NOVA Trial Research Articles

Abstract 12958: Temporal Association of Systemic Inflammatory Biomarkers With Incidence of Postoperative Atrial Fibrillation After Botulinum Toxin Type A Administration in Epicardial Fat Pads

Background: A one-time injection of botulinum toxin type A (BoNT/A) in epicardial fat pads was evaluated for post-operative atrial fibrillation (POAF) in patients undergoing open-chest cardiac surgery in the Ph2 NOVA trial. Treatment with 125U BoNT/A numerically reduced the incidence of POAF in the mITT (36.5% vs 46.1%) and CABG populations (28.4% vs 40.0%), with statistical significance observed in the CABG + ≥65 years subgroup (27.5% vs 56.4%; P <0.01). No significant reduction was observed in the 250U group vs placebo. Purpose: Explore systemic inflammatory biomarker changes after treatment with BoNT/A and the temporal relation to incidence of POAF. Methods: This analysis included 308 patients who received 125U BoNT/A (n=103), 250U BoNT/A (n=103), or placebo (n=102). Subgroup analysis was done for CABG (n=198), age ≥65 years (n=185), and CABG + ≥65 years (n=118). Serum samples were collected preoperatively prior to dosing on Day 1, then post-treatment on Days 2-4 to test for IL-6, IL-10, and hsCRP. A 2-sample t test was used for mean concentrations and a linear mixed model was used for fold change (FC) from baseline. Results: Baseline levels of IL-6, IL-10, and hsCRP were similar between treatment groups. Reduction of IL-6 (45.7 ± 4.4 vs 62.4 ± 5.8 pg/mL, P <0.05; 10.8 vs 15.9 FC, P <0.01) and IL-10 (1.49 ± 0.13 vs 2.04 ± 0.24 pg/mL, P <0.05; 1.96 vs 2.66 FC, P <0.01) was most significant on Day 2 in CABG patients treated with 125U vs placebo, which aligns with the highest rate and risk of POAF (Figure 1). Mean hsCRP was most significantly reduced on Day 4 in the 250U group among CABG patients (193 ± 8 vs 227 ± 10 mg/dL, P <0.01) followed by 125U vs placebo (196 ± 10 vs 227 ± 10 mg/dL, P <0.05); a similar dose-dependent reduction was observed by FC analysis. Conclusions: Treatment with 125U BoNT/A in cardiac surgery patients lowered the incidence of POAF vs placebo and reduced postoperative systemic IL-6 and IL-10 on Day 2, most significantly in the CABG population.

Ad hoc Analysis of the Phase III ENGOT-OV16/NOVA Study: Niraparib Efficacy in Germline BRCA Wild-type Recurrent Ovarian Cancer with Homologous Recombination Repair Defects.

We retrospectively evaluated the mutational profile of HRR genes in tumor samples from 331 patients from the non-germline BRCA-mutated cohort of the phase III NOVA trial of patients with platinum-sensitive high-grade serous ovarian cancer. Patients with non-BRCA HRR mutations generally benefited from second-line maintenance treatment with niraparib compared with placebo.

SY23-3 Clinical development of PARP inhibitors in ovarian cancer

Initial clinical development of PARP inhibitor (PARPi) started for ovarian patients with germline BRCA mutation (gBRCAm) based on the mechanistic assumptions. The first large phase 3 trial, SOLO2, focused on the patient with platinum-sensitive recurrent ovarian cancer known to have gBRCAm. On the other hand, the NOVA trial tested the innovative study design. The investigators challenged to include patients with not only gBRCAm but also with non-gBRCAm, which included HRD+ (tBRCAm only and BRCAwt) and HRD-negative population.

Maintenance niraparib therapy for patients with relapsed platinum sensitive ovarian cancer: experience at a south coast network

Ovarian cancer remains a challenge to treatment teams with approximately 20 new diagnoses each day. A new treatment has recently entered the treatment pathway using a drug call niraparib – a polymerase inhibitor. This paper reports on a local audit following first introduction of niraparib in the maintenance phase of treatment, following a clear response to initial platinum therapy to understand the real world experience. Results show a very well tolerated treatment with manageable toxicities such as fatigue anaemia and thrombocytopenia as seen in the initial NOVA trial. This successful introduction of maintenance treatment has led to workforce challenges of managing capacity and multidisciplinary teams. A nurse led clinic solution was crafted allowing patients to be safely managed without the need for attendance at hospital.

An In-Depth Review of Niraparib in Ovarian Cancer: Mechanism of Action, Clinical Efficacy and Future Directions.

Niraparib is an oral, potent, highly selective poly-ADP ribose polymerase 1 (PARP1) and PARP2 inhibitor. In most developed countries, it is approved as a maintenance treatment for epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients with complete or partial response to platinum-based therapy. These approvals are based on results of randomised, double-blind, placebo-controlled trials, particularly the NOVA trial and more recently the PRIMA trial. In this comprehensive review, we delve into the scientific basis of PARP inhibition, discussing both preclinical and clinical data which have led to the current approval status of niraparib. We also discuss ongoing trials and biological rationale of combination treatments involving niraparib, with particular focus on antiangiogenic drugs, immune checkpoint inhibitors and cyclic GMP-AMP synthase stimulator of interferon genes (cGAS/STING) pathway. In addition, we reflect on potential strategies and challenges of utilising current biomarkers for treatment selection of patients to ensure maximal benefit.

Niraparib efficacy and safety in patients with BRCA mutated (BRCAm) ovarian cancer: Results from three phase 3 niraparib trials.

5518 Background: Niraparib has been approved for the maintenance treatment of patients with advanced ovarian, fallopian tube, or primary peritoneal cancer after front-line chemotherapy (CT) and in the recurrent setting. Here, we summarize niraparib efficacy and safety in patients with BRCAm OC across three phase 3 trials: PRIMA/ENGOT-OV26/GOG-3012 (PRIMA; NCT02655016), ENGOT-OV16/NOVA (NOVA; NCT01847274), and NORA (NCT03705156). Methods: Patients enrolled in the PRIMA trial had newly diagnosed advanced ovarian, fallopian tube, or primary peritoneal cancer. All patients had stage III or IV high-grade serous or endometrioid tumors and had a complete or partial response to their first-line platinum-based CT treatment. Subgroup analysis by tumor BRCAm status was prespecified. Patients enrolled in the NOVA and NORA studies had platinum-sensitive, high-grade serous ovarian, fallopian tube, or primary peritoneal cancer. Patients had already received at least 2 lines of platinum-based CT regimens. In both studies, subgroup analysis by germline BRCAm status was prespecified. The primary endpoint in all trials was progression-free survival (PFS) by blinded independent central review. Results: The BRCAm populations from each trial are as follows: 223 (148 BRCA1m and 75 BRCA2m) from the PRIMA trial, 203 (128 BRCA1m, 69 BRCA2m, and 13 BRCA1/2m) from the NOVA trial, and 100 (78 BRCA1m, 21 BRCA2m, and 1 BRCA1/2m) from the NORA trial. PFS results are shown in the Table. Across the 3 trials, the most common treatment-emergent adverse events were thrombocytopenia, anemia, neutropenia, and hypertension. Conclusions: Patients with BRCAm OC derived a significant PFS benefit from niraparib maintenance treatment across all 3 trials. No new safety signals were identified. Clinical trial information: NCT02655016, NCT01847274, NCT03705156. [Table: see text]

Long-term safety in patients with recurrent ovarian cancer treated with niraparib versus placebo: Results from the phase III ENGOT-OV16/NOVA trial

ObjectiveNiraparib 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. MethodsThis 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). ResultsOverall, 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. ConclusionThese 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. Trial registrationClinicalTrials.gov identifier: NCT01847274.

Real-world adverse events with niraparib 200 mg/day maintenance therapy in ovarian cancer: a retrospective study.

Aim: To assess real-world occurrence of common clinical trial-reported adverse events (AE) among patients with recurrent ovarian cancer initiating niraparib 200 mg/day. Materials & methods: This retrospective observational study used physician-extracted anonymized medical record data of eligible patients initiating niraparib 200 mg/day after platinum-based chemotherapy. Results: Of 153 patients, 57 (37%) experienced ≥1 of the three most common all-grade AEs within 3 months after niraparib initiation: nausea (16%; grade 3/4: 2%), thrombocytopenia (14%; grade 3/4: 3%) and fatigue (24%; grade 3/4: 3%). In the ENGOT-OV16/NOVA trial, these respective AEs occurred in 74, 61 and 59% of patients. Conclusion: Incidence of common clinical trial-reported AEs was lower among patients initiating niraparib 200 mg/day in real-world practice versus patients initiating niraparib 300 mg/day in ENGOT-OV16/NOVA.

1005P - Evaluation of niraparib 200 mg/d as maintenance therapy in recurrent ovarian cancer and associated thrombocytopenia in a real-world US setting

BackgroundNiraparib, a poly(ADP-ribose) polymerase inhibitor approved in 2017 by the US FDA (300mg/d), has proven to be efficacious as maintenance therapy in patients (pts) with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (ROC) who are in complete or partial response (PR) to platinum-based chemotherapy (CT), with dose modification recommended to manage adverse reactions. This study assessed the rates of thrombocytopenia (TCP) among ROC pts who initiated niraparib 200mg/d in a real-world US setting. MethodsIn July 2018, we recruited experienced (practicing ≥5 years) oncologists (N=107), who were directly involved in treatment decisions, to complete an online survey and chart review (minimum of 1 and maximum of 2 charts) of adult pts (N=150) with ROC who initiated niraparib 200mg/d within 12 weeks of CT and had ≥3 months of follow-up. Data on pt demographics, disease history, comorbidities, biomarker status (BRCA and homologous recombination deficiency [HRD]), treatment use, and platelet counts (PC) were collected. Data were analyzed using descriptive statistics. ResultsAbout 56% and 44% of pts received 1 and ≥2 lines of CT, respectively, and 55% had a PR to platinum-based CT immediately before niraparib initiation. Pts had stage III (39%) and stage IV (40%) ROC at diagnosis, with a mean disease duration of 1.3 years. BRCA and HRD testing occurred in 87 (58%) and 44 pts (29%), respectively. When asked the reason for initiating niraparib at 200mg/d, 40% of oncologists reported starting all pts at 200mg/d, 37% reported pt preference, 33% reported pt concern of toxicity, and 28% reported pt weight (median: 71kg). Grade 3/4 TCP (per NCI CTCAE v4.03) occurred in 14% of pts post-initiation. Median time from niraparib initiation to the first PC test was 25.5 days. Of 77 pts (51%) with >1PC test, median time from the first to the next test was 28 days. ConclusionsIn this chart review study, <1 in 5 pts had TCP (grade 3/4) and the median time from initiation to PC test was 25.5 days, both of which are lower than observed rates reported in the ENGOT-OV16/NOVA trial. Niraparib dose initiation at 200mg/d may be beneficial in managing adverse reactions in pts with ROC. Legal entity responsible for the studyTesaro: A GSK Company. FundingTesaro: A GSK Company. DisclosureP. Thaker: Research funding: Merck, Tesaro; Grant for research / Consulting: Celsion Pharmaceuticals, AstraZeneca, Tesaro, Merck, AbbVie, Lovance, Unleash Oncolytics, Immunogen, Stryker. K. Travers: Full / Part-time employment: Tesaro: A GSK Company. C. Karki: Full / Part-time employment: Ipsos Insights, LLC. R.P. Patel: Full / Part-time employment: Ipsos Insights, LLC. C. Krebsbach: Full / Part-time employment: Ipsos Insights, LLC. B. Harrow: Full / Part-time employment: Tesaro: A GSK Company. S.N. Westin: Research Funding: ArQule; AstraZeneca; Bayer; Biomarin; Celgene (I); Clovis Oncology; Cotinga Pharmaceuticals; Critical Outcome Technologies; Karyopharm Therapeutics (I); Kite Pharma (I); Novartis; Roche/Genentech; Tesaro; Consulting / Advisory Role: AstraZeneca, BioAscent, Casdin Capital, Clovis Oncology, Genentech, Gerson Lehrman Group, Medivation, Medscape, Merck, Ovation Sciences, Pfizer, Roche, Tesaro, Vaniam Group, Vermillion, Watermark Research Partners.

Time without symptoms or toxicity in patients with recurrent ovarian cancer receiving niraparib maintenance treatment versus placebo: A TWIST analysis of the ENGOT24-OV16/NOVA trial

Time without symptoms or toxicity in patients with recurrent ovarian cancer receiving niraparib maintenance treatment versus placebo: A TWIST analysis of the ENGOT24-OV16/NOVA trial

Elucidation of PARP inhibitor activity in BRCAwt recurrent ovarian cancer by hrr mutational gene profile analysis.

5568 Background: Niraparib is an oral, selective poly(ADP-ribose) polymerase inhibitor (PARPi) approved for maintenance treatment of BRCA mutated ( BRCAmut) and BRCA wild-type ( BRCAwt) recurrent ovarian cancer patients (pts) who are in response to platinum-based chemotherapy. In the non-germline BRCA mutated (non-g BRCAmut) cohort of the ENGOT-OV16/NOVA trial, clinical benefit with niraparib vs placebo was seen in pts regardless of their Myriad myChoice HRD test status ( BRCAmut and homologous recombination deficiency [HRD] score), with a hazard ratio (HR) of 0.38 in HRD-positive (HRDpos) and 0.58 in HRD-negative (HRDneg) pts. To determine if treatment benefit in HRDneg pts may result from mutations in other homologous recombination repair ( HRR) genes, we examined the relationship between progression-free survival and other HRR gene mutations in the NOVA non-gBRCAmut cohort. Methods: A retrospective, exploratory biomarker analysis was conducted using all available tumor samples from 331 pts enrolled in the NOVA non-g BRCAmut cohort. Mutation status of HRR genes was evaluated using a 43-gene NGS assay (Myriad Genetics), including BRCA1/2 and 16 additional HRR genes. Results: In this exploratory analysis of the NOVA non-g BRCAmut cohort, niraparib demonstrated clinical benefit in pts with somatic BRCA mutation (HR, 0.27) and in BRCAwt pts (HR, 0.47). In addition, BRCAwt pts with other HRR gene mutations also derived benefit from niraparib (HR, 0.31), as did BRCAwt/ HRRwt pts (HR, 0.49). When BRCAwt/ HRRwt pts were categorized by HRD score, clinical benefit was also observed in both HRDpos and HRDneg pts, with HRs of 0.33 and 0.60, respectively. These results suggest that, although these biomarkers have good positive predictive value, they are not good negative predictors for niraparib benefit in this indication. Conclusions: This retrospective, exploratory analysis of the ENGOT-OV16/NOVA non-g BRCAmut cohort suggests that although pts with somatic BRCA mutation and other HRR mutations benefit from niraparib treatment, clinical benefit is also seen in HRDneg pts without HRR mutations, perhaps related to other genomic, epigenetic, or functional alterations within ovarian tumors yet to be defined.

Recurrence of ovarian cancer in BRCAwt patients without maintenance therapy: Real-world evidence.

5547 Background: Development of platinum resistance is a major clinical challenge in ovarian cancer (OC) treatment. In the phase 3 ENGOT-OV16/NOVA trial of the poly(ADP-ribose) polymerase inhibitor (PARPi) niraparib, 55% of BRCA wild-type ( BRCAwt) patients (pts) receiving placebo developed platinum resistance after their last platinum-based therapy (ie, progressive disease within 6 months of their last chemotherapy [CT] dose). Niraparib, a PARPi approved for the maintenance treatment of adult pts with recurrent OC following platinum-based CT, significantly prolongs progression-free survival (PFS). This real-world data analysis investigated the risk of platinum eligibility loss for BRCAwt pts who did not receive maintenance therapy after platinum treatment. Methods: This retrospective study identified 5,535 pts with OC from January 2011–October 2018 using data from Flatiron, a longitudinal, demographically and geographically diverse database derived from records of &gt; 265 cancer clinics and &gt; 2 million US cancer pts. BRCAwt pts who had received ≥2 lines of platinum-based CT, had disease progression ≥6 months after their previous line of therapy, and had no maintenance therapy (PARPi, bevacizumab, or CT agents) after their current treatment were included. Kaplan-Meier analysis was used to estimate the probability of pts initiating next treatment or death, whichever occurred first, within 6 months. Results: Of 5,535 pts diagnosed with OC, 147 BRCAwt pts met the inclusion/exclusion criteria of this analysis (similar to ENGOT-OV16/NOVA placebo arm). An estimated 56% of pts received the next treatment or died within 6 months after their last platinum-based therapy. Median time to next therapy or death was 5.1 months (95% confidence interval, 3.1–7.2). Conclusions: Our real-world data analysis shows that 56% of BRCAwt pts who received platinum-based treatment without maintenance therapy had recurrent OC within 6 months, classifying them as platinum resistant. Use of maintenance treatment options, such as niraparib, has been shown to significantly prolong PFS after platinum-based CT and may be beneficial in extending the platinum-free interval, enabling pts to remain eligible for further platinum therapy.

Efficacy and safety of niraparib as maintenance treatment in older patients (≥ 70 years) with recurrent ovarian cancer: Results from the ENGOT-OV16/NOVA trial

ObjectiveTo analyze the safety and efficacy of niraparib in patients aged ≥70 years with recurrent ovarian cancer in the ENGOT-OV16/NOVA trial. MethodsThe trial enrolled 2 independent cohorts with histologically diagnosed recurrent ovarian, fallopian tube, or peritoneal cancer who responded to platinum rechallenge, on the basis of germline breast cancer susceptibility gene mutation (gBRCAmut) status. Patients were randomized 2:1 to receive niraparib (300 mg) or placebo once daily until disease progression. The primary endpoint was progression-free survival (PFS) by blinded independent central review. Adverse events (AEs) of special interest were based on the known safety profile of poly(ADP-ribose) polymerase inhibitors. ResultsPatients aged ≥70 years in the gBRCAmut cohort receiving niraparib (n = 14) had not yet reached a median PFS compared with a median PFS of 3.7 months for the same age group in the placebo arm (hazard ratio [HR], 0.09 [95% confidence interval (CI), 0.01 to 0.73]). Non-gBRCAmut patients aged ≥70 years receiving niraparib (n = 47) had a median PFS of 11.3 months compared with 3.8 months in the placebo arm (HR, 0.35 [95% CI, 0.18 to 0.71]). Median duration of follow-up in the niraparib arm was 17.3 months in patients ≥70 years and 17.2 months in patients <70 years. Frequency, severity of AEs, and dose reductions in the niraparib arm were similar in patients aged <70 and ≥ 70 years population. The most common grade ≥ 3 AEs in patients ≥70 years were hematologic: thrombocytopenia event (34.4%), anemia event (13.1%), and neutropenia event (16.4%). ConclusionsFor patients ≥70 years of age receiving niraparib as maintenance treatment in the ENGOT-OV16/NOVA trial, PFS benefits and incidence of any grade or serious treatment-emergent AEs were comparable to results in the younger population. Use of niraparib should be considered in this population.

FDA Approval Summary: Niraparib for the Maintenance Treatment of Patients with Recurrent Ovarian Cancer in Response to Platinum-Based Chemotherapy.

The FDA approved niraparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, on March 27, 2017, for maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response to platinum-based chemotherapy. Approval was based on data from the NOVA trial comparing niraparib with placebo in two independent cohorts, based on germline BRCA mutation status (gBRCAm vs. non-gBRCAm). Progression-free survival (PFS) in each cohort was the primary endpoint. In the gBRCAm cohort, estimated median PFS on niraparib was 21 months versus 5.5 months on placebo [HR, 0.26; 95% confidence interval (CI), 0.17-0.41; P < 0.0001]. In the non-gBRCAm cohort, estimated median PFS for niraparib and placebo was 9.3 and 3.9 months, respectively (HR, 0.45; 95% CI, 0.34-0.61; P < 0.0001). Common adverse reactions (>20% and higher incidence in the niraparib arm) with niraparib included thrombocytopenia, anemia, neutropenia, nausea, constipation, vomiting, mucositis, fatigue, decreased appetite, headache, insomnia, nasopharyngitis, dyspnea, rash, and hypertension. There were five cases of myelodysplastic syndrome and acute myeloid leukemia (1.4%) in patients treated with niraparib compared with two cases (1.1%) on placebo. Niraparib is the first PARP inhibitor approved as maintenance therapy for patients with ovarian, fallopian tube, or primary peritoneal cancer, with improvement in PFS, regardless of gBRCAm status. Clin Cancer Res; 24(17); 4066-71. ©2018 AACRSee related commentary by Konstantinopoulos and Matulonis, p. 4062.

Safety and dose modification for patients receiving niraparib

BackgroundNiraparib is a poly(ADP-ribose) polymerase inhibitor approved in the USA and Europe for maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. In the pivotal ENGOT-OV16/NOVA trial, the dose reduction rate due to treatment-emergent adverse event (TEAE) was 68.9%, and the discontinuation rate due to TEAE was 14.7%, including 3.3% due to thrombocytopenia. A retrospective analysis was carried out to identify clinical parameters that predict dose reductions. Patients and methodsAll analyses were carried out on the safety population, comprising all patients who received at least one dose of study drug. Patients were analyzed according to the study drug consumed (i.e., as treated). A predictive modeling method (decision trees) was used to identify important variables for predicting the likelihood of developing grade≥3 thrombocytopenia within 30days after the first dose of niraparib and determine cut-off points for chosen variables. ResultsFollowing dose modification, 200mg was the most commonly administered dose in the ENGOT-OV16/NOVA trial. Baseline platelet count and baseline body weight were identified as risk factors for increased incidence of grade≥3 thrombocytopenia. Patients with a baseline body weight<77kg or a baseline platelet count<150000/µl in effect received an average daily dose ∼200mg (median=207mg) due to dose interruption and reduction. Progression-free survival in patients who were dose reduced to either 200 or 100mg was consistent with that of patients who remained at the 300mg starting dose. ConclusionsThe analysis presented suggests that patients with baseline body weight of<77kg or baseline platelets of<150000/µl may benefit from a starting dose of 200mg/day. ClinicalTrials.gov IDNCT01847274.

Niraparib: A Review in Ovarian Cancer.

Niraparib (Zejula®), a poly (ADP-ribose) polymerase (PARP) inhibitor, is approved for the maintenance treatment of recurrent, epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who are in complete or partial response to platinum-based chemotherapy. Approval was based on the results of the randomized, double-blind, placebo-controlled phase III NOVA trial. In NOVA, niraparib significantly prolonged progression-free survival (primary endpoint), chemotherapy-free interval and time to first subsequent therapy compared with placebo in patients with recurrent, platinum-sensitive, high grade serous ovarian, fallopian tube or primary peritoneal cancer. The beneficial effects of niraparib were consistent regardless of BRCA mutation or homologous recombination deficiency (HRD) status. Niraparib had a manageable tolerability profile, with the majority of grade 3 or 4 adverse events being haematologic abnormalities (e.g. thrombocytopenia, anaemia, neutropenia). Adverse events were generally well managed with dose interruption or modification of niraparib. Current evidence suggests that niraparib is an effective new option with a manageable tolerability profile for the maintenance treatment of recurrent, platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer in adults, with or without BRCA1/2 mutation or HRD.

The role of niraparib for the treatment of ovarian cancer.

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.

930O - Quality of life in patients with recurrent ovarian cancer (OC) treated with niraparib: Results from the ENGOT-OV16/NOVA Trial

930O - Quality of life in patients with recurrent ovarian cancer (OC) treated with niraparib: Results from the ENGOT-OV16/NOVA Trial

933PD - The exposure-response relationship of niraparib in patients with gBRCAmut and non-gBRCAmut: Results from the ENGOT-OV16/NOVA Trial

933PD - The exposure-response relationship of niraparib in patients with gBRCAmut and non-gBRCAmut: Results from the ENGOT-OV16/NOVA Trial

The successful phase 3 niraparib ENGOT-OV16/NOVA trial included a substantial number of patients with platinum resistant ovarian cancer (OC).

5560 Background: Niraparib is a highly selective poly (ADP-ribose) polymerase (PARP) 1/2 inhibitor (PARPi); in preclinical studies, it concentrates in the tumor relative to plasma to deliver durable, near complete PARP inhibition and persistent antitumor effects.Niraparib demonstrated significantly longer progression free survival (PFS) vs placebo in patients (pts) with recurrent OC who were randomized following a complete response (CR) or partial response (PR) to platinum based chemotherapy in the controlled, double-blind phase 3 ENGOT-OV16/NOVA trial. To more fully characterize the NOVA trial population, we assessed platinum resistance status, defined as a duration of response to platinum &lt; 6 months to the most recent (ultimate) platinum regimen. Analysis was limited to pts in the placebo arm, as inclusion of pts receiving active treatment (niraparib) would have confounded the ability to determine duration of response to platinum alone. Methods: Pts with recurrent OC, no prior PARPi use, ≥2 prior courses of platinum based chemotherapy, and CR or PR to the most recent platinum based chemotherapy were eligible. Pts were assigned to one of two cohorts based on g BRCA testing (g BRCAmut or non-g BRCAmut) and randomized 2:1 within each cohort to niraparib 300 mg or placebo qd until progressive disease (PD). Randomization occurred up to 8 weeks following the last dose of the most recent platinum based chemotherapy. PFS was measured from time of randomization to death or earliest PD as assessed by independent review committee. Estimated probability of pts having disease progression in each cohort and pooled across cohorts 6 months after the last dose of their most recent platinum therapy was calculated using the Kaplan-Meier methodology. Results: 181 pts were randomized to placebo (65 g BRCAmut and 116 non-g BRCAmut). Platinum resistance rate estimates for the g BRCAmut, non-g BRCAmut, and pooled cohorts were 42%, 53%, and 49%, respectively. Conclusions: Approximately half of the pts in the NOVA study, where niraparib treatment met its primary endpoint of prolonging PFS following a response to platinum, had developed platinum resistance to their last line of chemotherapy. Clinical trial information: NCT01847274.