Maintenance Treatment Of Adult Patients Research Articles

NETWORK META-ANALYSIS TO EVALUATE THE COMPARATIVE EFFICACY OF BIOLOGICS FOR MAINTENANCE TREATMENT OF ADULT PATIENTS WITH CROHN’S DISEASE

Abstract INTRODUCTION While the therapeutic armamentarium for Crohn’s disease (CD) is rapidly expanding, direct evidence on comparative efficacy of various treatments is lacking. CT-P13 subcutaneous (SC) provides patients with a new opportunity for maintenance treatment of their disease. METHODS A network meta-analysis (NMA) was conducted to evaluate comparative efficacy of licensed biologics. Phase 3 randomized controlled-trials (RCTs) evaluating biologics approved by the European Medicines Agency or United States Food and Drug Administration as of 31 March 2023 for maintenance treatment of adult patients with moderate-to-severe CD were included, i.e. infliximab (IFX) intravenous (IV) and SC, adalimumab (ADL) SC, vedolizumab (VDZ) IV and SC, ustekinumab (UST) SC, and risankizumab (RZB) SC. Eligible studies evaluated the efficacy of maintenance therapy with follow-up periods of 52–64 weeks in patients who responded to induction treatment. Each study was controlled with placebo (PBO) or an active comparator. Head-to-head studies directly comparing efficacy of licensed biologics in CD (including those with treat-through designs) were also considered for inclusion. Clinical remission rates following the maintenance treatment were compared in a Bayesian NMA fixed-effect model. RESULTS Overall, 8 RCTs were identified and included in the analysis (ACCENT I, LIBERTY-CD, CHARM, SEAVUE, GEMINI 2, VISIBLE 2, IM-UNITI, FORTIFY). Most studies enrolled both naïve and biologic- and/or Janus kinase inhibitor-exposed patients, apart from ACCENT-1 and SEAVUE which enrolled only anti-tumor necrosis factor- and biologic-naïve patients, respectively. Among 8 comparator arms, IFX SC 120 mg every 2 weeks (Q2W) showed the highest odds ratio (95% credible interval) vs. PBO for clinical remission during the maintenance phase (3.52 [2.18–5.65]), followed by ADL SC 40 mg Q2W (2.92 [1.90–4.47]), UST SC 90 mg every 8 weeks (Q8W) (2.79 [1.85–4.21]), IFX IV 5 mg/kg Q8W (2.55 [1.29–5.27]), VDZ IV 300 mg Q8W (2.33 [1.43–3.86]), RZB SC 180 mg Q8W (1.80 [1.15–2.84]), VDZ SC 108 mg Q2W (1.76 [1.14–2.70]), and RZB SC 360 mg Q8W (1.60 [1.00–2.52]). In addition, IFX SC 120 mg Q2W showed the highest surface under the cumulative ranking curve (SUCRA) values (0.887), followed by ADL SC 40 mg Q2W (0.763), UST SC 90 mg Q8W (0.718), IFX IV 5 mg/kg Q8W (0.630), VDZ IV 300 mg Q8W (0.566), RZB SC 180 mg Q8W (0.353), VDZ SC 108 mg Q2W (0.327), RZB SC 360 mg Q8W (0.252), and PBO (0.005). CONCLUSION In this updated NMA on the comparative efficacy of licensed biologics, IFX SC 120 mg Q2W showed favorable efficacy in terms of clinical remission during maintenance treatment of 52–64 weeks’ duration in patients with moderate-to-severe CD.

P623 Network meta-analysis to evaluate the comparative efficacy of advanced therapies as first line for maintenance treatment of adult patients with moderate-to-severe Crohn’s disease

Abstract Background Subcutaneous (SC) CT-P13 provides patients and physicians with a new opportunity for maintenance treatment of Crohn’s disease (CD).1 Given the rapidly expanding therapeutic armamentarium for CD and lack of direct comparative evidence,2 an updated network meta-analysis (NMA) of data from Phase 3 randomised controlled trials (RCTs) was performed to evaluate the comparative efficacy of advanced CD therapies licensed in Europe or the US. Methods Eligible studies, identified by systematic literature review (PROSPERO no.: CRD42023413752), evaluated the efficacy of maintenance therapy using intravenous (IV) or SC infliximab, SC adalimumab, IV or SC vedolizumab, SC ustekinumab, SC risankizumab or oral upadacitinib, in patients with moderate-to-severe CD who responded to induction therapy. Head-to-head studies (including with treat-through designs) comparing licensed advanced therapies were also eligible. Studies were placebo- (PBO) or active-controlled and included 52–64 weeks of follow-up. Patients had not received prior tumour necrosis factor inhibitors, other biologics or Janus kinase inhibitors, thus each drug was received as first-line advanced therapy. Clinical remission and endoscopic response rates achieved with maintenance treatment were synthesised and analysed in a frequentist NMA random-effects model. Results There were 9 eligible RCTs (ACCENT I, LIBERTY-CD, CHARM, SEAVUE, GEMINI 2, VISIBLE 2, IM-UNITI, FORTIFY, U-ENDURE). Among 14 compared treatment arms, SC infliximab 120 mg every 2 weeks (Q2W) showed the highest risk difference (RD) versus PBO for achieving clinical remission during the maintenance phase (0.38 [95% confidence interval (CI): 0.23, 0.53]), followed by SC adalimumab 40 mg QW (0.32 [0.17, 0.48]) and oral upadacitinib 30 mg once daily (0.30 [0.08, 0.53]) (Figure A). Endoscopic response data were available from LIBERTY-CD, FORTIFY and U-ENDURE: among 5 treatment arms, SC infliximab 120 mg Q2W showed the highest RD (95% CI) versus PBO for achieving endoscopic response (0.39 [0.29, 0.49]), followed by SC risankizumab 180 mg Q8W (0.37 [0.17, 0.56]) and SC risankizumab 360 mg Q8W (0.27 [0.06, 0.48]) (Figure B). Conclusion In this updated NMA, SC infliximab 120 mg Q2W demonstrated a favourable efficacy profile in terms of achieving clinical remission and endoscopic response, when administered as a first-line advanced therapy for maintenance treatment of patients with moderate-to-severe CD. 1Remsima summary of product characteristics (https://www.ema.europa.eu/en/documents/product-information/remsima-epar-product-information_en.pdf). Accessed 1 November 2023. 2Barberio B et al. Gut 2023;72:264–74.

Take vedolizumab home: transition from intravenous to subcutaneous treatment.

In 2020, the European Medicines Agency approved subcutaneous (SC) vedolizumab (VDZ) for the maintenance treatment of adult patients with moderate to severe inflammatory bowel disease (IBD). This article reviews the efficacy, safety, persistence, pharmacology, patient satisfaction, and economic implications of transitioning to SC VDZ treatment and explores whether SC formulations can be recommended by the same guidelines as intravenous (IV) formulations. Clinical trials and real-world evidence indicate that transitioning from IV to SC VDZ in patients with IBD maintains clinical, biochemical, and patient-reported clinical remission and is well-tolerated, with no new safety issues identified, except for injection site reactions. Moreover, SC VDZ has an exposure-response relationship and low immunogenicity, is economical, and provides a high level of patient satisfaction. Owing to these advantages, transitioning may be advisable. In the future, more studies are needed to clarify the exact role of SC VDZ in IBD treatment, including optimization and transitioning strategies and individualized treatments based on baseline characteristics.

S1130 Network Meta-Analysis to Evaluate the Comparative Efficacy of Biologics for Maintenance Treatment of Adult Patients With Crohn’s Disease

S1130 Network Meta-Analysis to Evaluate the Comparative Efficacy of Biologics for Maintenance Treatment of Adult Patients With Crohn’s Disease

A real-world disproportionality analysis of Rucaparib: Post-marketing Pharmacovigilance Data

BackgroundRucaparib has been approved for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. However, the long-term safety of rucaparib in large sample population was unknown. The presented study aimed to evaluate rucaparib-associated adverse events (AEs) according to the real-world pharmacovigilance database.MethodsDisproportionality analysis was conducted to assess the association between rucaparib and its AEs. Data were collected from the international pharmacovigilance database of US FDA Adverse Event Reporting System (FAERS) between January 2017 and June 2022. The characteristics of rucaparib-related AEs, and the onset time were further analyzed.ResultsA total of 9,296,694 AE reports were recorded in the FAERS during the study period, among which 7,087 reports were associated with rucaparib. About 135 rucaparib-related AE signals in 15 system organ class (SOCs) were identified. The most common AEs included anaemia, thrombocytopenia, nausea, vomiting, fatigue, blood creatinine increase, alanine aminotransferase increase, and aspartate aminotransferase increase, which were listed in the label for rucaparib. Of note, 21 new and unexpected significant AEs that off-label were also found in our study, such as preferred term (PTs) of intestinal obstruction, gastrooesophageal reflux disease, blood iron decreased, dehydration, and hypersomnia. The median onset time of rucaparib-related AEs was 12 days (interquartile range [IQR] 1–62 days), and had early failure types.ConclusionOur study demonstrated potential new AEs of rucaparib, and further studies were expected to confirm the results.

P445 Network meta-analysis to evaluate the comparative efficacy of intravenous and subcutaneous infliximab and vedolizumab in the maintenance treatment of adult patients with Crohn’s Disease and Ulcerative Colitis

Abstract Background Network meta-analysis (NMA) using randomised controlled trial (RCT) data can provide indirect evidence on comparative efficacy of various treatments.1 The NMA reported herein was conducted to evaluate infliximab (IFX) and vedolizumab (VDZ) comparative efficacy during maintenance treatment of moderate-to-severe Crohn’s disease (CD) and ulcerative colitis (UC), covering various dosing regimens and administration routes for each biologic. Methods Studies were identified by literature searches that included publications up to 1 November 2022. Parallel-group RCTs evaluating IFX or VDZ (intravenous [IV] or subcutaneous [SC]) for maintenance treatment of adult patients with moderate-to-severe CD or UC that reported clinical remission rates were included. Eligible studies treated patients for a minimum of 22 weeks, with follow-up of 30–60 weeks for maintenance. Clinical remission rates in tumour necrosis factor inhibitor (TNFi)-naïve patients from each study were analysed in a Bayesian NMA fixed-effect model. Results Overall, 13 RCTs were identified and included in the analysis (Table 1 for CD and Table 2 for UC). The difference in study design between IFX (treat-through) and VDZ (re-randomisation of induction responders only) was noted. A connected network of evidence could be generated using CD and UC studies (Figures 1A and 1B, respectively). In both CD and UC, IFX SC 120 mg had the highest odds ratio (95% confidence interval [CI]) vs. placebo for clinical remission during the maintenance phase (CD: 5.90 [1.90–18.2]; UC: 5.45 [1.94–15.3]), albeit with the CIs overlapping with the CIs of the other tested regimens (Figures 2A and 2B). In both CD and UC, IFX SC 120 mg ranked highest for clinical remission among the biological agents, dosing regimens, and routes of administration tested. Conclusion In both CD and UC, IFX SC showed a favourable efficacy profile for achieving clinical remission during maintenance treatment of TNFi-naïve adult patients, when compared with the other IFX IV or VDZ IV/SC regimens tested.

POSC66 Cost-Effectiveness of Avelumab as First-Line Maintenance Treatment for Locally Advanced or Metastatic Urothelial Carcinoma in Finland

Avelumab is a fully human IgG1 antibody that targets PD-L1. Avelumab is approved in Finland as monotherapy for first-line maintenance treatment of adult patients with locally advanced or metastatic urothelial carcinoma that has not progressed during platinum-based chemotherapy. This study aimed to assess the cost-effectiveness of avelumab + best supportive care (BSC) versus BSC alone in the aforementioned indication in the Finnish healthcare setting.

Budget impact analysis of niraparib for first-line maintenance therapy in advanced ovarian cancer from a US payer perspective.

BACKGROUND: Ovarian cancer (OC) is the fifth leading cause of cancer death in women and has the highest mortality rate of gynecological cancers. Niraparib was recently approved by the FDA for the maintenance treatment of adult patients with advanced epithelial OC in complete or partial response to first-line platinum-based chemotherapy (PBC) regardless of biomarker status. OBJECTIVE: To estimate the direct economic impact on US payers of adding niraparib as a first-line maintenance therapy for patients with advanced OC. METHODS: The model considered 2 scenarios: a current scenario in which niraparib does not have regulatory approval for first-line maintenance therapy and a future scenario in which niraparib has regulatory approval for first-line maintenance therapy. The budget impact was calculated as the difference in cost between the 2 scenarios. The budget impact model (BIM) considered 2 different US health care payer perspectives: a commercial health plan and a Medicare plan. Both payer perspectives were assumed to have a hypothetical 1 million affiliates that were covered. Epidemiological data was used to estimate the eligible incident population of patients with OC. Active surveillance, bevacizumab (as a monotherapy), and olaparib (as a monotherapy restricted to patients with the breast cancer gene [BRCA] mutation) were included in the model as alternative maintenance treatment options (maintenance treatment options required 1% market share for inclusion). Cost categories considered in the BIM included diagnostic testing, treatment acquisition and administration, treatment-emergent adverse events, and subsequent therapy. Results were presented as an incremental budget impact to payers over 3 years. RESULTS: For a commercial health plan of 1 million affiliates, the estimated impact of adding niraparib as a first-line maintenance treatment option for advanced epithelial OC was calculated as $87,906, $93,106, and $87,037 for years 1, 2, and 3, respectively. The average budget impact per member per month was $0.007. For a Medicare health plan of 1 million affiliates, the estimated impact was calculated as $206,785, $219,017, and $204,739 for years 1, 2, and 3, respectively. The average budget impact per member per month was $0.018. One-way sensitivity analyses suggested that budget impact was most sensitive to the treatment duration and market share of niraparib, the non-treatment-specific data on overall survival rates, and the treatment duration of bevacizumab. Treatment of drug-specific adverse events had little impact on the budget model. CONCLUSIONS: The model estimated a minimal budget impact to both a commercial or Medicare health plan following the introduction of niraparib as a first-line maintenance therapy for patients with advanced epithelial OC who are in complete or partial response to first-line PBC regardless of biomarker status. DISCLOSURES: This study was financially supported by GlaxoSmithKline. Liu, Hawkes, Maiese, and Hurteau are employees of GlaxoSmithKline. Travers was employed by GlaxoSmithKline at the time of this study. Spalding and Walder are employees of FIECON Ltd., which was contracted by GlaxoSmithKline to develop the budget impact model used in this study.

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

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

Interim results of the non-interventional C-PATROL study: Real-world treatment data from patients who switched from olaparib capsules to tablets

Objective: Olaparib (50-mg hard capsules) has been approved in the European Union since December 2014 as monotherapy for maintenance treatment of adult patients with platinum-sensitive relapsed BRCA-mutated ovarian cancer (PSR-OC) who are in response to platinum-based chemotherapy. Subsequently, film-coated tablets (100/150 mg) were approved in the European Union in May 2018, but regardless of BRCA status. So far, no real-world olaparib treatment data from patients who switched from olaparib hard capsules to film-coated tablets (switcher) are available.

Pharmacokinetics and safety following a single oral dose of niraparib in patients with moderate hepatic impairment.

6054 Background: Niraparib is approved for the maintenance treatment of adult patients (pts) with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy, or with similar cancers but advanced, associated with homologous recombination deficiency (HRD) and have been treated with ³3 prior chemotherapy regimens. Niraparib is extensively metabolized in the liver and eliminated via both hepatobiliary and renal routes. Objectives of this study included characterization of niraparib pharmacokinetics (PK) and safety in pts with normal hepatic function vs. pts with moderate hepatic impairment. Methods: This phase I, open-label, parallel-group, single-dose study enrolled pts with advanced solid tumors into 2 groups: normal hepatic function and moderately impaired hepatic function, defined as bilirubin >1.5 to 3 times the upper limit of normal and any aspartate aminotransferase elevation. Pts received a single 300-mg dose and underwent PK sampling for 7 days. Exposure parameters included maximum concentration (Cmax), area under the concentration-time curve calculated to last measured concentration (AUClast), and extrapolated to infinity (AUCinf). PK parameters were determined using a non-compartmental analysis in WinNonlin. Results: Seventeen pts were enrolled; 9 with normal hepatic function and 8 with hepatic impairment. Niraparib Cmax was 7% lower in pts with moderate hepatic impairment compared with pts with normal hepatic function (Table). Overall exposure was increased in pts with moderate hepatic impairment, with niraparib AUClast and AUCinf increased 45% and 60%, respectively. Safety data during the PK phase of the study is consistent with the known profile for niraparib. Conclusions: Pts with moderate hepatic impairment experienced increased niraparib exposure which did not noticeably alter the toxicity profile in this population. Clinical trial information: NCT03359850. [Table: see text]

Symptomatic and functional outcomes after treatment with paliperidone palmitate 3-month formulation for 52 weeks in patients with clinically stable schizophrenia.

Background:Paliperidone palmitate 3-monthly (PP3M) formulation is a long-acting, injectable antipsychotic treatment approved in many countries worldwide for the maintenance treatment of adult patients with schizophrenia. This single-arm, open-label, phase IIIb study evaluated the efficacy and safety of converting patients with schizophrenia stabilized with paliperidone palmitate 1-month (PP1M) to PP3M in a naturalistic clinical setting.Methods:After screening (days –7 to 1), patients were converted from PP1M (50–150 mg eq.) to PP3M (175–525 mg eq.), and entered a 52-week, flexible-dose PP3M treatment period. The primary efficacy endpoint was symptomatic remission (SR) (Andreasen criteria) at last observation carried forward (LOCF) endpoint.Results:Patients (n = 305) received PP3M, of whom 291 (95.4%) completed the study. Doses of PP3M remained stable during the 12-month treatment period, and changes in dose were uncommon. Overall, 56.8% of patients [95% confidence interval (CI): 51.0, 62.4] achieved SR, and 31.8% achieved both symptomatic and functional remission (Personal and Social Performance scale total score > 70) at LOCF endpoint. Secondary endpoint results were generally consistent with primary endpoint results. There were improvements in Positive and Negative Syndrome Scale total, subscale and Marder factor scores, and also Clinical Global Impression-Severity and -Change scores from baseline to LOCF endpoint. Carer burden was reduced, and the proportion of patients requiring hospitalization for psychiatric reasons decreased from 13.5% in the 12 months prior to baseline to 4.6% during the treatment period. No new safety signals were identified.Conclusion:Results from this naturalistic study were similar to those observed in previous randomized clinical trials of PP3M and underline the importance of continuous maintenance treatment in patients with schizophrenia.

1007P - Results of the 3rd interim analysis of C-Patrol: A non-interventional study on olaparib in German routine clinical practice

1007P - Results of the 3rd interim analysis of C-Patrol: A non-interventional study on olaparib in German routine clinical practice

Results of the second interim analysis of C-PATROL: A non-interventional study on olaparib within German routine clinical practice

Objective: Olaparib (50 mg hard capsules, HC) is approved in the European Union as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed BRCA-mutated (BRCAm) ovarian cancer (PSR-OC) who are in response to platinum-based chemotherapy. So far, only limited data on real-world olaparib treatment are available.

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.

Abstract 1724: Evaluation of niraparib in combination with anti-PD1/anti-PD-L1 in preclinical models

Abstract Niraparib is an orally available and selective poly(ADP-ribose) polymerase (PARP)-1/-2 inhibitor approved 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. PARP inhibition may enhance the immune response in tumors treated with anti-PD-1 therapy via generation of cytosolic DNA that activates T cells through the stimulator of interferon gene (STING) pathway, rendering tumors immunologically “hot” with an increase in infiltrating lymphocytes. In this study, we explored the responses and mechanism of action of niraparib and anti-PD-1/anti-PD-L1 combination therapy in preclinical models. Out of a cohort of 14 immune-competent mouse tumor models, the combination treatment demonstrated enhanced anti-tumor activity in eight tumor models derived from BRCA-proficient and BRCA-deficient genetic backgrounds. Substantial increases compared to monotherapies in anti-tumor activity was observed in 5 models, indicative of synergy between niraparib and anti-PD-1/anti-PD-L1 therapy. The combination triggered durable responses that were coincident with induction of immune memories in a BRCA-deficient ovarian syngeneic model. Mechanistically, niraparib treatment increased the number of infiltrating CD8+ and CD4+ cells within the intratumoral region. The enhanced immune cell infiltration was accompanied by elevated interferon-stimulated gene expression. Pathway analyses using transcriptome profiling identified interferon response gene signatures as the significantly differentially-upregulated gene sets following niraparib treatment. Consistently, niraparib treatment activated the STING pathway in vitro in BRCA-deficient MDA-MB-436 human triple negative breast cancer cells. STING pathway markers including p-STING(Ser366), p-TBK1(Ser172) and p-NFκB p65 were elevated following niraparib treatment and was accompanied by an increase in IFNB mRNA expression. In summary, our data suggested that niraparib treatment in combination with anti-PD-1/anti-PD-L1 therapy enhanced immune cell infiltration, interferon-stimulated gene expression and tumor responses. Citation Format: Sarah Wang, Kaiming Sun, Yonghong Xiao, Bin Feng, Keith Mikule, Sridhar Ramaswamy, Jeffrey Hanke, Jing Wang. Evaluation of niraparib in combination with anti-PD1/anti-PD-L1 in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1724.

Cost-effectiveness of niraparib versus routine surveillance, olaparib, and rucaparib for the maintenance treatment of adult patients with ovarian cancer in the United States.

5559 Background: To estimate the cost-effectiveness of niraparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, compared with routine surveillance (RS), olaparib and rucaparib for the maintenance treatment of patients with recurrent ovarian cancer. Methods: A decision-analytic model estimated the cost per quality-adjusted life-year gained for niraparib versus RS, olaparib and rucaparib from a US payer perspective. Recurrent ovarian cancer patients with or without germline BRCA mutation, who were responsive to their last platinum-based chemotherapy regimen, entered the model (non-gBRCAmut, gBRCAmut). The model had three health states; progression-free disease, progressed disease and dead. For non-gBRCAmut and gBRCAmut, mean progression-free survival (PFS) was estimated for niraparib and RS, and rucaparib using parametric survival distributions based on ENGOT-OV16/NOVA (Niraparib Phase III trial) and ARIEL3 (Rucaparib Phase III trial), respectively. For non-gBRCAmut, olaparib PFS was estimated from Study 19 (Olaparib Phase II trial). For gBRCAmut, a cost-minimisation analysis was conducted versus olaparib. Due to immature overall survival (OS) data in ENGOT-OV16/NOVA and ARIEL3, mean OS benefit was estimated as double the mean PFS benefit for niraparib, olaparib and rucaparib versus RS. Costs included; drug, chemotherapy, monitoring, adverse events, and terminal care. EQ-5D captured quality-of-life. A 3% annual discount rate was used. Results: Treatment with niraparib increased costs and QALYs versus RS, with an incremental cost-effectiveness ratio of $94,186 and $58,804, for non-gBRCAmut and gBRCAmut. Niraparib had lower costs and higher QALYs compared to olaparib and rucaparib in both populations, with a cost difference of -$57,575 and -$60,400 versus olaparib, and a cost difference of -$117,916 and -$261,950 versus rucaparib for non-gBRCAmut and gBRCAmut. Conclusions: These estimates indicate that niraparib was cost-effective compared to olaparib and rucaparib. Additionally, the cost-effectiveness ratio falls within an acceptable range versus RS. Mature OS data is required to validate these results.

PCN127 - Cost-Effectiveness of Niraparib Versus Routine Surveillance and Olaparib for the Maintenance Treatment of Adult Patients with Ovarian Cancer in the United States

To estimate the cost-effectiveness of niraparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, compared with routine surveillance (RS) and olaparib for the maintenance treatment of patients with recurrent ovarian cancer. A decision-analytic model estimated the cost per quality-adjusted life-year (QALY) gained for niraparib versus RS and olaparib from a US payer perspective. Recurrent ovarian cancer patients with or without germline BRCA mutation, who were responsive to their last platinum-based chemotherapy regimen, entered the model (non-gBRCAmut, gBRCAmut). The model had three health states; progression-free disease, progressed disease and dead. For both non-gBRCAmut and gBRCAmut populations, mean progression-free survival (PFS) was estimated for niraparib and RS using parametric survival distributions based on ENGOT-OV16/NOVA (Niraparib Phase III trial). For non-gBRCAmut, olaparib PFS was estimated from Study 19 (Olaparib Phase II trial). For gBRCAmut, a cost-minimisation analysis was conducted for niraparib versus olaparib. Due to the immaturity of OS data in ENGOT-OV16/NOVA, mean OS benefit was estimated from the Study 19 RS arm, as double the mean PFS benefit for both niraparib and olaparib. Costs included; drug, subsequent chemotherapy, monitoring, adverse events, and terminal care. Quality-of-life was captured using EQ-5D. A 3.00% discount rate per annum was used. Treatment with niraparib increased costs and QALYs compared to RS, resulting in an incremental cost-effectiveness ratio of $94,186 and $58,804, for non-gBRCAmut and gBRCAmut, respectively. Niraparib dominated olaparib in both populations, with a cost difference of -$60,400 and similar QALYS in gBRCAmut, and a cost difference of -$55,858 and incremental QALYs of 1.437 in non-gBRCAmut. This cost decrease was driven by lower monthly drug costs for niraparib compared with olaparib based on average dose. These estimates indicate that niraparib dominates olaparib and falls within an acceptable cost-effectiveness range versus RS. Mature OS data is required to validate these findings.

The effect of food on the pharmacokinetics of niraparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, in patients with recurrent ovarian cancer

PurposeNiraparib is a highly selective inhibitor of PARP-1 and PARP-2 approved in the United States for maintenance treatment of adult patients with recurrent ovarian cancer in complete or partial response to platinum-based chemotherapy. In this open-label crossover study, we evaluated the effects of food on niraparib pharmacokinetics (PK) and safety.MethodsPatients received a single 300-mg dose of niraparib either after a high-fat meal or under fasting conditions. After a 7-day PK assessment, all patients received a second 300-mg dose of niraparib under the opposite condition, followed by 7-day PK assessment. Blood samples for PK analyses were collected at baseline (on days 1 and 8) and up to 168 h post-dose. Bioequivalence between conditions was defined by the 90% confidence intervals (CIs) for area under the plasma concentration–time curve (AUC) from 0 to last measurable concentration (AUC0–last) and from 0 to infinity (AUC0–∞) being within the 80–125% range.ResultsThe high-fat meal/fasting ratios of geometric least-squares means for AUC0–last and AUC0–∞ were 106.8 (90% CI 97.8–116.6) and 110.1 (90% CI 99.7–121.6), respectively, indicating bioequivalence between conditions. Mean half-life, maximum plasma concentration (Cmax), and time to Cmax after the high-fat meal were similar to, 27% smaller than, and 128% greater than after fasting, respectively. Adverse events were similar between conditions.ConclusionsA high-fat meal did not impact the PK profile of niraparib, indicating that niraparib can be taken with or without food. Niraparib was safe and well-tolerated.

Abstract A102: A comparative pharmacokinetic-pharmacodynamic-treatment study of PARP inhibitors demonstrates favorable properties for niraparib activity in preclinical tumor models

Abstract Introduction: Niraparib is an orally bioavailable and selective poly (ADP-ribose) polymerase (PARP)-1/-2 inhibitor approved for 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. This study examined the pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of niraparib as compared to two other approved PARP inhibitors, olaparib and rucaparib, in several ovarian cancer and triple-negative breast cancer xenograft models. Experimental Procedures: Niraparib, olaparib, and rucaparib were administered orally to mice at near maximum tolerated dose (MTD) for each drug in the BRCA1 deficient MDA-MB-436 cell line-derived triple-negative breast cancer model, BRCA wildtype A2780 cell line-derived ovarian cancer model, and two BRCA wildtype patient-derived ovarian cancer xenograft models. Tumor growth was monitored twice per week post randomization for the efficacy studies. Tumor growth inhibition was calculated after prolonged treatment at the end of study for each model. For PK and PD analysis, plasma, tumor, and brain tissue samples were collected at 7 different time points on the 5th day of continuous treatment. Results: Niraparib demonstrated potent antitumor activities in both the BRCA deficient and BRCA wildtype models tested. Among the 3 clinically approved PARP inhibitors, niraparib consistently demonstrated a high level of antitumor activity at a relatively lower dose. Niraparib showed high tumor exposure (AUC0-24h: 213,959 ng/g•hr) and high brain exposure (AUC0-24h: 18,721 ng/g•hr) as compared to rucaparib (tumor AUC0-24h: 74,338 ng/g•hr; brain AUC0-24h: 4,380 ng/g•hr) and olaparib (tumor AUC0-24h: 7,586 ng/g•hr; brain AUC0-24h: 336 ng/g•hr) in MDA-MB-436 xenograft model at steady state. A unique feature of niraparib was that its exposure in tumor was more than 3 times higher than that in plasma, which is consistent with its high volume of distribution in the animal models and the clinical setting. Pharmacodynamic analysis indicated that niraparib is able to deliver ~90% PARP inhibition for 24 hours at steady state. Conclusions: Niraparib treatment induces potent antitumor activities in multiple ovarian and breast cancer models regardless of BRCA status. The potent antitumor activity induced by niraparib is consistent with its high exposure and durable PARP inhibition in tumor. Our nonclinical findings suggest that niraparib exhibits unique pharmacologic properties within the PARP class of inhibitors. Citation Format: Kaiming Sun, Grace Poon, Sarah Wang, Paul Vancutsem, Sridhar Ramaswamy, Jeffrey Hanke, Jing Yu Wang. A comparative pharmacokinetic-pharmacodynamic-treatment study of PARP inhibitors demonstrates favorable properties for niraparib activity in preclinical tumor models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A102.