PARP inhibitors in preclinical models of ovarian cancer

223 (PB211): PHI-101 synergizes with chemotherapy and PARP inhibitors in preclinical models of ovarian cancer

Beyond the PARP inhibition: what is the future of ovarian cancer treatment?

Beyond the PARP inhibition: what is the future of ovarian cancer treatment?

Poly (ADP-ribose) Polymerase Inhibitor Resistance Driven by Emergence of Polyclonal Mutations With Convergent Evolution: A Molecular Tumor Board Discussion.

Polyclonal convergent evolution to PARPi resistance in a patient with metastatic breast cancer with gPALB2.

Uptake of germline genetic testing in patients with advanced breast, ovarian, pancreatic, or prostate cancer.

19 Background: With FDA approval of PARP inhibitors for treatment of BRCA1/2 -associated advanced breast, ovarian, pancreatic, and prostate cancer, National Comprehensive Cancer Network guidelines for germline genetic testing (GGT) have expanded for patients with these tumor types since 2019. We aimed to analyze factors associated with GGT uptake in these patient populations. Methods: We conducted a retrospective cohort study among patients diagnosed with metastatic breast and prostate cancer and all stages of ovarian and pancreatic cancer in 2020-2023 at Columbia University Irving Medical Center in New York City. We extracted data from the electronic medical record on demographics (age at diagnosis, sex, race/ethnicity, Jewish ancestry, marital status) and clinical characteristics (tumor type, year of diagnosis, family history of cancer, receipt of somatic testing, genetic counseling, targeted therapy). The primary outcome was receipt of GGT. Descriptive statistics were generated and multivariable logistic regression analyses were used to estimate the association between demographic/clinical factors and GGT uptake. Results: Among 884 evaluable patients, mean age was 67 years (SD, 14) and the study population included 45% Whites, 15% Blacks, 21% Hispanics, and 9% Asians/Others; 14% had Jewish ancestry. Only 16% were seen by a genetic counselor, 66% had undergone GGT, and 57% had somatic testing. After adjustment for confounders, younger age, Jewish ancestry, later year at diagnosis, and family history of breast or pancreatic cancer were significantly associated with GGT uptake. Patients with pancreatic or prostate cancer were about 60% less likely to undergo GGT compared to patients with ovarian cancer. Patients who had somatic testing were over 4.5-fold more likely to receive GGT. No significant differences were observed based upon sex or race/ethnicity. Among patients who underwent GGT, 20% were found to have a PV and over half of patients who received targeted therapy had PVs detected. Conclusions: We observed increasing use of oncologist-led GGT over time with over 65% of patients with advanced breast, ovarian, pancreatic, or prostate cancer undergoing testing, of which 20% had PVs detected. Given the evolution of targeted therapies and the potential downstream impact of known PVs for family members, under-utilization of GGT in patients with pancreatic and prostate cancer as well as older individuals should be addressed in future studies.

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

196 (PB184): The direct evaluation of homologous recombination activity in tissues to predict the risk of hereditary breast and ovarian cancer and the sensitivity to PARP inhibitor

196 (PB184): The direct evaluation of homologous recombination activity in tissues to predict the risk of hereditary breast and ovarian cancer and the sensitivity to PARP inhibitor

341 (PB329): Acute BRCAness Induction and AR Signaling Blockage through CDK12/7/9 Degradation Enhances PARP Inhibitor Sensitivity in Prostate Cancer

341 (PB329): Acute BRCAness Induction and AR Signaling Blockage through CDK12/7/9 Degradation Enhances PARP Inhibitor Sensitivity in Prostate Cancer

EP.03B.01 The Genomic Scarring Score as a Biomarker for the Use of PARP Inhibitors in Early-Stage Non-Small Cell Lung Cancer

EP.03B.01 The Genomic Scarring Score as a Biomarker for the Use of PARP Inhibitors in Early-Stage Non-Small Cell Lung Cancer

O13-3 Predicting therapeutic response to PARP inhibitors in high-grade serous ovarian cancer: a comprehensive proteomics study

O13-3 Predicting therapeutic response to PARP inhibitors in high-grade serous ovarian cancer: a comprehensive proteomics study