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. 2024 Aug;46(8):612-621.
doi: 10.1016/j.clinthera.2024.06.001. Epub 2024 Jul 16.

Niraparib Population Pharmacokinetics and Exposure-Response Relationships in Patients With Newly Diagnosed Advanced Ovarian Cancer

Bradley J Monk  1 , Ignacio Romero  2 , Whitney Graybill  3 , Cristina Churruca  4 , David M O'Malley  5 , Anja Ør Knudsen  6 , Oi Wah Stephanie Yap  7 , Jean-François Baurain  8 , Peter G Rose  9 , Hannelore Denys  10 , Sharad Ghamande  11 , Carmela Pisano  12 , Michel Fabbro  13 , Elena Ioana Braicu  14 , Paula M Calvert  15 , Amnon Amit  16 , Emily Prendergast  17 , Adekemi Taylor  18 , Leila Kheibarshekan  18 , Zhi-Yi Zhang  19 , Stefan Zajic  20 , Roxanne C Jewell  21 , Divya Gupta  19 , Antonio González-Martín  22
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Free article

Niraparib Population Pharmacokinetics and Exposure-Response Relationships in Patients With Newly Diagnosed Advanced Ovarian Cancer

Bradley J Monk et al. Clin Ther. 2024 Aug.
Free article

Abstract

Purpose: Niraparib is a poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor approved for the maintenance treatment of advanced ovarian cancer (OC). Niraparib was originally approved in recurrent OC at a fixed starting dose (FSD) of 300 mg once daily (QD). This analysis characterized the population pharmacokinetics (PK) of niraparib and evaluated the relationships between exposure, efficacy, and safety to support clinical use of an individualized dosing strategy, in which the starting dose of niraparib was adjusted based on patient characteristics to improve the benefit-risk profile.

Methods: A population PK model was developed by pooling data from four niraparib clinical trials (PN001 [n = 104], QUADRA [n = 455], NOVA [n = 403], and PRIMA [n = 480]) in patients with solid tumors, including OC. Exposure-response analyses were conducted to explore the relationships of niraparib exposure with progression-free survival (PFS) and adverse events in the PRIMA study. A multivariate logistic regression model was also developed to estimate the probability of grade ≥3 thrombocytopenia, using data from patients enrolled in PRIMA and NOVA. The impact of an individualized starting dose (ISD) regimen (200 mg QD in patients with body weight [BW] <77 kg or platelet count [PLT] <150,000/µL, or 300 mg QD in patients with BW ≥77 kg and PLT ≥150,000/µL) on systemic exposure, efficacy, and safety was assessed.

Findings: Niraparib disposition was best described by a 3-compartment model with linear elimination. Key covariates included baseline creatinine clearance, BW, albumin, and age, all of which had minor effects on niraparib exposure. Comparable model-predicted exposure up to the time of disease progression/death or censoring in the 300-mg FSD and 200-/300-mg ISD groups was consistent with the lower rate of dose reduction in the ISD groups. No consistent niraparib exposure-response relationship was observed for efficacy in all PRIMA patients (first-line OC), and no statistically significant difference was seen in PFS curves for patients receiving a niraparib dose of 200 mg versus 300 mg. In the multivariate regression model, performed using combined data from PRIMA and NOVA, higher niraparib exposure (area under the concentration-time curve at steady-state [AUCss]), lower BW, and lower PLT were associated with an increased risk of grade ≥3 thrombocytopenia.

Implications: Population PK and exposure-response analyses support use of an ISD to improve the safety profile of niraparib, including reducing the rate of grade ≥3 thrombocytopenia, without compromising efficacy.

Clinical trial registration: ClinicalTrials.gov, NCT01847274 (NOVA), NCT00749502 (PN001), NCT02655016 (PRIMA), NCT02354586 (QUADRA), www.

Clinicaltrials: gov.

Keywords: Niraparib; Ovarian cancer; PARP inhibitor; Population pharmacokinetics.

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Conflict of interest statement

Declaration of competing interest Bradley J. Monk is an Associate Editor for Annals of Oncology and was not involved in the editorial review or the decision to publish this article. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Bradley J. Monk reports consulting fees from Agenus, Akeso Biopharma, Amgen, Aravive, Bayer, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, ImmunoGen, Iovance, Karyopharm, MacroGenics, Mersana, Myriad, Novartis, Novocure, Pfizer, Puma, Regeneron, Sorrento, US Oncology Research, and VBL and speakers’ bureau honoraria from AstraZeneca, Clovis, Eisai, Merck, Roche/Genentech, and Tesaro/GSK. Ignacio Romero reports consulting or advisory role at AstraZeneca, Clovis, GSK, MSD, and Roche; speakers bureau at AstraZeneca, GSK, PharmaMar, and Roche; research funding from AstraZeneca and Roche; and travel expenses from AstraZeneca, Clovis, GSK, MSD, PharmaMar, and Roche. Whitney Graybill reports personal fees from GSK. David M. O'Malley reports personal fees from Agenus, Eisai, GSK, and Immunogen; consultant/advisory board for AbbVie, Ambry, Amgen, Array Biopharma, Clovis, EMD Serono, Ergomed, Janssen/J&J, Myriad Genetics, Novocure, Regeneron, Tarveda, and VentiRx; steering committee for Genentech/Roche and Merck; institutional funding from Ajinomoto, BMS, Cerulean Pharma, GOG Foundation, INC Research, InVentiv Health Clinical, Iovance Biotherapeutics, Ludwig Cancer Research, New Mexico Cancer Care Alliance, PRA International, Serono, Stemcentrx, Tracon Pharmaceuticals, and Yale University. Hannelore Denys reports consulting or advisory role at Amgen, AstraZeneca, Eli Lilly, Gilead, GSK, MSD, Novartis, Pfizer, PharmaMar, and Seagen; institutional research funding from Gilead; and travel expenses from AstraZeneca, Gilead, GSK, Pfizer, PharmaMar, Roche, and Teva. Sharad Ghamande reports consulting fees from Seattle Genetics; speakers bureau fees from GSK; and institutional grants from AbbVie, Advaxis, BMS, Clovis, Genentech, GSK, Merck, Roche, Seattle Genetics, Takeda, and Tesaro. Carmela Pisano reports speakers’ bureau fee and advisory role from AstraZeneca, GSK, and MSD. Michel Fabbro reports honoraria from GSK. Elena Iona Braicu reports honoraria from AstraZeneca, GSK, and Merck; consulting or advisory roles at AstraZeneca and GSK; institutional research funding from AstraZeneca, Bayer, Clovis, Eisai, GSK, Merck, and Resolve; travel support from AstraZeneca; and relationship with medical director of the North Eastern German Society of Gynecological Oncology (NOGGO). Paula M. Calvert reports an educational grant for meeting attendance, flights, and accommodations from MSD. Emily Prendergast reports consulting or advisory role at AstraZeneca and Merck. Adekemi Taylor reports being an employee of Certara (a biosimulation company) and, as a Certara employee, provided consulting services to GSK and Tesaro for this analysis and also provides consulting services to various pharmaceutical and biotech companies. Zhi-Yi Zhang was an employee of GSK when these analyses were undertaken and held shares/stock options in GSK. Stefan Zajic is an employee of GSK and holds shares/stock in GSK. Roxanne C. Jewell is an employee of GSK and holds shares/stock in GSK. Divya Gupta was an employee of GSK when these analyses were undertaken and held shares/stock options in GSK. Antonio González-Martín reports consulting fees from Alkermes, Amgen, AstraZeneca, Clovis, Daichii ,Genmab, GSK, Hedera DX, Illumina, Immunogen, Incyte, Kartos, Karyopharm, Mersana, MSD, Novartis, Novocure, Oncoinvent, Pharma&, PharmaMar, Roche, Seagen SOTIO, Sutro, Takeda, and Tubulis; grants or contracts from Asociación Española Contra el Cáncer, GSK, Instituto de Salud Carlos III, and Roche; payment or honoraria for lectures, presentations, or speakers bureau from AstraZeneca, Clovis, GSK, Immunogen, Mersana, MSD, Novocure, PharmaMar, Roche, Takeda, Seagen, and Zai Lab; and travel support from AstraZeneca, Clovis, GSK, Immunogen, Mersana, MSD, Novocure, PharmaMar, Roche, and Takeda. Peter G. Rose, Amnon Amit, Leila Kheibarshekan, Cristina Churruca, Anja Ør Knudsen, Oi Wah Stephanie Yap, and Jean-François Baurain have nothing to disclose.

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