piperidines and Carcinoma--Ovarian-Epithelial

The standard of care for newly diagnosed advanced ovarian cancer is surgical cytoreduction plus platinum-based chemotherapy; however, recurrent disease frequently occurs after treatment. Poly(ADP-ribose) polymerase (PARP) inhibitors as first-line maintenance therapy have been demonstrated to significantly reduce the risk of disease progression or death in patients with advanced ovarian cancer who have a complete or partial response to first-line platinum-based chemotherapy. Niraparib is the only PARP inhibitor that offers a significant progression-free survival benefit compared with placebo in this patient population regardless of the homologous recombination status. However, predictive factors for treatment responses and approaches to dose optimization remain to be investigated. In this study, two Chinese patients with newly diagnosed advanced ovarian cancer exhibited long-term responses to niraparib treatment, and hematological toxicity was successfully managed by dose adjustment. The literature on clinical trials and real-world experience on the efficacy, tolerability, and dose individualization of niraparib treatment in Western and Chinese patients was also reviewed. Future research is warranted to identify the characteristics of 'long responders' to niraparib treatment.

Topics: Asian People; Carcinoma, Ovarian Epithelial; Female; Humans; Indazoles; Ovarian Neoplasms; Piperidines

Patients with epithelial ovarian cancer (EOC), treated with niraparib maintenance, present with haematological and gastrointestinal toxicities. Limited data exist on niraparib safety assessment.. To evaluate niraparib safety profile, as maintenance therapy, in women with platinum-sensitive EOC.. PubMed and Cochrane searches were carried out up to April 2021 for randomised controlled trials (RCTs) evaluating niraparib versus placebo in EOC patients with a response to platinum-based chemotherapy. Regarding the meta-analysis, for dichotomous data, the pooled risk ratio (RR) was calculated.. A total of 1539 patients from three RCTs revealed that niraparib-treated patients are associated with a significantly higher risk of any grade of nausea (RR, 2.15; 95% CI, 1.86 to 2.48), fatigue (RR, 1.26; 95% CI, 1.05 to 1.52,. Niraparib is considered an effective and well-tolerated choice, with an improved safety profile, for the maintenance treatment of EOC patients.

Topics: Carcinoma, Ovarian Epithelial; Female; Humans; Indazoles; Neoplasm Recurrence, Local; Ovarian Neoplasms; Piperidines

We reviewed clinical data for niraparib monotherapy in

Topics: Carcinoma, Ovarian Epithelial; Female; Humans; Indazoles; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Quality of Life

Niraparib (Zejula™) is a PARP inhibitor which is approved for maintenance therapy in adults with advanced ovarian cancer in complete or partial response to platinum-based chemotherapy. In a placebo-controlled phase III trial in patients with newly diagnosed advanced ovarian cancer, niraparib significantly extended progression free survival in two predefined populations, namely a patient population with altered homologous-recombination DNA repair pathways [i.e. homologous-recombination deficiency positive (HRd)] and the overall trial population. A prespecified exploratory subgroup analysis indicated that niraparib was also efficacious in patients who were homologous recombination deficiency negative or homologous recombination proficient (HRp). Niraparib has a manageable tolerability profile with myelosuppression as the main safety concern. Haematological reactions were managed with monitoring and dose reduction or interruption. A weight- and platelet count-based individualised dosage regimen introduced during the trial (and subsequently approved) appeared to improve haematological tolerability. Niraparib is a useful option for first-line maintenance therapy for advanced ovarian cancer in adults who responded to platinum-based chemotherapy, regardless of homologous-recombination deficiency status and is a promising option for HRp patients, for whom maintenance treatment options are limited.. In 2021, ovarian cancer is predicted to be responsible for ≈ 43,770 deaths in Europe and the USA combined. Niraparib (Zejula™) is a once-daily oral treatment for first-line maintenance therapy in adults with advanced ovarian cancer that is responsive to chemotherapy. Although other agents of the same drug class (e.g. olaparib) are only approved for use against tumours with compromised DNA repair mechanisms, niraparib is approved without this restriction. Niraparib reduced the risk of disease progression or death in patients with newly diagnosed ovarian cancer, irrespective of whether the patients had compromised or functional DNA repair mechanisms. Abnormal blood counts are the main safety concern with niraparib, though adverse drug reactions may be managed through monitoring and interrupting or decreasing the dosage. Starting treatment at a personalised lower dosage may also reduce the likelihood of adverse drug reactions. Niraparib is a useful option for first-line maintenance therapy for advanced ovarian cancer, regardless of the patient's DNA repair mechanisms, and is a promising option for patients with functional DNA repair mechanisms, a group for which maintenance treatment options are limited.

Topics: Adult; Carcinoma, Ovarian Epithelial; Female; Humans; Indazoles; Maintenance Chemotherapy; Ovarian Neoplasms; Piperidines

In early stages, standard treatment is adjuvant chemotherapy, consisting of platinum-based combination for 6 cycles, especially in serous and endometrioid high grade carcinomas. In advanced stages, indication of neoadjuvant chemotherapy must be discussed on a case-by-case basis in multidisciplinary meetings (MDM). Bevacizumab can also be considered in the neoadjuvant setting in some circumstances, always after discussion in MDM. Carboplatin plus paclitaxel every 21 days, with or without bevacizumab remains the standard of care for first-line chemotherapy. Inhibitors of poly-(ADP-riboses) polymerases (PARPi) have been approved and are reimbursed as maintenance monotherapy in tumors carrying BRCA1 or BRCA2 mutation after complete or partial response to chemotherapy. Two recent studies demonstrated the efficacy of PARPi on progression free survival, one for niraparib single-agent in patients with high-grade ovarian carcinoma regardless of BRCA status, the other one for the combination of bevacizumab and olaparib in patients with high grade carcinoma, with positive test for homologous recombination DNA repair deficiency (regardless of BRCA status). These two new modalities of maintenance therapy are now available in compassionate use programs or post compassionate use programs. Depending on pending decisions upon reimbursement, these indications might be somewhat modified.

Topics: Algorithms; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carboplatin; Carcinoma, Ovarian Epithelial; Chemotherapy, Adjuvant; Drug Administration Schedule; Female; Genes, BRCA1; Genes, BRCA2; Humans; Indazoles; Maintenance Chemotherapy; Neoadjuvant Therapy; Neoplasm Grading; Neoplasm Staging; Ovarian Neoplasms; Paclitaxel; Phthalazines; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors

The standard treatment for advanced ovarian cancer is cytoreductive surgery followed by cytotoxic chemotherapy. However, it has high risk of recurrence and poor prognosis. Poly(ADPribose) polymerase (PARP) inhibitors selectively target DNA double-strand breaks (DSBs) in tumor cells that cannot be repaired and induce the synthetic lethality of BRCA1/2 mutation cancers. PARP inhibitors are clinically used to treat recurrent ovarian cancer and show significant efficacy in ovarian cancer patients with homologous recombination repair (HRR) pathway defects. PARP inhibitors also have significant clinical benefits in patients without HR defects. With the increasingly extensive clinical application of PARP inhibitors, the possibility of acquiring drug resistance is high. Therefore, clinical strategies should be adopted to manage drug resistance of PARP inhibitors. This study aims to summarize the indications and toxicity of PARP inhibitors, the mechanism of action, targeted treatment of drug resistance, and potential methods to manage drug-resistant diseases. We used the term "ovarian cancer" and the names of each PARP inhibitor as keywords to search articles published in the Medical Subject Headings (MeSH) on Pubmed, along with the keywords "clinicaltrials.gov" and "google.com/patents" as well as "uspto.gov." The FDA has approved olaparib, niraparib, and rucaparib for the treatment of recurrent epithelial ovarian cancer (EOC). Talazoparib and veliparib are currently in early trials and show promising clinical results. The mechanism underlying resistance to PARP inhibitors and the clinical strategies to overcome them remain unclear. Understanding the mechanism of resistance to PARP inhibitors and their relationship with platinum resistance may help with the development of antiresistance therapies and optimization of the sequence of drug application in the future clinical treatment of ovarian cancer.

Topics: Antineoplastic Agents; Benzimidazoles; BRCA1 Protein; BRCA2 Protein; Carcinoma, Ovarian Epithelial; DNA Repair; Drug Resistance, Neoplasm; Female; Humans; Indazoles; Indoles; Neoplasm Recurrence, Local; Ovarian Neoplasms; Phthalazines; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases

To summarize the data supporting the use of maintenance therapy in ovarian cancer treatment.. Since December 2016, the United States Food and Drug Administration has approved four drugs for six different ovarian cancer maintenance indications based on the results of clinical trials demonstrating efficacy and tolerability. These include antiangiogenesis and poly (adenosine diphosphate-ribose) inhibitors (PARP inhibitors). Four drugs are approved for use in maintenance therapy for recurrent ovarian cancer, including bevacizumab (GOG-0213 and OCEANS), niraparib (NOVA), olaparib (Study 19 and SOLO2) and rucaparib (ARIEL3). Two drugs are approved for use in maintenance therapy in newly diagnosed ovarian cancer, including bevacizumab (GOG-0218) and olaparib (SOLO1). New data were reported at the European Society for Medical Oncology Congress in October 2019 that may lead to the approval of additional strategies in front-line maintenance, including the use of niraparib (PRIMA), veliparib (VELIA) and bevacizumab + olaparib (PAOLA).. The landscape of maintenance treatment options for ovarian cancer has been rapidly expanding and continues to evolve as new data emerge. Currently approved strategies include antiangiogenesis and PARP inhibitor treatments.

Topics: Angiogenesis Inhibitors; Bevacizumab; Carcinoma, Ovarian Epithelial; Female; Humans; Indazoles; Indoles; Neoplasm Recurrence, Local; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Randomized Controlled Trials as Topic

To review the efficacy and safety of niraparib for the treatment of recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer (OC, FTC, and PPC).. A literature search via MEDLINE through PubMed from August 2013 to January 2020 was performed using the key terms. Completed and ongoing trials were identified through a review of the website trial registry https://www.clinicaltrials.gov.. In a phase III, double-blind clinical trial, progression-free survival improved in patients treated with niraparib compared with placebo as maintenance treatment for patients with platinum-sensitive, recurrent OC: 21 versus 5.5 months in the germline breast cancer susceptibility gene (. Poly (ADP-ribose) polymerase (PARP) inhibitors have gained a place in the therapeutic management of OC, FTC, and PPC because of their ability to suppress growth of homologous recombination deficiency-positive tumors, including those with. PARP inhibitors can be used as a single agent for maintenance therapy for platinum-sensitive recurrent disease in patients with partial or complete response following 2 or more rounds of platinum-based therapy.

Topics: Carcinoma, Ovarian Epithelial; Clinical Trials, Phase III as Topic; Fallopian Tube Neoplasms; Female; Humans; Indazoles; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms; Peritoneal Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival

Niraparib is an oral poly(ADP ribose) polymerase (PARP) inhibitor that is currently approved by the United States Food and Drug Administration (US FDA) as well as recently approved by the European Medicines Agency (EMA) for the maintenance treatment of women with recurrent ovarian cancer who are in complete or partial response to platinum-based chemotherapy. The mechanisms of action of niraparib include inhibition of PARP enzymatic activity as well as increased formation of PARP-DNA complexes through "trapping" the PARP enzyme on damaged DNA. Phase I and III studies have demonstrated activity and benefit of niraparib in both BRCA mutated (BRCAm) and BRCA wild-type (BRCAwt) cancers. Phase I testing of niraparib established the maximally tolerated dose of 300mg by mouth (PO) daily, and the phase 3 ENGOT-OV16/NOVA study demonstrated the benefit of niraparib maintenance therapy compared to placebo after completion of and response to platinum-based chemotherapy in both BRCAm and BRCAwt ovarian cancer patient populations. Toxicities seen with niraparib include hematologic, gastrointestinal, fatigue, and cardiovascular. Hematologic toxicities include thrombocytopenia, anemia, neutropenia and leukopenia; upfront dose modification to 200mg niraparib for patients with baseline weight of ≤77kg and/or baseline platelets of ≤150,000K/uL should be considered to avoid significant hematologic toxicity, especially thrombocytopenia, based on recent analyses of the ENGOT-OV16/NOVA study. Cardiovascular toxicities include hypertension, tachycardia, as well as palpitations, and patients should be monitored for hypertension. PARP inhibitors have been associated with low risks of acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), and the overall risk of AML and MDS is 0.9% of all patients treated with niraparib. Niraparib testing is ongoing in newly diagnosed ovarian cancer patients as maintenance therapy following completion of platinum-based chemotherapy, in BRCAwt cancers as treatment, as well as in combinations with other biologic drugs such as immunotherapy and anti-angiogenic agents.

Topics: Carcinoma, Ovarian Epithelial; Clinical Trials as Topic; Female; Humans; Indazoles; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors

Ovarian cancer is a disease with a propensity to recur despite dramatic responses to initial treatment, which typically consists of a combination of cytoreductive surgery and platinum-based chemotherapy. A maintenance therapy, which may prevent or delay relapse while not negatively impacting quality of life, is critical to improving outcomes. Areas covered: This review discusses the pharmacologic properties, clinical efficacy, and safety profile of niraparib, a poly(ADP-ribose) polymerase (PARP) inhibitor indicated for the maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. Expert opinion: Following presentation of ENGOT-OV16/NOVA at the European Society for Medical Oncology (ESMO) 2016 Congress, niraparib became the first PARP inhibitor to receive full approval by the U.S. Food and Drug Administration (FDA) for the maintenance treatment of recurrent ovarian cancer, regardless of a patient's germline or somatic mutational status. This approval has had a sweeping impact on treatment strategies, moving the indication for a PARP inhibitor earlier in the treatment course and greatly expanding the population of patients who may benefit from this class of drugs. Active clinical trials suggest that new indications and novel treatment combinations are eagerly sought.

Topics: Animals; Antineoplastic Agents; Carcinoma, Ovarian Epithelial; Fallopian Tube Neoplasms; Female; Humans; Indazoles; Neoplasm Recurrence, Local; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Peritoneal Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Quality of Life

Epithelial ovarian cancer (EOC) remains a leading cause of cancer death in women. Approximately 10-15% of patients with EOC harbor a genetic predisposition due to mutations in BRCA1/2 genes. In the recurrent setting, prolonging time to platinum-resistance may improve progression-free survival. In BRCA1/2 mutated ovarian cancer, the use of a polyadenosine diphosphate-ribose polymerase inhibitors has been studied in the maintenance and recurrent setting. In the pivotal Phase III NOVA trial, maintenance therapy post platinum response with niraparib significantly improved outcomes in all subgroups, leading to the first polyadenosine diphosphate-ribose polymerase inhibitors approval by the US FDA in this setting. In this review, we will focus on the role of niraparib in the treatment of EOC.

Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Ovarian Epithelial; Female; Genes, BRCA1; Genes, BRCA2; Humans; Indazoles; Mutation; Neoplasm Recurrence, Local; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors

Use of poly(ADP-ribose) polymerase (PARP) inhibitors has greatly increased over the past 5 years. With several new Food and Drug Administration (FDA) approvals, three PARP inhibitors have entered into standard of care treatment for epithelial ovarian cancer (including ovarian, fallopian tube, and primary peritoneal cancer). Olaparib and rucaparib currently have indications for treatment of recurrent BRCA mutant ovarian cancer. Olaparib, rucaparib, and niraparib all have indications for maintenance therapy in recurrent platinum-sensitive ovarian cancer after response to platinum-based therapy. In our practice, we use both olaparib and rucaparib in the recurrent setting, and all three PARP inhibitors in the maintenance setting. Choice of which PARP inhibitor to use in either setting is largely based upon baseline laboratory values, number of prior therapies, and presence of a BRCA mutation and/or homologous recombination deficiency (HRD). As (HRD) and other biomarker assessments continue to improve, we anticipate being able to better identify which patients might most benefit from PARP inhibitor therapy in the future. The clinically available PARP inhibitors are currently undergoing extensive investigations in clinical trials. Other newer agents such as talazoparib, veliparib, 2X-121, and CEP-9722 are in earlier stages of development. As more FDA-approved indications for PARP inhibitor therapy in ovarian cancer become available, we anticipate the decision of which PARP inhibitor to use will become increasingly complex.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; BRCA1 Protein; BRCA2 Protein; Carbazoles; Carcinoma, Ovarian Epithelial; Female; Humans; Indazoles; Indoles; Neoplasm Recurrence, Local; Ovarian Neoplasms; Ovary; Phthalazines; Phthalimides; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors

Given the expanding clinical use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPis), there is a significant need for optimal strategies with which to treat patients whose cancer progresses while using a PARPi. However, the treatment consensus after PARPi has not been established. The aim of the Korean Gynecologic Oncology Group (KGOG) 3056/NIRVANA-R trial is to investigate the efficacy of niraparib in combination with bevacizumab as a maintenance therapy in platinum-sensitive ovarian cancer patients who were previously treated with a PARPi.. The KGOG 3056/NIRVANA-R is a multi-centre, investigator-initiated, single-arm, phase II trial of patients with platinum-sensitive recurrent ovarian cancer recruited from seven KGOG sites. This study included patients with platinum-sensitive recurrent epithelial ovarian cancer who received at least 2 previous courses of platinum-containing therapy and had been treated with a PARPi. Mucinous histology type was excluded. Patients who had responded to the last platinum regimen (either complete or partial response) were eligible to participate in this study. Forty-four patients will be recruited. All enrolled patients are treated with niraparib and bevacizumab for maintenance therapy until disease progression, unacceptable toxicity, or withdrawal of patient consent. The primary endpoint of the study is 6-month progression-free survival rate. Accrual is expected to be completed in 2022, followed by presentation of results in 2023.. ClinicalTrials.gov Identifier: NCT04734665.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Ovarian Epithelial; Female; Humans; Indazoles; Neoplasm Recurrence, Local; Ovarian Neoplasms; Piperidines; Platinum; Poly(ADP-ribose) Polymerase Inhibitors; Republic of Korea

To evaluate the association between surgical timing and postoperative residual disease status on the efficacy of niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer at high risk of recurrence.. Post hoc analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) study of niraparib in patients with newly diagnosed primary advanced ovarian, primary peritoneal, or fallopian tube cancer with a complete/partial response to first-line platinum-based chemotherapy. Progression-free survival (PFS) was assessed by surgical status (primary debulking surgery [PDS] vs neoadjuvant chemotherapy/interval debulking surgery [NACT/IDS]) and postoperative residual disease status (no visible residual disease [NVRD] vs visible residual disease [VRD]) in the intent-to-treat population.. In PRIMA (N = 733), 236 (32.2%) patients underwent PDS, and 481 (65.6%) received NACT/IDS before enrollment. Median PFS (niraparib vs placebo) and hazard ratios (95% CI) for progression were similar in PDS (13.7 vs 8.2 months; HR, 0.67 [0.47-0.96]) and NACT/IDS (14.2 vs 8.2 months; HR, 0.57 [0.44-0.73]) subgroups. In patients who received NACT/IDS and had NVRD (n = 304), the hazard ratio (95% CI) for progression was 0.65 (0.46-0.91). In patients with VRD following PDS (n = 183) or NACT/IDS (n = 149), the hazard ratios (95% CI) for progression were 0.58 (0.39-0.86) and 0.41 (0.27-0.62), respectively. PFS was not evaluable for patients with PDS and NVRD because of sample size (n = 37).. In this post hoc analysis, niraparib efficacy was similar across PDS and NACT/IDS subgroups. Patients who had NACT/IDS and VRD had the highest reduction in the risk of progression with niraparib maintenance.

Topics: Carcinoma, Ovarian Epithelial; Chemotherapy, Adjuvant; Cytoreduction Surgical Procedures; Female; Humans; Indazoles; Neoadjuvant Therapy; Neoplasm Staging; Neoplasm, Residual; Ovarian Neoplasms; Piperidines

Platinum based chemotherapy is the treatment of choice for ovarian cancer patients with a platinum treatment free interval of >6 months. Niraparib is an oral poly (ADP-ribose) polymerase inhibitor approved as maintenance therapy after a response to platinum rechallenge, regardless of BRCA status. Atezolizumab is a humanized monoclonal antibody targeting programmed death-ligand 1 (PD-L1). A combination of poly (ADP-ribose) polymerase inhibitor and anti-PD-L1/programmed cell death protein 1 (PD-1) has shown synergy in preclinical models and promising clinical activity.. To determine whether the addition of atezolizumab to carboplatin based chemotherapy and to subsequent maintenance with niraparib improves progression free survival compared with placebo in patients with recurrent disease and a platinum treatment free interval of >6 months.. The Atezolizumab and NIraparib Treatment Association (ANITA) trial is a GEICO (Grupo Español de Investigación en Cáncer de Ovario) led phase III, randomized, double-blinded, multicenter European Network for Gynecological Oncological Trials (ENGOT) study. Patients will be randomized to arm A (control arm) consisting of platinum based chemotherapy (investigator's choice) plus a placebo of atezolizumab followed by maintenance niraparib plus a placebo of atezolizumab, or to arm B (experimental arm) consisting of platinum based chemotherapy (investigator's choice) plus atezolizumab followed by maintenance niraparib plus atezolizumab.. Inclusion criteria are women aged over 18 years, diagnosed with relapsed high grade serous, endometrioid, or undifferentiated ovarian, fallopian tube, or primary peritoneal carcinoma. Patients are eligible if they received no more than two previous lines of chemotherapy, relapsed ≥6 months after the last platinum containing regimen, and have at least one measurable lesion according to the response evaluation criteria in solid tumors, version 1.1.. The primary endpoint for this study is progression free survival.. Approximately 414 patients will be recruited and randomized in a 1:1 ratio, with the aim of demonstrating a benefit in progression free survival for the experimental arm with a hazard ratio of O.7, using a two sided alpha of 0.05 and a power of 80%.. The trial was launched in the fourth quarter of 2018 and is estimated to close in the second quarter of 2021. Mature results for progression free survival are expected to be presented by 2023.. Clinicaltrials.gov NCT03598270.

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Ovarian Epithelial; Double-Blind Method; Fallopian Tube Neoplasms; Female; Humans; Indazoles; Peritoneal Neoplasms; Piperidines; Platinum; Progression-Free Survival; Time Factors

Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor approved for use in heavily pretreated patients and as maintenance treatment in patients with newly-diagnosed or recurrent ovarian cancer following a response to platinum-based chemotherapy. We present long-term safety data for niraparib from the ENGOT-OV16/NOVA trial.. This multicenter, double-blind, randomized, controlled phase III trial evaluated the efficacy and safety of niraparib for the treatment of recurrent ovarian cancer. Patients were randomly assigned 2:1 to receive either once-daily niraparib 300 mg or placebo. Two independent cohorts were enrolled based on germline BRCA mutation status. The primary endpoint was progression-free survival, reported previously. Long-term safety data were from the most recent data cutoff (September 2017).. Overall, 367 patients received niraparib 300 mg once daily. Dose reductions due to TEAEs were highest in month 1 (34%) and declined every month thereafter. Incidence of any-grade and grade ≥ 3 hematologic and symptomatic TEAEs was also highest in month 1 and subsequently declined. Incidence of grade ≥ 3 thrombocytopenia decreased from 28% (month 1) to 9% and 5% (months 2 and 3, respectively), with protocol-directed dose interruptions and/or reductions. Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) were reported in 2 and 6 niraparib-treated patients, respectively, and in 1 placebo patient each. Treatment discontinuations due to TEAEs were <5% in each month and time interval measured.. These data demonstrate the importance of appropriate dose reduction according to toxicity criteria and support the safe long-term use of niraparib for maintenance treatment in patients with recurrent ovarian cancer.. ClinicalTrials.gov identifier: NCT01847274.

Topics: Carcinoma, Ovarian Epithelial; Double-Blind Method; Female; Humans; Indazoles; Maintenance Chemotherapy; Middle Aged; Neoplasm Recurrence, Local; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival

Anticancer drugs may cause cardiovascular toxicities, including QT interval prolongation. Niraparib, a potent and selective once-daily oral poly (ADP-ribose) polymerase inhibitor, is approved as a maintenance therapy in platinum-sensitive recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer (EOC). Here, we present the effects of niraparib on cardiac repolarization, and the correlation between changes in baseline QT interval corrected by Fridericia's formula (ΔQTcF) and niraparib plasma concentrations.. Patients with EOC from the NOVA study (subset of n = 15), the food effect NOVA substudy (n = 17), and a QTc substudy (n = 26) underwent intensive electrocardiographic (ECG) monitoring that included triplicate ECG testing on Day 1 at baseline (predose) and at 1, 1.5, 2, 3, 4, 6, and 8 h postdose concurrent with time-matched blood sampling for determination of niraparib plasma concentrations. All patients received once-daily 300-mg niraparib until disease progression or toxicity.. Across the 3 substudies, the upper limit of the two-sided 90% confidence interval (CI) of ΔQTcF was ≤ 10 ms at every postdose timepoint, with a maximum upper limit of 4.3 ms, which indicates no clinically meaningful effect on QTc prolongation. No statistically significant relationship between ΔQTcF and niraparib plasma concentration was observed (estimated slope: 0.0049; 95% CI: - 0.0020, 0.0117; P = 0.164). There were no clinically relevant changes in other ECG parameters that could be attributable to niraparib.. Niraparib administration at the recommended daily dose of 300 mg for EOC is not associated with clinically relevant alteration of ECGs, including QTc prolongation.

Topics: Aged; Carcinoma, Ovarian Epithelial; Cardiotoxicity; Double-Blind Method; Electrocardiography; Fallopian Tube Neoplasms; Female; Humans; Indazoles; Long QT Syndrome; Middle Aged; Peritoneal Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors

Late-line treatment options for patients with ovarian cancer are few, with the proportion of patients achieving an overall response typically less than 10%, and median overall survival after third-line therapy of 5-9 months. In this study (QUADRA), we investigated the activity of niraparib monotherapy as the fourth or later line of therapy.. QUADRA was a multicentre, open-label, single-arm, phase 2 study that evaluated the safety and activity of niraparib in adult patients (≥18 years) with relapsed, high-grade serous (grade 2 or 3) epithelial ovarian, fallopian tube, or primary peritoneal cancer who had been treated with three or more previous chemotherapy regimens. The study was done in the USA and Canada, and 56 sites screened patients (50 sites treated at least one patient). Patients received oral niraparib 300 mg once daily continuously, beginning on day 1 and every cycle (28 days) thereafter until disease progression. The primary objective was the proportion of patients achieving an investigator-assessed confirmed overall response in patients with homologous recombination deficiency (HRD)-positive tumours (including patients with BRCA and without BRCA mutations) sensitive to their last platinum-based therapy who had received three or four previous anticancer therapy regimens (primary efficacy population). Efficacy analyses were additionally done in all dosed patients with measurable disease at baseline.. Between April 1, 2015 and Nov 1, 2017, we screened 729 patients for eligibility and enrolled 463 patients, who were initiated on niraparib therapy. At the time of database lock (April 11, 2018), enrolment had closed and the study was ongoing, with 21 patients still on treatment. Patients had received a median of four (IQR 3-5) previous lines of therapy, and the median follow-up for overall survival was 12·2 months (IQR 3·7-22·1). 151 (33%) of 463 patients were resistant and 161 (35%) of 463 patients were refractory to the last administered platinum therapy. 13 (28%) of 47 patients in the primary efficacy population achieved an overall response according to RECIST (95% CI 15·6-42·6; one-sided p=0·00053). The most common drug-related grade 3 or worse treatment-emergent adverse events were anaemia (113 [24%] of 463 patients) and thrombocytopenia (95 [21%] of 463 patients). The most common treatment-emergent serious adverse events were small intestinal obstruction (34 [7%] of 463 patients), thrombocytopenia (34 [7%] of 463 patients), and vomiting (27 [6%] of 463 patients). One death due to gastric haemorrhage was considered treatment related.. We observed clinically relevant activity of niraparib among women with heavily pretreated ovarian cancer, especially in patients with HRD-positive platinum-sensitive disease, which includes not only patients with a BRCA mutation but also a population with BRCA wild-type disease. We identified no new safety signals. Our data support expansion of the treatment indication for poly(ADP-ribose) polymerase inhibitors to include patients with HRD-positive ovarian cancer beyond those with BRCA mutations.. Tesaro.

Topics: Adolescent; Adult; Aged; BRCA1 Protein; BRCA2 Protein; Canada; Carcinoma, Ovarian Epithelial; Fallopian Tube Neoplasms; Female; Humans; Indazoles; Middle Aged; Mutation; Ovarian Neoplasms; Peritoneal Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival; Time Factors; United States; Young Adult

Combining poly(ADP-ribose) polymerase (PARP) inhibitors with antiangiogenic agents appeared to enhance activity vs PARP inhibitors alone in a randomized phase II trial.. In AVANOVA (NCT02354131) part 1, patients with measurable/evaluable high-grade serous/endometrioid platinum-sensitive ovarian cancer received bevacizumab 15 mg/kg every 21 days with escalating doses of niraparib capsules (100, 200, or 300 mg daily) in a 3 + 3 dose-escalation design. Primary objectives were to evaluate safety and tolerability and to determine the recommended phase II dose (RP2D).. Three of 12 enrolled patients had germline BRCA2 mutations. In cycle 1, nine patients experienced grade 3 toxicities: five with hypertension, three with anemia, and one with thrombocytopenia. There was one dose-limiting toxicity (grade 4 thrombocytopenia with niraparib 300 mg), thus the RP2D was bevacizumab 15 mg/kg with niraparib 300 mg. The response rate was 50%; disease was stabilized in a further 42%. Median progression-free survival was 11.6 (95% confidence interval 8.4-20.1) months. Niraparib pharmacokinetics were consistent with historical single-agent data. Overlapping exposure was observed across the dose ranges tested on days 1 and 21.. There was one dose-limiting toxicity; other adverse events were typical PARP inhibitor and antiangiogenic class effects. Niraparib-bevacizumab showed promising activity; Part 2 (vs bevacizumab) was recently reported and phase III comparison with standard-of-care therapy is planned.

Topics: Adult; Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Ovarian Epithelial; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Indazoles; Middle Aged; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival

Quality of life (QOL) has become an important complementary endpoint in cancer clinical studies alongside more traditional assessments (eg, tumour response, progression-free survival, overall survival). Niraparib maintenance treatment has been shown to significantly improve progression-free survival in patients with recurrent ovarian cancer. We aimed to assess whether the benefits of extending progression-free survival are offset by treatment-associated toxic effects that affect QOL.. The ENGOT-OV16/NOVA trial was a multicentre, double-blind, phase 3, randomised controlled trial done in 107 study sites in the USA, Canada, Europe, and Israel. Patients with recurrent ovarian cancer who were in response to their last platinum-based chemotherapy were randomly assigned (2:1) to receive either niraparib (300 mg once daily) as a maintenance treatment or placebo. Randomisation was stratified based on time to progression after the penultimate platinum-based regimen, previous use of bevacizumab, and best response (complete or partial) to the last platinum-based regimen with permuted-block randomisation (six in each block) using an interactive web response system. The trial enrolled two independent cohorts on the basis of germline BRCA (gBRCA) mutation status (determined by BRACAnalysis Testing, Myriad Genetics, Salt Lake City, UT, USA). The primary endpoint of the trial was progression-free survival, and has already been reported. In this study, we assessed patient-reported outcomes (PROs) in the intention-to-treat population using the Functional Assessment of Cancer Therapy-Ovarian Symptoms Index (FOSI) and European QOL five-dimension five-level questionnaire (EQ-5D-5L). We collected PROs from trial entry every 8 weeks for the first 14 cycles and every 12 weeks thereafter. If a patient discontinued, we collected PROs at discontinuation and during a postprogression visit 8 weeks (plus or minus 2 weeks) later. We assessed the effect of haematological toxic effects on QOL with disutility analyses of the most common grade 3-4 adverse events (thrombocytopenia, anaemia, and neutropenia) using a mixed model with histology, region, previous treatment, age, planned treatment, and baseline score as covariates. This study is registered with ClinicalTrials.gov, number NCT01847274.. Between Aug 28, 2013, and June 1, 2015, 553 patients were enrolled and randomly assigned to receive niraparib (n=138 in the gBRCAmut cohort, n=234 in the non-gBRCAmut cohort) or placebo (n=65 in the gBRCAmut cohort, n=116 in the non-gBRCAmut cohort). The mean FOSI score at baseline was similar between the two groups (range between 25·0-25·6 in the two groups). Overall QOL scores remained stable during the treatment and preprogression period in the niraparib group; no significant differences were observed between the niraparib and placebo group, and preprogression EQ-5D-5L scores were similar between the two groups in both cohorts (0·838 [0·0097] in the niraparib group vs 0·834 [0·0173] in the placebo group in the gBRCAmut cohort; and 0·833 [0·0077] in the niraparib group vs 0·815 [0·0122] in the placebo group in the non-gBRCAmut cohort). The most common adverse events reported at screening (baseline) were lack of energy (425 [79%]; 97 [18%] reporting severe lack of energy), pain (236 [44%]), and nausea (118 [22%]). All symptoms, except nausea, either remained stable or improved over time in the niraparib group. The most common grade 3 or 4 toxicities observed in the niraparib group were haematological in nature: thrombocytopenia (124 [34%] of 367 patients), anaemia (93 [25%]), and neutropenia (72 [20%]); disutility analyses showed no significant QOL impairment associated with these toxic effects.. These PRO data suggest that women who receive niraparib as maintenance treatment for recurrent ovarian cancer after responding to platinum treatment are able to maintain QOL during their treatment when compared with placebo.. TESARO.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Ovarian Epithelial; Double-Blind Method; Female; Humans; Indazoles; Maintenance Chemotherapy; Middle Aged; Neoplasm Recurrence, Local; Patient Reported Outcome Measures; Piperidines; Progression-Free Survival; Quality of Life; Surveys and Questionnaires

Vandetanib is an oral tyrosine kinase inhibitor of VEGFR-2/3, EGFR and RET, which has demonstrated clinical activity as a single agent and in combination with taxanes. We explored the efficacy, safety and toxicity of docetaxel and vandetanib in women with recurrent ovarian cancer (OC).. Women with refractory or progressive OC were randomised 1:1 to docetaxel (75 mg/m(2), IV)+vandetanib (100mg daily, PO, D+V) or docetaxel (75 mg/m(2), D). Up to three additional cytotoxic regimens for recurrence and prior anti-angiogenic agents (as primary therapy) were allowed. The primary end-point was progression free survival (PFS). The study had 84% power to detect a PFS hazard ratio of 0.65, using a one-sided P of 0.1. This corresponds to an increase in median PFS from 3.6 months to 5.6 months. Patients progressing on D were allowed to receive single agent vandetanib (D → V).. 131 Patients were enrolled; two were excluded. 16% had received prior anti-angiogenic therapy. The median PFS estimates were 3.0 mos (D+V) versus 3.5 (D); HR: 0.99 (80% CI: 0.79-1.26). 61 Patients on D+V were assessable for toxicity; 20(33%) had treatment-related Grade (G) 4 events, primarily haematologic. Similarly, 17 (27%) of 64 patients receiving D had G4 events, primarily haematologic. 27 Evaluable patients crossed-over to V. 1/27(4%) experienced a G4 event. G3 diarrhoea was observed in 4% D → V patients. Median OS was 14 mos (D+V) versus 18 mos (D → V); HR(OS): 1.25 (80% CI: 0.93-1.68). Crossover vandetanib response was 4% (1/27 evaluable patients). High plasma IL-8 levels were associated with response to D+V.. Combination docetaxel+vandetanib did not prolong PFS relative to docetaxel alone in OC patients. No unexpected safety issues were identified.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Carcinoma, Ovarian Epithelial; Disease-Free Survival; Docetaxel; Fallopian Tube Neoplasms; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Peritoneal Neoplasms; Piperidines; Quinazolines; Taxoids; Treatment Outcome

This study evaluates whether a molecular targeted therapy with the farnesyltransferase inhibitor lonafarnib added to standard chemotherapy in first-line treatment of advanced ovarian cancer (OC) could improve progression-free (PFS) and overall survival (OS).. We performed a prospective randomized phase II study to compare standard therapy carboplatin (C; AUC 5) and paclitaxel (T; 175 mg/m(2)) in primary advanced OC with or without lonafarnib (L). Lonafarnib was given in a dose of 100mg orally twice a day during chemotherapy and was increased afterwards to 200mg up to six months as a maintenance therapy.. 105 patients were recruited (53 patients were randomized to receive LTC, 52 to TC). Hematologic toxicity was similar in both arms. Grade 3 and 4 non-hematological toxicity, occurred significantly more often with LTC (23% versus 4%, p=0.005) and was associated with a higher dropout rate. PFS and OS were not significantly different among both arms. The LTC arm showed inferiority in the stratum with residual tumor of more than 1cm: median PFS was 11.5 months (95% CI: 7.4-14.2) compared with 16.4 (95% CI: 10.3-40.4) for TC (p=0.0141; HR=0.36 (95% CI: 0.15-0.84)) with median OS 20.6 months (95% CI: 13.1-31.0) and 43.4 months (95% CI: 15.7-) for the TC arm (p=0.012; HR=0.32 (95% CI: 0.13-0.8)).. The addition of lonafarnib did not improve PFS or OS. Patients with a residual tumor of more than 1cm had significantly shorter PFS and OS. Incorporation of lonafarnib into future studies for primary therapy of OC is not recommended.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Ovarian Epithelial; Disease-Free Survival; Female; Humans; Middle Aged; Neoplasm Staging; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Paclitaxel; Piperidines; Prospective Studies; Pyridines; Survival Analysis; Young Adult

Poly (ADP-ribose) polymerase (PARP) inhibitors are a new maintenance therapy option for patients with ovarian cancer (OC).. To evaluate the efficacy and influencing factors of the novel PARP inhibitor niraparib for maintenance treatment of Chinese patients with advanced OC.. In this retrospective multicenter real-world study patients with advanced OC from 15 hospitals throughout China were enrolled. The primary endpoint was progression-free survival (PFS) and the secondary endpoints included the time to treatment discontinuation and safety. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used to identify possible risk factors for PFS, after which a prediction model was established to evaluate the likelihood of achieving an 18-month PFS. The relationship between the dose of niraparib and PFS was also evaluated.. The PFS rates of 199 patients at 6, 12, 18, 24, and 30 months were 87.4%, 75.9%, 63.6%, 56.1%, and 51.8%, respectively. LASSO regression model revealed that only age < 65 years (P = 0.011), BRCA mutations (P < 0.001), and R0 status after cytoreductive surgery (P = 0.01) were significant factors associated with prolonged PFS times. Based on the LASSO logistic regression analysis, a clinical prediction formula was developed: - 2.412 + 1.396Age. For Chinese OC patients, niraparib, particularly at a 200 mg individual starting dose, was an effective therapy with easily manageable safety.. Maintenance therapy with poly (ADP-ribose) polymerase inhibitors is a new option for patients with ovarian cancer (OC) after they have received platinum-based chemotherapy to reduce the recurrence or relapse rates, but it remains unclear whether there are any changes in efficacy and safety when different starting doses of niraparib are administrated to Chinese patients, who typically have a bodyweight < 77 kg. We found that niraparib exhibited satisfactory efficacy with tolerable safety during maintenance therapy for advanced OC whether administered at 100 mg or 200 mg doses. We believe these regimens can serve as a valuable addition to the previous results of randomized controlled trials.

Topics: Aged; Carcinoma, Ovarian Epithelial; Female; Humans; Indazoles; Ovarian Neoplasms; Piperidines

Topics: Carcinoma, Ovarian Epithelial; Female; Humans; Indazoles; Indoles; Ovarian Neoplasms; Phthalazines; Piperazines; Piperidines; Platinum; Poly(ADP-ribose) Polymerase Inhibitors

Topics: Carcinoma, Ovarian Epithelial; Cytoreduction Surgical Procedures; Female; Humans; Indazoles; Ovarian Neoplasms; Piperidines

In a previous paper, we demonstrated the synergistic action of the anti-ischemic lubeluzole (Lube S) on the cytotoxic activity of doxorubicin (Dox) and paclitaxel in human ovarian cancer A2780 and lung cancer A549 cells. In the present paper, we extended in vitro the study to the multi-drug-resistant A2780/DX3 cell line to verify the hypothesis that the Dox and Lube S drug association may potentiate the antitumor activity of this anticancer compound also in the context of drug resistance. We also evaluated some possible mechanisms underlying this activity. We analyzed the antiproliferative activity in different cancer cell lines. Furthermore, apoptosis, Dox accumulation, MDR1 downregulation, ROS, and NO production in A2780/DX3 cells were also evaluated. Our results confirm that Lube S improves Dox antiproliferative and apoptotic activities through different mechanisms of action, all of which may contribute to the final antitumor effect. Moderate stereoselectivity was found, with Lube S significantly more effective than its enantiomer (Lube R) and the corresponding racemate (Lube S/R). Docking simulation studies on the ABCB1 Cryo-EM structure supported the hypothesis that Lube S forms a stable MDR1-Dox-Lube S complex, which hampers the protein transmembrane domain flipping and blocks the efflux of Dox from resistant A2780/DX3 cells. In conclusion, our in vitro studies reinforce our previous hypothesis for repositioning the anti-ischemic Lube S as a potentiating agent in anticancer chemotherapy.

Topics: Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Doxorubicin; Female; Humans; Ovarian Neoplasms; Piperidines

Niraparib is effective against epithelial ovarian cancer (EOC), but with adverse effects. In this study, we retrospectively investigated niraparib maintenance treatment feasibility in Korean patients newly diagnosed with EOC.. The medical records of 35 patients were reviewed. Data on the baseline clinical characteristics were collected, and adverse effects were described.. Sixteen patients underwent treatment suspension or dose reduction. There was no significant difference in adverse effects (A/E) due to the interval between adjuvant chemotherapy conclusion and niraparib initiation. The two groups had similar International Federation of Gynaecology and Obstetrics (FIGO) stages. The number of patients with a history of bevacizumab use was higher in the dose modification group than in the standard dose group.. Niraparib use must be considered in those previously treated with bevacizumab. There is a need for prospective research on lower dose (<200 mg) treatments in patients with risk factors.

Topics: Carcinoma, Ovarian Epithelial; Chemotherapy, Adjuvant; Drug Tapering; Feasibility Studies; Female; Humans; Indazoles; Maintenance Chemotherapy; Neoplasm Staging; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Republic of Korea; Retrospective Studies; Survival Analysis; Treatment Outcome

Topics: Carcinoma, Ovarian Epithelial; Female; Humans; Indazoles; Ovarian Neoplasms; Piperidines

Topics: Carcinoma, Ovarian Epithelial; Fallopian Tubes; Female; Humans; Indazoles; Ovarian Neoplasms; Piperidines

Epithelial ovarian cancer (EOC) is the most lethal of gynecologic malignancies. The standard-of-care treatment for EOC is platinum-based chemotherapy such as cisplatin. Platinum-based chemotherapy induces cellular senescence. Notably, therapy-induced senescence contributes to chemoresistance by inducing cancer stem-like cells (CSC). However, therapeutic approaches targeting senescence-associated CSCs remain to be explored. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT) inhibition suppresses senescence-associated CSCs induced by platinum-based chemotherapy in EOC. Clinically applicable NAMPT inhibitors suppressed the outgrowth of cisplatin-treated EOC cells both

Topics: Acrylamides; Aldehyde Dehydrogenase 1 Family; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Cellular Senescence; Cisplatin; Cytokines; Drug Resistance, Neoplasm; Female; Humans; Mice; Neoplastic Stem Cells; Nicotinamide Phosphoribosyltransferase; Ovarian Neoplasms; Piperidines; Retinal Dehydrogenase; Spheroids, Cellular; Xenograft Model Antitumor Assays

Olaparib was approved on December 19, 2014 by the US FDA as 4th-line therapy (and beyond) for patients with germline BRCA1/2 mutations; rucaparib was approved on December 19, 2016 as 3rd-line therapy (and beyond) for germline or somatic BRCA1/2-mutated recurrent disease. On October 23, 2019, niraparib was approved for treatment of women with damaging mutations in BRCA1/2 or other homologous recombination repair genes who had been treated with three or more prior regimens. We compared the cost-effectiveness of PARPi(s) with intravenous regimens for platinum-resistant disease.. Median progression-free survival (PFS) and toxicity data from regulatory trials were incorporated in a model which transitioned patients through response, hematologic complications, non-hematologic complications, progression, and death. Using TreeAge Pro 2017, each PARPi(s) was compared separately to non‑platinum-based and bevacizumab-containing regimens. Costs of IV drugs, managing toxicities, infusions, and supportive care were estimated using 2017 Medicare data. Incremental cost-effectiveness ratios (ICERs) were calculated and PFS was reported in quality adjusted life months for platinum-resistant populations.. Non‑platinum-based intravenous chemotherapy was most cost effective ($6,412/PFS-month) compared with bevacizumab-containing regimens ($12,187/PFS-month), niraparib ($18,970/PFS-month), olaparib ($16,327/PFS-month), and rucaparib ($16,637/PFS-month). ICERs for PARPi(s) were 3-3.5× times greater than intravenous non‑platinum-based regimens.. High costs of orally administered PARPi(s) were not mitigated or balanced by costs of infusion and managing toxicities of intravenous regimens typically associated with lower response and shorter median PFS. Balancing modest clinical benefit with costs of novel therapies remains problematic and could widen disparities among those with limited access to care.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Ovarian Epithelial; Cost-Benefit Analysis; Drug Costs; Female; Humans; Indazoles; Indoles; Infusions, Intravenous; Markov Chains; Models, Statistical; Neoplasm Recurrence, Local; Ovarian Neoplasms; Phthalazines; Piperazines; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Quality of Life; United States

Niraparib maintenance after frontline chemotherapy for advanced ovarian cancer extends progression free survival. The objective of this study was to determine the cost effectiveness of niraparib maintenance therapy in patients with newly diagnosed ovarian cancer.. Decision analysis models compared the cost of observation versus niraparib maintenance following chemotherapy for five groups: all newly diagnosed ovarian cancer patients (overall), those with homologous recombination deficiency, those harboring. For the overall group, the cost of observation was US$5.8 billion versus $20.5 billion for niraparib maintenance, with an incremental cost effectiveness ratio of $72 829. For the homologous recombination deficiency group, the observation cost was $3.0 billion versus $14.8 billion for niraparib maintenance (incremental cost effectiveness ratio $56 329). Incremental cost effectiveness ratios for the. For patients with newly diagnosed ovarian cancer, maintenance therapy with niraparib was cost effective. Cost effectiveness was improved when analyzing those patients with homologous recombination deficiency and

Topics: Carcinoma, Ovarian Epithelial; Cost-Benefit Analysis; Decision Support Techniques; Female; Humans; Indazoles; Ovarian Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Progression-Free Survival; Quality-Adjusted Life Years

Ovarian cancer is prone to recurrence and chemotherapy resistance. Ovarian tumours of some patients have been positive for anaplastic lymphoma kinase fusion gene expression (ALK+). Preclinical studies indicate that anaplastic lymphoma kinase inhibitor can suppress the growth of ovarian cancer cells and transplantation tumours. Here, we present a patient with metastatic ALK+ high-grade serous ovarian cancer that testing positive for EML4-ALK (microtubule-associated protein-like 4 gene, fused to the anaplastic lymphoma kinase gene), experienced dramatic benefit after administration of the anaplastic lymphoma kinase inhibitor alectinib. This is the first clinical evidence that treatment with alectinib may provide a personalized maximum benefit for patients with high-grade serous ovarian cancer who are positive for EML4-ALK.

Topics: Anaplastic Lymphoma Kinase; Carbazoles; Carcinoma, Ovarian Epithelial; Female; Humans; Middle Aged; Molecular Targeted Therapy; Oncogene Proteins, Fusion; Ovarian Neoplasms; Piperidines; Protein Kinase Inhibitors; Treatment Outcome

There are large randomized clinical trials-SOLO-1 (Olaparib Maintenance Monotherapy in Patients With BRCA Mutated Ovarian Cancer Following First Line Platinum Based Chemotherapy [December 2018]), PRIMA (A Study of Niraparib Maintenance Treatment in Patients With Advanced Ovarian Cancer Following Response on Front-Line Platinum-Based Chemotherapy [September 2019]), and PAOLA-1 (Platine, Avastin and Olaparib in 1st Line [December 2019])-reporting positive efficacy results for maintenance regimens for women with primary, advanced epithelial ovarian cancer. The findings resulted in approval by the US Food and Drug Administration of the treatments studied as of May 2020. However, there are pressing economic considerations given the many eligible patients and substantial associated costs.. To evaluate the cost-effectiveness of maintenance strategies for patients with (1) a BRCA variant, (2) homologous recombination deficiency without a BRCA variant, or (3) homologous recombination proficiency.. In this economic evaluation of the US health care sector using simulated patients with primary epithelial ovarian cancer, 3 decision trees were developed, one for each molecular signature. The maintenance strategies evaluated were olaparib (SOLO-1), olaparib-bevacizumab (PAOLA-1), bevacizumab (PAOLA-1), and niraparib (PRIMA). Base case 1 assessed olaparib, olaparib-bevacizumab, bevacizumab, and niraparib vs observation of a patient with a BRCA variant. Base case 2 assessed olaparib-bevacizumab, bevacizumab, and niraparib vs observation in a patient with homologous recombination deficiency without a BRCA variant. Base case 3 assessed olaparib-bevacizumab, bevacizumab, and niraparib vs observation in a patient with homologous recombination proficiency. The time horizon was 24 months. Costs were estimated from Medicare claims, wholesale acquisition prices, and published sources. Probabilistic sensitivity analyses with microsimulation were then conducted to account for uncertainty and assess model stability. One-way sensitivity analyses were also performed. The study was performed from January through June 2020.. Incremental cost-effectiveness ratios (ICERs) in US dollars per progression-free life-year saved (PF-LYS).. Assuming a willingness-to-pay threshold of $100 000/PF-LYS, none of the drugs could be considered cost-effective compared with observation. In the case of a patient with a BRCA variant, olaparib was the most cost-effective (ICER, $186 777/PF-LYS). The third-party payer price per month of olaparib would need to be reduced from approximately $17 000 to $9000 to be considered cost-effective. Olaparib-bevacizumab was the most cost-effective in the case of a patient with homologous recombination deficiency without a BRCA variant (ICER, $629 347/PF-LYS), and bevacizumab was the most cost-effective in the case of patient with homologous recombination proficiency (ICER, $557 865/PF-LYS). Even at a price of $0 per month, niraparib could not be considered cost-effective as a maintenance strategy for patients with homologous recombination proficiency.. The findings of this study suggest that, at current costs, maintenance therapy for primary ovarian cancer is not cost-effective, regardless of molecular signature. For certain therapies, lowering the drug price alone may not make them cost-effective.

Topics: Antineoplastic Agents, Immunological; Bevacizumab; Carcinoma, Ovarian Epithelial; Computing Methodologies; Cost-Benefit Analysis; Female; Genes, BRCA1; Genes, BRCA2; Homologous Recombination; Humans; Indazoles; Maintenance Chemotherapy; Medicare; Neoplasm Staging; Ovarian Neoplasms; Phthalazines; Piperazines; Piperidines; United States

Topics: Carcinoma, Ovarian Epithelial; Female; Humans; Indazoles; Ovarian Neoplasms; Piperidines

Oral niraparib, a highly-selective, potent poly(ADP-ribose) polymerase (PARP)-1 and PARP-2 inhibitor, is approved in the USA 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. It is also under regulatory review in the EU for use in maintenance treatment in patients with platinum-sensitive, recurrent epithelial ovarian cancer who are in response to platinum-based chemotherapy. In the multinational, phase 3 NOVA trial in adult patients with platinum-sensitive, recurrent ovarian cancer, niraparib significantly prolonged median progression-free survival, irrespective of the presence or absence of a germline BRCA (gBRCA) mutation and irrespective of the presence or absence of homologous recombinant deficiency. Niraparib is also in development for use in other solid tumours, including breast and prostate cancer. This article summarizes the milestones in the development of niraparib leading to its first global approval for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer.

Topics: Adult; Carcinoma, Ovarian Epithelial; Double-Blind Method; Drug Approval; Fallopian Tube Neoplasms; Female; Humans; Indazoles; Maintenance Chemotherapy; Middle Aged; Neoplasm Recurrence, Local; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Peritoneal Neoplasms; Piperidines; Poly(ADP-ribose) Polymerase Inhibitors; Randomized Controlled Trials as Topic; United States; United States Food and Drug Administration

The purpose is to investigate the effects of the sequential combination treatment of Taxol and flavopiridol on human ovarian carcinoma in vitro and in vivo.. Cell viabilities were determined using the cell counting kit and by flow cytometry. RT-PCR, TUNEL, and immunoblotting assays were used to detect cellular apoptotic activities following treatments. Tumor growth and microvessel density (MVD) detection of mice bearing SKOV3 cells were studied.. Taxol or flavopiridol alone was cytotoxic against SKOV3 cells in vitro with a viability rate of 38.2 ± 1.3 % for 1 µmol/L Taxol and 44.3 ± 5.9 % for 300 nM flavopiridol. Sequential combination treatment with Taxol and flavopiridol resulted in a viability rate of 9.1 ± 0.8 %. The apoptotic rate of SKOV3 cells was 15.7 ± 1.7, 9.4 ± 0.4 and 51.1 ± 2.5 % for Taxol, flavopiridol, and combination of Taxol and flavopiridol, respectively. Significant synergisms were observed in SKOV3 cells in vitro, following the sequential combination of Taxol for 24 h followed by flavopiridol for 24 h, which resulted in the most substantial cell death and the highest apoptotic rate. All treatments showed significant suppression of tumor growth at the end point of the in vivo study. All treatments significantly reduce the value of MVD.. Sequential combination treatment with Taxol and flavopiridol exerted synergistic cytotoxic activities against SKOV3 cells in vitro and significantly suppress the tumor growth of mice bearing SKOV3 cells. It should be further explored as a potential clinically useful regimen against ovarian cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Drug Synergism; Female; Flavonoids; Humans; In Situ Nick-End Labeling; Mice; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Paclitaxel; Piperidines; Xenograft Model Antitumor Assays