Olaparib Administration Research Articles

Susceptibility of Brca1(L63X/+) rat to ovarian reserve dissipation by chemotherapeutic agents to breast cancer.

BRCA1 is one of the causative genes for hereditary breast and ovarian cancer syndrome with a high risk of early-onset breast cancer. Whereas olaparib (OLA), an inhibitor of poly-ADP-ribose polymerase, has been applied as adjuvant therapy to those cancer patients, its effect on ovarian reproductive function remains unelucidated. Recently, a rat model (MUT; Brca1(L63X/+) mutation) mimicking a human BRCA1 pathogenic variant has been established. Using this model, we evaluated the effects of OLA on ovarian reproductive function in comparison with the wild-type (WT) rats. MUT showed a significantly reduced number of primordial follicles and subfertility in accordance with aging. Oxidative stress was significantly elevated in the young MUT granulosa cells (GCs) accompanied by increased mTOR but decreased PTEN signals. OLA administration in MUT further decreased primordial follicles, with gene set enrichment analysis, indicating upregulated DNA repair pathways. Furthermore, a combination of OLA and cyclophosphamide (CPA) induced empty primordial follicles, recognized as CPA-induced severe ovarian toxicity. Whereas OLA + CPA caused greater reduction in primordial follicles both in MUT and WT in comparison with CPA alone, MUT ovaries were more susceptible to oxidative stress, potentially depleting primordial follicles via activation of GCs and inducing oocyte death due to accumulated DNA damage by OLA treatment. Our findings in this preclinical model underscore the importance of evaluating ovarian reserve prior to chemotherapy by performing reproductive consultation with female patients with BRCA1 pathogenic variants.

Pharmacokinetic Interaction Between Olaparib and Regorafenib in an Animal Model.

Olaparib (OLA) and regorafenib (REG) are metabolized by the CYP3A4 isoenzyme of cytochrome P450. Both drugs are also substrates and inhibitors of the membrane transporters P-glycoprotein and BCRP. Therefore, the potential concomitant use of OLA and REG may result in clinically relevant drug-drug interactions. Knowledge of the influence of membrane transporters and cytochrome P450 enzymes on the pharmacokinetics of drugs makes it possible to assess their impact on the efficacy and safety of therapy. The study aimed to evaluate the bilateral pharmacokinetic interactions of OLA and REG and its active metabolites after a single administration in healthy rats. The study was performed in male Wistar rats (n = 24) randomly divided into three groups: one study group, IREG+OLA (n = 8), received REG with OLA, and two control groups, IIREG (n = 8) and IIIOLA (n = 8), received REG and OLA, respectively. The concentrations of OLA, REG, REG-N-oxide (M-2), and N-desmethyl-REG-N-oxide (M-5) were determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The values of the pharmacokinetic parameters of OLA, REG, M-2, and M-5 were determined by non-compartmental analysis with linear interpolation. After OLA administration, the pharmacokinetic parameters of REG (AUC0-∞, tmax, and t0.5) increased significantly by 3.38-, 2.66-, and 1.82-fold, respectively. On the other hand, REG elimination parameters, i.e., kel and Cl/F, were significantly reduced in the study group by 1.77- and 1.70-fold, respectively. In the study group, Cmax and AUC0-t values were also 7.22- and 8.86-fold higher for M-2 and 16.32- and 17.83-fold higher for M-5, respectively. The Metabolite M-2/Parent and Metabolite M-5/Parent ratios for Cmax and AUC0-t increased by 6.52-, 10.74-, 28-, and 13-fold, respectively. After administration of OLA with REG, the Cmax, AUC0-t, and AUC0-∞ of OLA increased by 2.0-, 3.4-, and 3.4-fold, respectively, compared to the control group. Meanwhile, Cl/F and Vd/F of OLA were significantly decreased in the presence of REG. OLA was shown to significantly affect the pharmacokinetics of REG and its active metabolites M-2 and M-5 in rats after co-administration of both drugs. There was also a significant effect of REG on the pharmacokinetics of OLA, which may have clinical relevance. The AUC ratios (study group/control group) were 3.41 and 3.39 for REG and OLA, respectively, indicating that REG and OLA were moderate inhibitors in this preclinical study. The results obtained need to be confirmed in clinical studies. This study may provide guidance on the safety of using both drugs in clinical practice.

Real-World Clinical Outcomes of Treatment With Olaparib for BRCA1/2 Mutation-Positive Metastatic Breast Cancer in Japanese Patients.

Background Olaparib is effective in the treatment of metastatic breast cancer (MBC) patients, mainly confirmed by deleterious germline BRCA mutations. However, real-world data are scarce. Methodology A total of 10 cases from our institute and 17 cases from the relevant Japanese literature were reviewed. All 27 patients had MBC with confirmed deleterious germline BRCA mutations. Tumor reduction, response duration, disease-free interval (DFI), overall survival (OS), and safety were assessed. Additionally, exploratory research was conducted on the characteristics of a subgroup of patients who had a long-term response to olaparib. Results In the 10 cases from two Juntendo hospitals who received olaparib from July 2018 to December 2021, the median age was 48 years (range = 37-63 years). The same numbers of BRCA1 and BRCA2 mutations and the same ratios of luminal and triple negative (TN) breast cancer cases were observed. The metastatic sites, mainly visceral, included the lungs (n = 4), liver (n = 5), and bone (n = 6). The median duration of drug use was four months (range = 1-36 months). The median number of treatment regimens from metastasis to olaparib administration was 2.0 (range = 1-9 regimens). The median DFI was 21 months (range = 0-106 months). The median OS was not reached (range = 16-191 months). In the subgroup analysis of six cases in which olaparib was effective for four months or more, there was a case where DFI was longer than 100 months. Treatment-related toxicities (TRTs) included neutropenia (n = 5; 50%), anemia (n = 4; 40%), thrombocytopenia (n = 2; 20%), nausea (n = 1; 10%), and fatigue (n = 1; 10%). CTCAE (version 5.0) grade ≥3 TRTs included anemia (n = 1; 10%) and neutropenia (n = 5; 50%). On the other hand, neutropenia was previously said to be as low as 27.3%, lower than anemia (40.0%), in a population including various races. We additionally examined another 17 cases from the Japanese literature. Conclusions To our knowledge, this study reports the first real-world data of Japanese patients with MBC and confirmed deleterious germline BRCA mutations. Our data showed that olaparib is effective in the real world. The incidence of neutropenia seemed higher in Japanese patients.

Predictors of olaparib discontinuation owing to adverse drug events in patients with ovarian, peritoneal, or fallopian tube cancer: a retrospective observational study

We investigated predictors of olaparib discontinuation owing to adverse effects. Patients with ovarian, peritoneal, or fallopian tube cancers treated with olaparib at Osaka Medical and Pharmaceutical University Hospital between April 2018 and September 2022 were included in this study. The exclusion criteria were as follows: discontinuation of treatment due to disease progression, use of anaemia medications, and use of cytochrome P450 (CYP3A4) inhibitors. The follow-up period was 90 d. Of the 46 eligible patients, 21 patients discontinued olaparib, including 15 patients with grade 3 or higher anaemia, eight patients with grade 3 or higher neutropenia, and four patients with non-haematological toxicity (including multiple onset). Multivariate logistic regression analysis showed that grade 4 neutropenia and anaemia progression to grades 2–3 due to chemotherapy administered before olaparib administration were predictors of olaparib discontinuation. The severity of neutropenia and anaemia due to chemotherapy before olaparib administration may be a potential marker for its discontinuation.

Tolerability of Olaparib Combined with Abiraterone in Patients with Metastatic Castration-resistant Prostate Cancer: Further Results from the Phase 3 PROpel Trial

BackgroundThe PROpel study (NCT03732820) demonstrated a statistically significant progression-free survival benefit with olaparib plus abiraterone versus placebo plus abiraterone in the first-line metastatic castration-resistant prostate cancer (mCRPC) setting, irrespective of homologous recombination repair mutation status. ObjectiveWe report additional safety analyses from PROpel to increase clinical understanding of the adverse-event (AE) profiles of olaparib plus abiraterone versus placebo plus abiraterone. Design, setting, and participantsA randomised (1:1), double-blind, placebo-controlled trial was conducted at 126 centres in 17 countries (October 2018–January 2020). Patients had mCRPC and no prior systemic mCRPC treatment. InterventionOlaparib (300 mg bid) or placebo with abiraterone (1000 mg od) plus prednisone/prednisolone (5 mg bid). Outcome measurements and statistical analysisThe data cut-off date was July 30, 2021. Safety was assessed by AE reporting (Common Terminology Criteria for Adverse Events v4.03) and analysed descriptively. Results and limitationsThe most common AEs (all grades) for olaparib plus abiraterone versus placebo plus abiraterone were anaemia (46.0% vs 16.4%), nausea (28.1% vs 12.6%), and fatigue (27.9% vs 18.9%). Grade ≥3 anaemia occurred in 15.1% versus 3.3% of patients in the olaparib plus abiraterone versus placebo plus abiraterone arm. The incidences of the most common AEs for olaparib plus abiraterone peaked early, within 2 mo, and were managed typically by dose modifications or standard medical practice. Overall, 13.8% versus 7.8% of patients discontinued treatment with olaparib plus abiraterone versus placebo plus abiraterone because of an AE; 3.8% versus 0.8% of patients discontinued because of anaemia. More venous thromboembolism events were observed in the olaparib plus abiraterone arm (any grade, 7.3%; grade ≥3, 6.8%) than in the placebo plus abiraterone arm (any grade, 3.3%; grade ≥3, 2.0%), most commonly pulmonary embolism (6.5% vs 1.8% for olaparib plus abiraterone vs placebo plus abiraterone). ConclusionsOlaparib plus abiraterone has a manageable and predictable safety profile. Patient summaryThe PROpel trial showed that in patients who had not received any previous treatment for metastatic castration-resistant prostate cancer, olaparib combined with abiraterone was more effective in delaying progression of the disease than abiraterone alone. Most side effects caused by combining olaparib with abiraterone could be managed with supportive care methods, by pausing olaparib administration for a short period of time and/or by reducing the dose of olaparib.

KPT330 promotes the sensitivity of glioblastoma to olaparib by retaining SQSTM1 in the nucleus and disrupting lysosomal function

ABSTRACT PARP (poly(ADP-ribose) polymerase) inhibitors have demonstrated promising clinical activity in multiple homologous recombination (HR) deficiency tumors. However, glioblastoma (GBM) patients have obtained little benefit from PARP inhibitors alone. PARP inhibition shows considerable promise when used together with other therapeutic agents. Thus, novel combination therapies may enhance PARP inhibitor efficacy and overcome resistance mechanisms in GBM. Herein, we report that concurrent treatment with the PARP inhibitor olaparib and XPO1 (exportin 1) inhibitor KPT330 showed synergetic anticancer effects on GBM cells. Mechanistically, in the nucleus, we show that KPT330 induced the nuclear retention of SQSTM1 (sequestosome 1) and further inhibited the ubiquitination of the DNA repair signal H2AX (H2A.X variant histone) mediated by olaparib, thus inhibiting DNA damage response and repair in GBM. Moreover, in the cytoplasm, KPT330 blocked the activation of autophagic flux caused by olaparib reagent, downregulated the expression of LAPTM4B (lysosomal protein transmembrane 4 beta) and induced the dysfunction of lysosomes, thereby preventing the degradation of autophagosome, and ultimately promoted cell death. Furthermore, in the LN229-luc mouse orthotopic xenograft model, combination treatment showed significantly increased antitumor efficacy compared to each monotherapy. These data illustrate the application prospects of combined oral administration of olaparib and KPT330 for the treatment of glioblastoma. Abbreviations AO: acridine orange; ATM: ATM serine/threonine kinase; CHEK1: checkpoint kinase 1; CHEK2: checkpoint kinase 2; CI: combination index; DMSO: dimethyl sulfoxide; DSBs: double-strand breaks; GBM: glioblastoma; HR: homologous recombination; H2AX: H2A.X variant histone; IHC: immunohistochemistry; LAPTM4B: lysosomal protein transmembrane 4 beta; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PARP: poly(ADP-ribose) polymerase; RAD51: RAD51 recombinase; SQSTM1: sequestosome 1; SSBs: single-strand breaks; RNF168: ring finger protein 168; XPO1: exportin 1.

Serum CA125 level as predictors of the efficacy of olaparib maintenance therapy for platinum-sensitive relapsed ovarian cancer.

Ovarian cancer is a gynecological malignancy with a poor prognosis. For platinum-sensitive relapsed ovarian cancer, maintenance therapy with poly-ADP ribose polymerase (PARP) inhibitors after chemotherapy is considered; however, olaparib treatment does not always lead to sufficient progression-free survival (PFS). This study aimed to identify factors that predict the efficacy of maintenance therapy using olaparib in platinum-sensitive relapsed ovarian cancer. Twenty-seven patients with platinum-sensitive relapsed ovarian cancer, who received initial treatment and showed complete or partial response to prior chemotherapy at our hospital, were included. The primary outcome was the time from the end of previous platinum-based chemotherapy to disease progression (PFS). The Kaplan-Meier method was used to generate time-to-event curves for PFS; multivariate analysis was performed using the Cox proportional hazards regression model. The median PFS was 12 months (95% confidence interval [CI]: 8.3-15.8). Before olaparib administration, the median PFS was 12 months in the <4.1 neutrophil-to-lymphocyte ratio group and 4 months in the ≥4.1 group, with PFS being significantly better in the <4.1 group (log-rank: p = 0.023). When comparing serum cancer antigen 125 (CA125) levels, the median PFS was 13 months in the <18 U/mL group and 6 months in the >18 U/mL group (log-rank: p = 0.022). Multivariate Cox regression analysis revealed that CA125 was the factor affecting PFS (hazard ratio: 4.85; 95% CI: 1.53-15.38). Serum CA125 levels at olaparib initiation in patients with platinum-sensitive relapsed ovarian cancer may predict PFS as an effect of maintenance therapy using olaparib to treat recurrent disease.

Drug-induced interstitial lung disease caused by olaparib: three case reports and review of the Japanese Adverse Drug Event Report database and literature

BackgroundOlaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, has demonstrated effectiveness in treating ovarian, breast, and other cancers, particularly those with specific molecular subtypes including, but not limited to, BRCA1/2 mutations. Consequently, its utilization is expected to increase in the future. For this reason, it is important to acknowledge the potential for adverse events associated with olaparib, including the relatively rare but significant risk of drug-induced interstitial lung disease (DIILD). Since DIILD can lead to fatal outcomes, its early detection is crucial. The dissemination of knowledge regarding DIILD can be facilitated through case reports; however, specific reports of DIILD caused by olaparib have only been published in Japanese. To the best of our knowledge, this is the first report in English of our experience with three cases of DIILD caused by olaparib.Case presentationCases 1, 2, and 3 involved Japanese women with ovarian cancer who had been receiving olaparib at a dose of 600 mg/day. Case 1, a 72-year-old woman who had been on olaparib for 4 months, and case 2, a 51-year-old woman who had been on olaparib for 8 months, reported fever and general malaise. Chest computed tomography (CT) revealed pale ground glass opacity (GGO) similar to hypersensitivity pneumonitis. The severity grade was 2 in both cases. Case 3, a 78-year-old woman who had been on olaparib for 3 weeks, presented with cough and reported dyspnea on exertion. Chest CT revealed non-specific interstitial pneumonia and organizing pneumonia-like shadows. The severity grade was 4. Olaparib was discontinued in all cases. Case 1 received 0.6 mg/kg of prednisolone due to mild hypoxia, while prednisolone was not administered in case 2 due to the absence of hypoxia. Case 3 received steroid pulse therapy due to severe hypoxia. Olaparib administration was not resumed in any patient.ConclusionDIILD caused by olaparib in Japan, including the present three cases, commonly presents with GGO, similar to hypersensitivity pneumonitis on chest CT. The prognosis for the majority of patients is favorable; however, there have been instances of severe cases. Early recognition of drug-induced lung injury and further accumulation of cases is important.

Factors for the development of anemia in patients with newly introduced olaparib: A retrospective case-control study.

Anemia is the most common dose-limiting toxicity of olaparib. However, few studies have analyzed the clinical features of olaparib-induced anemia. This study investigated the clinical features of olaparib-induced anemia. Additionally, the role of folate or vitamin B12 in olaparib-induced anemia was examined. This retrospective case-control study included patients who received olaparib at Mie University Hospital between January 2018 and December 2020. Data were collected between initiation of olaparib and discontinuation of olaparib or till December 2021. We investigated the development of grade ≥ 3 anemia during olaparib administration for at least 1 year. We examined patients with grade ≥ 3 anemia considering the mean corpuscular volume (MCV), its association with gastrointestinal events and cumulative dose of carboplatin. For the sub-study analysis, data on patients treated with olaparib for ovarian or endometrial cancer were collected to evaluate the Common Terminology Criteria for Adverse Events (CTCAE) or monthly changes in folate or vitamin B12 levels from baseline to 3 months after olaparib initiation. These data were collected between initiation of olaparib and discontinuation of olaparib or till November 2022. Patients with no data on folic acid or vitamin B12 levels were excluded from the sub-study. In the main study, 40 patients were included. Eighteen patients (45%) developed grade ≥ 3 anemia, and all patients discontinued treatment (94%) or reduced olaparib dose (67%) after developing anemia. Among the patients with grade ≥ 3 anemia, 9 (50%) exhibited macrocytic anemia and 15 (83%) had previously received carboplatin. The incidence of grade ≥ 2 dysgeusia was significantly higher in patients with grade ≥ 3 anemia (P = .034). Moreover, the cumulative dose of previously administered carboplatin was higher in patients who had 3 episodes of anemia (P = .102). In sub-study, 12 had data on folic acid and vitamin B12 levels. Sub-study analysis showed that none fulfilled the criteria for deficiency of folate or vitamin B12, while 3 developed grade 3 anemia. This study revealed that olaparib-induced anemia frequently occurs as macrocytic and normocytic erythroblastic anemia without folate or vitamin B12 deficiencies. A high cumulative dose of previously administered carboplatin and dysgeusia may be associated with olaparib-induced anemia.

Mental distress, quality of life and physical symptoms in Chinese women with ovarian cancer receiving olaparib treatment during the COVID-19 pandemic.

ObjectivesWomen with ovarian cancer (OC) have experienced unprecedented challenges since the novel coronavirus disease-2019 (COVID-19) outbreak in China. We aim to evaluate the experience of psychological status, physical symptoms and quality of life (QoL) and investigate the impact of COVID-19 pandemic on OC patients receiving olaparib.MethodsThe survey was conducted online from April 22 to May 12 in 2020. Demographic and clinical questions were listed to collect general information. The degree of insomnia, depression, anxiety, stress symptoms and QoL were assessed by the Chinese versions of the Insomnia Severity Index, the Patient Health Questionnaire-9, the Generalized Anxiety Disorder-7, the Impact of Event Scale-Revised, and the General Functional Assessment of Cancer Therapy, respectively. Multivariate logistic regression analysis was conducted to analyze the risk factors for mental distress and QoL.ResultsA total of 56 respondents coming from 15 various provinces in China participated in the survey. The prevalence of insomnia, depressive, anxiety, stress symptoms and reduced QoL were 37.5, 51.8, 37.5, 30.4, and 51.8%, respectively. Unfavorable disease status, shorter period of olaparib administration, adverse events of olaparib and delay in cancer care were correlated with mental health problems. Reduced QoL was also significantly associated with psychological distress.ConclusionsThis study emphasized that mental health problems and reduced QoL should gain more attention in women with OC who are receiving oral olaparib at home. Appropriate psychological healthcare strategies are necessary for OC patients during the COVID-19 pandemic.

Expression of MUS81 Mediates the Sensitivity of Castration-Resistant Prostate Cancer to Olaparib.

This project attempts to clarify the expression of MUS81 in castration-resistant prostate cancer (CRPC) and the effect on drug sensitivity to Olaparib. We collected clinical surgical samples of patients who were suffering from benign prostatic hyperplasia (BPH), common prostate cancer (PCa), and castration-resistant prostate cancer (CRPC) and detected the expression of MUS81 in healthy prostate epithelial cells, PCa cells, and androgen-independent PCa cells. We subsequently performed CCK-8 assays, flow cytometry, and Transwell invasion and migration assay to determine the proliferation, apoptosis, invasion, and metastasis abilities of transfected CRPC cells as well as drug toxicity of Olaparib to CRPC cells. The expression of MUS81 indicated marked upregulation in PCa and CRPC tissues, compared with the level of MUS81 in BPH tissues. MUS81 silencing inhibited the proliferation of CRPC cells and promoted their sensitivity to Olaparib. MUS81 silencing in CRPC cells remarkably accelerated cell apoptosis and greatly inhibited cell invasion and metastasis after Olaparib administration. MUS81 silencing in CRPC cells has significantly enhanced the sensitivity of cells to Olaparib, which provides evidence for the prediction of Olaparib resistance in CRPC cells by the MUS81 gene and is expected to become a promising gene target in CRPC therapy.

Abstract CT562: PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of Olaparib to Platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients

Abstract Background: Triple Negative Breast Cancers (TNBC) are a biologically diverse and aggressive subgroup lacking targeted therapy. TNBC and Germline BRCA (gBRCA) breast cancer share certain phenotypic and molecular similarities, with gBRCA mutations seen in 10% to 20% of TNBC patients. Homologous recombination deficient tumours, especially those caused by germline or somatic BRCA mutations, are thought to be particularly sensitive to PARP inhibitors. Aim: To establish if the addition of Olaparib to neoadjuvant Platinum-based chemotherapy in the treatment of basal TNBC and/or gBRCA breast cancer is safe and increases efficacy. Trial design: 3-stage open label randomised phase II/III trial of neoadjuvant Paclitaxel and Carboplatin +/- Olaparib, followed by clinicians' choice of Anthracycline regimen. Stages 1 and 2: Randomisation (1:1:1) to control (3-weekly carboplatin AUC5/weekly with paclitaxel 80mg/m2 for 4 cycles), or to one of two research arms. These use an identical chemotherapy regimen and also include different treatment schedules of Olaparib 150mg BD for 12 days. Stage 3: Randomisation (1:1) to either the control or research arm chosen following stage 2. End-points: Stage 1: Safety; Stage 2: Schedule selection based on pCR rate and Olaparib completion rate using a “pick-the-winner” design. Stage 3: pCR rate. This trial includes an optional pathway (PARTNERING) for patients with evidence of residual disease after six chemotherapy cycles. This aims to establish if the addition of new agents (ATR inhibitor and PD-L1 inhibitor) improves treatment response. Eligibility criteria: Aged 16-70; histologically confirmed invasive breast cancer; ER-negative, HER2-negative with TNBC basal phenotype or gBRCA positive, HER2-negative irrespective of hormone status; stage T1-4 N0-2; performance status 0-1; treatment within 6 weeks of diagnostic biopsy; biomarker scores: TILs, CK 5/6, EGFR +/- AR. Statistical methods: The recruitment of TNBC non-gBRCA and gBRCA patients is independent. Enrichment design is applied with an overall significance level 0.05(α) and 80% power. A minimum of 780 patients will be included to detect an absolute improvement of 15% (all patients and TNBC non-gBRCA cohort) and 20% (gBRCA patients) by combining Olaparib with Platinum based chemotherapy. A minimum of 478 TNBC non-gBRCA and 188 gBRCA patients will be recruited. Each PARTNERING cohort will consist of 15 patients. Current Enrollment: Since May 2016, 756 patients from 30 sites have been enrolled. Stages 1 and 2 are completed. An IDSMC review identified no safety concerns and Research Arm 2 was selected. This arm involves Olaparib administration on days 3-14. Stage 3 Phase I (recruitment of non-gBRCA and gBRCA patients) completed in December 2021. Stage 3 Phase II (recruitment of gBRCA patients only) remains open to patients to UK and internationally. 5 patients have been enrolled in PARTNERING. ClinicalTrials.gov Identifier: NCT03150576 Citation Format: Lynsey Drewett, Karen A. Pinilla, Louise Grybowicz, Jerome Wulff, Alimu Dayimu, Nikolaos Demiris, Rebecca Lucey, Anne-Laure Vallier, Wendi Qian, Andrea Machin, PARTNER Research Team, Karen McAdam, Rebecca Roylance, Ellen R. Copson, Anne Armstrong, Nicola Levitt, Elena Provenzano, Marc Tischkowitz, Emma McMurtry, Helena Earl, Jean E. Abraham. PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of Olaparib to Platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT562.

PARTNER: A randomized, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in patients with triple-negative and/or germline BRCA-mutated breast cancer.

TPS619 Background: Triple negative breast cancers (TNBCs) are a biologically diverse and aggressive subgroup lacking targeted therapy. TNBC and germline BRCA (gBRCA) breast cancer share certain phenotypic and molecular similarities, with gBRCA mutations seen in 10% to 20% of TNBC patients. Homologous recombination-deficient tumors, especially those caused by germline or somatic BRCA mutations, are thought to be particularly sensitive to PARP inhibitors. Methods: This is a 3-stage open-label randomized phase II/III trial of neoadjuvant paclitaxel and carboplatin +/- olaparib, followed by clinicians' choice of anthracycline regimen. The aim is to establish whether the addition of olaparib to neoadjuvant platinum-based chemotherapy in the treatment of basal TNBC and/or gBRCA breast cancer is safe and increases efficacy. In stages 1 and 2, all patients receive 4 cycles of 3-weekly carboplatin AUC5/weekly paclitaxel 80mg/m2. They are randomly assigned 1:1:1 to a control arm, or to one of two research arms. These research arms include different treatment schedules of olaparib 150 mg BD for 12 days. In stage 3, patients are randomly assigned 1:1 to either the control or research arm chosen following stage 2. The primary endpoints are: Stage 1: Safety; Stage 2: Schedule selection based on pCR rate and olaparib completion rate using a “pick-the-winner” design. Stage 3: pCR rate. Key eligibility criteria are age 16-70; histologically confirmed invasive breast cancer; ER-negative, HER2-negative with TNBC basal phenotype or gBRCA positive, HER2-negative irrespective of hormone status; stage T1-4 N0-2; performance status 0-1; treatment within 6 weeks of diagnostic biopsy; biomarker scores: TILs, CK 5/6, EGFR +/- AR. The recruitment of TNBC non-gBRCA and gBRCA patients is independent. Enrichment design is applied with an overall significance level 0.05(α) and 80% power. A minimum of 780 patients will be included to detect an absolute improvement of 15% (all patients) and 20% (gBRCA patients) by combining olaparib with platinum-based chemotherapy. This trial includes an optional pathway called PARTNERING for patients with residual disease after six chemotherapy cycles. This aims to establish if adding new agents (ATR inhibitor and PD-L1 inhibitor) improves treatment response. Each cohort will consist of 15 patients. Since May 2016, 756 patients from 30 sites have been enrolled. An IDSMC review following stages 1 and 2 identified no safety concerns and Research Arm 2 was selected (olaparib administration on days 3-14). Stage 3 phase I (recruitment of non-gBRCA and gBRCA patients) completed December 2021. Stage 3 phase II (recruitment of gBRCA patients) remains open to patients in the U.K. and internationally. 5 patients have enrolled in PARTNERING. Follow-up duration is 10 years. Clinical trial information: NCT03150576.

Abstract P2-13-18: Activity and tolerability of combination of trastuzumab deruxtecan with olaparib in preclinical HER2+ and HER2-low breast cancer models

Abstract Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor approved for HER2+ metastatic breast and gastric cancer. Clinically, T-DXd has demonstrated antitumor activity in both HER2+ and HER2-low cancers. PARP performs a key role as a mediator in the resolution of topoisomerase1 cleavage complexes (TOP1cc) through recruitment of tyrosyl-DNA phosphodiesterase 1 (TDP1). We hypothesized that combination of T-DXd with the PARP1/2 inhibitor olaparib, will halt the resolution of TOP1cc and enhance the activity of T-DXd. Methods: To test the hypothesis, we evaluated the antiproliferative ability of the combination of T-DXd with olaparib in a panel of 27 breast cancer cell lines in an in vitro 7-day viability assay. The combination was also evaluated in vivo in two non-HRD models, a HER2+ (KPL4) and HER2-low (JIMT1) cell line xenograft at 3mg/kg and 10mg/kg Q3W for T-DXd, as well as 100mg/kg BID of olaparib. To evaluate the specificity of the combination activity in tumor cells (vs normal tissue), we further evaluated the combination in a human 2D in vitro bone marrow progenitor assay. Results: We found that the combination had enhanced in vitro cell killing activity over single agents in 8/27 of the models tested. The benefit was present in both Homologous Repair Deficient (HRD) as well as wild-type models, suggesting it does not depend on HRD (as defined by mutations in DNA damage repair genes). In vivo, the combination was more active than monotherapy of either compound in both KPL4 (28d TGI of 76% with T-DXd, olaparib 17% TGI, and T-DXd + olaparib 94.4% TGI; p=0.009) and JIMT1 (28d TGI of 80.8% with T-DXd, olaparib 52%, and T-DXd + Olaparib 88.1%; p=0.03). In the in vitro human bone marrow assay, the combination demonstrated modest enhancement over monotherapy activity (average Loewe Synergy Score of 2.5). To explore the ability to optimize therapeutic index, we tested alternative doses and schedules of the combination in vivo. Specifically, we tested whether lower doses of T-DXd or delayed administration of olaparib would provide greater activity. We found that combination of 3mg/kg of T-DXd with olaparib provided greater activity in KPL4 xenograft model than 3mg/kg T-DXd alone (69% TGI for combination vs. 35% TGI for monotherapy on d28), but this was no greater than high dose 10mg/kg monotherapy T-DXd (76% TGI on d28; p=0.19). Interestingly, 7-day delay of olaparib in combination with 10mg/kg T-DXd provided greater activity (91% TGI on d28) than monotherapy T-DXd or olaparib alone (76% TGI and 17% TGI on d28, respectively). Conclusions: These results suggest that T-DXd combined with olaparib is a potentially active combination in breast cancer, with preclinical activity demonstrated in HRD and non-HRD models. Citation Format: Theresa Proia, Yann Wallez, Azadeh Cheraghchi Bashi, Zena Wilson, Suzanne Randle, Mark Anderton, Danielle Carroll, Zeshaan Rasheed, J. Elizabeth Pease, Elisabetta Leo, Jerome Mettetal. Activity and tolerability of combination of trastuzumab deruxtecan with olaparib in preclinical HER2+ and HER2-low breast cancer models [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-18.

KDM6 Demethylases Integrate DNA Repair Gene Regulation: Loss of KDM6A Sensitizes AML to PARP Inhibition and Potentiates with BCL2 Blockade

Acute myeloid leukemia (AML) is a heterogeneous, aggressive hematological malignancy with dismal prognosis where limited targeted therapies are currently available. Poly-(ADP-ribose)-polymerase (PARP) inhibition has emerged as an important therapeutic arsenal to target homologous recombination-deficient tumors. However, molecular understanding of PARP blockade in the context of epigenetic derangements and transcriptional plasticity in human elderly AML pathogenesis remains unexplored. KDM6 proteins are H3K27 demethylases that critically regulate chromatin architecture in multi-cellularity and tumorigenesis (Tran, Mol Cell Biol 2020). KDM6A escapes X-chr inactivation, and Utx-/- female mice spontaneously develop aging associated myeloid leukemia (Gozdecka, Nat Genet 2018; Sera, Blood 2021). In addition, KDM6A loss of function mutation is implicated in AML relapse (Stief, Leukemia 2020). In contrast, KDM6B primarily exerts an oncogenic function in heme-malignancies. Together, KDM6A and KDM6B play cell type-specific function in leukemia, and KDM6 proteins and associated signaling emerge as important focal point for developing molecular targeted therapy.We identify that KDM6 demethylase activity critically regulates DNA damage repair (DDR) gene expression program in AML. Transcriptome analysis indicated a significant downregulation of expression of DDR genesets in both KDM6A deficient human AML and Utx -/- pre-leukemic cells. Lentiviral shRNA screening performed in response to low-dose γ-irradiation in AML stem cells, revealed a radioprotective function of KDM6A. Expression of KDM6s is regulated by genotoxic stress in a time-dependent manner, and deficiency of JmjC catalytic function impaired DDR transcriptional activation and compromised repair potential. Mechanistically, quantitative ChIP experiments also revealed co-operation between KDM6A and SWI/SNF facilitating dynamic chromatin remodeling at TSS/promoter to induce DDR gene expression. To interrogate changes in chromatin accessibility we performed ATAC-seq analysis in KDM6 deficient AML. Motif enrichment highlighted that while KDM6A depletion led to reduced chromatin access to 140 transcription factors (TFs), only 56 TF binding sites showed increased accessibility. Overall, changes in chromatin accessibility, associated with a reduced binding of DDR regulatory TFs in KDM6 deficient AML, account for a compromised DDR function.In agreement with these findings an array of KDM6 deficient AML cells were more sensitive to PARP inhibition, and pre-clinical mice models xenotransplanted with KDM6A loss of function AML line showed an increased susceptibility to PARP blockade in vivo. FLT3-ITD positive AML with a lower KDM6A expression was more sensitive to olaparib. In addition, olaparib administration significantly reduced bone marrow engraftment of patient-derived xenografts of KDM6A-mutant primary AML. Interestingly, KDM6A expression is upregulated in venetoclax-resistant monocytic-AML compared to venet-sensitive primitive-AML. Using venet responsive isogenic lines we demonstrated that attenuation of KDM6 function increased mitochondrial activity, intracellular ROS levels, de-repressed BCL2 expression, and sensitized AML cells to venetoclax. Additionally, KDM6 loss resulted in transcriptional repression of BCL2A1, commonly associated with venet resistance (Zhang, Nat Cancer 2020). Corroborating these results, dual targeting of PARP with BCL2 was superior to PARP or BCL2 inhibitor monotherapy in inducing primary AML apoptosis, and KDM6A loss further enhanced this synergism.In sum, our study illustrates a molecular mechanistic rationale in support for a novel combination targeted therapy for AML, and posit KDM6A as a molecular determinant for therapeutic efficacy. Intriguingly, KDM6A functions as a gatekeeper of BCL2 and BCL2A1 expression. Similar to TET2 although bi-allelic Utx loss causes evolution to myeloid neoplasms, minimal KDM6 activity is important for survival of human AML cells. KDM6s have been implicated in solid tumors, and both PARP and BCL2 inhibitors are being tested in cancer patients, underscoring a wider scope of application. To conclude, KDM6A unfolds to be a central regulator for susceptibility of AML to both PARP and BCL2 inhibition, expanding the possibility to characterize effective combination targeted therapy for AML in clinical settings. DisclosuresMinden: Astellas: Consultancy. Dick: Celgene, Trillium Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Olaparib effectively treats local recurrence of extrahepatic cholangiocarcinoma in a patient harboring a BRCA2-inactivating mutation: a case report

Cholangiocarcinoma (CCA) is a malignant tumor with poor prognosis and high recurrence rate. There is no standard treatment for advanced CCA beyond first-line chemotherapy, which provides only limited benefits. In this study, we report a case of a postoperative recurrence ECC patient harboring a breast cancer 2 (BRCA2)-inactivating rearrangement mutation that had an obvious reaction to olaparib therapy. The patient was a 68-year-old man with postoperative recurrence of extrahepatic CCA (ECC) who declined systemic chemotherapy. In August 2015, abdominal computed tomography (CT) of the patient revealed intrahepatic bile duct dilatation, obstruction at the hepatic hilar region proximal to the common hepatic duct, and splenomegaly, and radical surgical resection was performed. Postoperative histopathology diagnosis was ECC without metastases. In February 2017, abdominal CT revealed local recurrence, and the patient refused chemotherapy. BRCA2 rearrangement were detected by next-generation sequencing. Oral administration of olaparib was initiated. The patient achieved stable disease 1 month later, progression-free survival for >10 months without any significant adverse reactions, and an overall survival (OS) of 27 months. This is the first report demonstrating the clinical benefits of olaparib in a BRCA2 rearrangement-harboring patient with ECC. This observation would help determine the best treatment option for advanced ECC patients.

Neoadjuvant chemoteraphy in unresectable ovarian cancer with olaparib and weekly carboplatin plus paclitaxel: a phase II, open label multicenter study (NUVOLA trial)

BackgroundNeoadjuvant chemotherapy with interval debulking surgery represents an alternative treatment for advanced ovarian cancer. Currently, there are few data about the use of poly adenosine diphosphate-ribose polymerase inhibitors in the...

Discovery of novel PARP/PI3K dual inhibitors with high efficiency against BRCA-proficient triple negative breast cancer.

Co-targeting PARP and PI3K by PARP/PI3K dual inhibitors has been recognized as a promising chemotherapeutic strategy for the treatment of triple negative breast cancer (TNBC) in our previous work. To further explore novel and more potent PARP/PI3K dual inhibitors, a series of compounds were designed, synthesized and evaluated for their pharmacological properties, resulting in the candidate compound 12, a potent and highly selective PARP/PI3K dual inhibitor. Compared to Olaparib, compound 12 exhibits a superior antiproliferative profile against BRCA-proficient MDA-MB-468cells. In MDA-MB-468 cell-derived xenograft model, compound 12 displayed excellent antitumor efficacy at a dose of 50mg/kg, which is considerably more efficacious than the single administration of Olaparib or BKM120. Furthermore, compound 12 displayed good metabolic stability and high safety. Taken together, these results suggest that compound 12 as a novel PARP/PI3K dual inhibitor is worthy for further study.

Similar Molecular Pattern in Therapy Related Acute Myeloid Leukemia in Patients Treated with Purp Inhibitors for Metastatic Ovarian Cancer

Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors exploit defects in DNA repair to induce tumor-selective damage, in fact PARP inhibition can lead to the accumulation of DNA double strand breaks in neoplastic cells sparing normal ones. Olaparib (AZD2281; KU-0059436) is a novel, orally active PARP inhibitor that induces synthetic lethality in homozygous BRCA-deficient cells. It is indicated for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy. Overall in clinical trials, the incidence of Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) in patients treated with Olaparib monotherapy, including long-term follow up, was &amp;lt;1.5% and the majority of events had a fatal outcome. The duration of therapy with Olaparib in patients who developed secondary MDS/cancer-therapy related AML varied from &amp;lt; 6 months to &amp;gt; 2 years. All of these patients had received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy. Here we describe 5 consecutive patients affected by metastatic ovarian cancer BRCA+ treated after chemotherapy with PURPi who developed therapy-related AML (sAML) in our center in a short period between June 2019 and July 2020. Patients'characteristics: Median age at ovarian cancer diagnosis was 49y (range 45-53), the median number of chemotherapy lines before PURPi treatment was 4 (range 3-5), the median interval between PURPi treatment and the onset of sAML was 22 months (range 18-24). Four out of 5 patients were submitted to Olaparib administration and one to Niraparib. At the onset of cytopenia all patients were submitted to bone marrow aspiration, molecular and cytogenetic tests; in all cases the diagnosis was of sAML according to WHO classification. Cytogenetic analysis was not evaluable in 1 out 5 patients, in the other cases we discovered: 1) a complex karyotype including chromosome 17 deletion, 2) -5q and -7q, 3) -5q and 4) normal karyotype. None of them had recurrent molecular alterations including NPM1 mutations or FLT3-ITD, but when we analysed subclonal mutations we found that in 4 of them TP53 mutations were recurrent (1 one patient'analysis is still ongoing). We found the following TP53 mutations: c.376-1G&amp;gt;A (splice acceptor), c.78delT, c.524G&amp;gt;A (in two patients). The median variant allelic frequency was 25%. In two of them we were able to study the ovarian tissue collected at cancer diagnosis and the TP53 mutations were not present. This is the first report which describes subclonal mutations in sAML developing after PURP inhibitor therapy In conclusion therapy-related AML is a well described complication of chemotherapy and our patients had exposure to chemotherapy and therefore had higher risk for developing leukemia from exposure to chemotherapy and PARP inhibitors. In the natural history of the ovarian cancer, patients might be exposed to leukemogenic therapies which may have an additive effect and increase the risk of developing AML during PURP inhibitors' therapy. Molecular mechanism undergoing this complications, including mutations of TP53, should be further investigated. Disclosures Sica: F. Hoffmann-La Roche Ltd:Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding.

Modulation of Inflammasome and Pyroptosis by Olaparib, a PARP-1 Inhibitor, in the R6/2 Mouse Model of Huntington's Disease.

Pyroptosis is a type of cell death that is caspase-1 (Casp-1) dependent, which leads to a rapid cell lysis, and it is linked to the inflammasome. We recently showed that pyroptotic cell death occurs in Huntington’s disease (HD). Moreover, we previously described the beneficial effects of a PARP-1 inhibitor in HD. In this study, we investigated the neuroprotective effect of Olaparib, an inhibitor of PARP-1, in the mouse model of Huntington’s disease. R6/2 mice were administered Olaparib or vehicle from pre-symptomatic to late stages. Behavioral studies were performed to investigate clinical effects of the compound. Immunohistochemical and Western blotting studies were performed to evaluate neuroprotection and the impact of the compound on the pathway of neuronal death in the HD mice. Our results indicate that Olaparib administration starting from the pre-symptomatic stage of the neurodegenerative disease increased survival, ameliorated the neurological deficits, and improved clinical outcomes in neurobehavioral tests mainly by modulating the inflammasome activation. These results suggest that Olaparib, a commercially available drug already in use as an anti-neoplastic compound, exerts a neuroprotective effect and could be a useful pharmaceutical agent for Huntington’s disease therapy.