Quality-adjusted time without symptoms of disease or toxicity and quality-adjusted progression-free survival with niraparib maintenance in first-line ovarian cancer in the PRIMA trial

Abstract

Background: The PRIMA phase 3 trial showed niraparib significantly prolongs median progression-free survival (PFS) versus placebo in patients with advanced ovarian cancer (OC) responsive to first-line platinum-based chemotherapy, including those who had tumors with homologous recombination deficiency (HRd). This analysis of PRIMA examined the quality-adjusted PFS (QA-PFS) and quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) of patients on maintenance niraparib versus placebo.

Methods: Patients were randomized 2:1 to receive once-daily maintenance niraparib (n = 487) or placebo (n = 246). QA-PFS was defined as the PFS of patients adjusted for their health-related quality of life (HRQoL) prior to disease progression, measured using European Quality of Life Five-Dimension (EQ-5D) questionnaire index scores from the PRIMA trial. Q-TWiST was calculated by combining data on PFS, duration of symptomatic grade ⩾2 adverse events (fatigue or asthenia, nausea, vomiting, abdominal pain, and abdominal bloating) prior to disease progression, and EQ-5D index scores. Analyses used data collected up to the last date of PFS assessment (May 17, 2019).

Results: The restricted mean QA-PFS was significantly longer with niraparib versus placebo in the HRd (n = 373) and overall intention-to-treat (ITT; n = 733) populations (mean gains of 6.5 [95% confidence interval; CI, 3.9-8.9] and 4.1 [95% CI, 2.2-5.8] months, respectively). There were also significant improvements in restricted mean Q-TWiST for niraparib versus placebo (mean gains of 5.9 [95% CI, 3.5-8.6] and 3.5 [95% CI, 1.7-5.6] months, respectively) in the HRd and ITT populations.

Conclusions: In patients with advanced OC, first-line niraparib maintenance was associated with significant gains in QA-PFS and Q-TWiST versus placebo. These findings demonstrate that niraparib maintenance treatment is associated with a PFS improvement and that treatment benefit is maintained even when HRQoL and/or toxicity data are combined with PFS in a single measure.

Trial registration: ClinicalTrials.gov: NCT02655016; trial registration date: January 13, 2016.

Plain language summary: Background: In a large clinical trial called PRIMA, patients with advanced cancer of the ovary (ovarian cancer) were given either niraparib (a type of cancer medicine) or placebo (a pill containing no medicine/active substances) after having chemotherapy (another type of cancer medicine). Taking niraparib after chemotherapy is called maintenance therapy and aims to give patients more time before their cancer returns or gets worse than if they were not given any further treatment. In the PRIMA trial, patients who took niraparib did have more time before their cancer progressed than if they took placebo. However, it is important to consider patients' quality of life, which can be made worse by cancer symptoms and/or side effects of treatment. Here, we assessed the overall benefit of niraparib for patients in PRIMA.Methods: Both the length of time before disease progression (or survival time) and quality of life were considered using two different analyses:● The first analysis was called quality-adjusted PFS (QA-PFS) and looked at how long patients survived with good quality of life.● The second analysis was called quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) and looked at how long patients survived without cancer symptoms or treatment side effects.Results: The PRIMA trial included 733 patients; 487 took niraparib and 246 took placebo. Around half of the patients in both groups had a type of ovarian cancer that responds particularly well to drugs like niraparib - they are known as homologous recombination deficiency (HRd) patients.● When information on quality of life (collected from patient questionnaires) and survival was combined in the QA-PFS analysis, HRd patients who took niraparib had approximately 6.5 months longer with a good quality of life before disease progression than those who took placebo. In the overall group of patients (including HRd patients and non-HRd patients), those who took niraparib had approximately 4 months longer than with placebo.● Using the second analysis (Q-TWiST) to combine information on survival with cancer symptoms and treatment side effects, the HRd patients taking niraparib had approximately 6 months longer without cancer symptoms or treatment side effects (such as nausea or vomiting) than patients taking placebo. In the overall group of patients, those taking niraparib had approximately 3.5 months longer without these cancer symptoms/side effects than patients receiving placebo.Conclusions: These results show that the survival benefits of niraparib treatment remain when accounting for patients' quality of life. These benefits were seen not only in HRd patients who are known to respond better to niraparib, but in the overall group of patients who took niraparib.

Keywords: maintenance therapy; niraparib; ovarian cancer; quality of life.

Conflict of interest statement

Competing interests: MPBG reports receiving lecture fees, advisory board fees, and travel support from AstraZeneca, Clovis Oncology, GSK, Merck, PharmaMar, Roche, and Tesaro. BJM has received honoraria and lecture fees from Tesaro. BP has received institutional grant support from AstraZeneca, Celsion, Clovis Oncology, Genentech/Roche, Merck, Mersana, Tesaro/GSK, Toray, I-Mab, Incyte, and Seagen; and advisory board compensation from Arquer, AstraZeneca, Eisai, Elevar, Lilly, Merck, Mersana, Tesaro/GSK, I-Mab, ImmunoGen, InxMed, Onconova Therapeutics, Seagen, and Toray. AAu reports receiving consulting fees from GSK. DMC reports personal fees from GSK; has received honoraria from Roche; has served as a consultant to AstraZeneca and Mateon Therapeutics; and has received research grants to her institution from Genentech. DL reports receiving advisory board fees from Amgen, AstraZeneca, Clovis Oncology, Genmab, and ImmunoGen; grant support, paid to her institution, and consulting fees from PharmaMar; and grant support, paid to her institution, and advisory board fees from Merck. EIB reports receiving consulting fees, lecture fees, and travel support from AstraZeneca, Clovis, GSK, Tesaro, Roche, Roche Diagnostics, Eisai, and Merck Sharp & Dohme; and grant support to their institution from Roche Diagnostics, Merck Sharp & Dohme, and Bayer. AR has received grant support, advisory fees, and travel support from PharmaMar and Roche; advisory fees and travel support from AstraZeneca and Tesaro/GSK; advisory fees from Clovis; and grant support from Eisai. RS is an employee of Open Health Evidence and Access, which received research funding from GSK for this study. NK was an employee of Open Health Evidence and Access at the time of the study. CH and DG are employees of GSK. TW is a former employee of GSK. DMO reports grants and personal fees from Clovis; has served on advisory boards for Agenus, AstraZeneca, Eisai, Genentech/Roche, ImmunoGen, Iovance Biotherapeutics, Janssen/Johnson & Johnson, Merck, Mersana, Myriad, Novartis Pharmaceuticals, Novocure, Regeneron Pharmaceuticals, Seagen, Tarveda, and Tesaro/GSK; has served on steering committees for Amgen; has served as a consultant to AbbVie, Agenus, Ambry, AstraZeneca, Eisai, Genentech/Roche, GOG Foundation, ImmunoGen, Iovance Biotherapeutics, Merck, Mersana, Novartis Pharmaceuticals, Novocure, Seagen, and Tesaro/GSK; and has received research support to his institution from AbbVie, Agenus, Ajinomoto, Amgen, Array BioPharma, AstraZeneca, Bristol-Myers Squibb, Cerulean Pharma, Eisai, EMD Serono, Ergomed Clinical Research, Genentech/Roche, Genmab, GOG Foundation, ImmunoGen, INC Research, inVentiv Health Clinical, Iovance Biotherapeutics, Janssen/Johnson & Johnson, Ludwig Institute for Cancer Research, Merck, Mersana, New Mexico Cancer Care Alliance, Novocure, PRA International, Regeneron Pharmaceuticals, Seagen, Serono, Stemcentrx, Tesaro/GSK, TRACON Pharmaceuticals, VentiRx, and Yale University. AGM reports receiving consulting fees from Alkermes, Amgen, AstraZeneca, Clovis, Genmab, GSK, Immunogen, Mersana, Merck Sharp & Dohme, Oncoinvent, PharmaMar, Roche, SOTIO, and Takeda; lecture fees from AstraZeneca, Clovis, GSK, Merck Sharp & Dohme, PharmaMar, and Roche; travel support from AstraZeneca, GSK, and PharmaMar; grant support to their institution from Roche Holding and Tesaro. SH, CA, SAL, NC, and AAm have no conflicts to disclose.

© The Author(s), 2022.

Figures

Figure 1.

Partitioned survival curves for the (a) HRd and (b) overall ITT populations. TOX included grade ⩾2 AEs of interest (fatigue or asthenia, nausea, vomiting, abdominal pain, and abdominal bloating). HRd and overall ITT populations had a maximum PFS of 27.8 months. AE, adverse event; HRd, homologous recombination deficient; ITT, intention-to-treat; PFS, progression-free survival; TOX, time before PFS during which patients experienced grade ⩾2 AEs; TWiST, time without symptoms of disease or toxicity.

Figure 2.

Mean Q-TWiST gain for the HRd and overall ITT populations at maximum PFS of the treatment group. CI, confidence interval; HRd, homologous recombination deficient; ITT, intention-to-treat; PFS, progression-free survival; Q-TWiST, quality-adjusted time without symptoms of disease or toxicity.