Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial

Kathleen N. Moore, Angeles Alvarez Secord, Melissa A. Geller, David Scott Miller, Noelle Cloven, Gini F. Fleming, Andrea E. Wahner Hendrickson, Masoud Azodi, Paul DiSilvestro, Amit M. Oza, Mihaela Cristea, Jonathan S. Berek, John K. Chan, Bobbie J. Rimel, Daniela E. Matei, Yong Li, Kaiming Sun, Katarina Luptakova, Ursula A. Matulonis, Bradley J. Monk

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347 Scopus citations

Abstract

Background: 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. Methods: 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. Findings: 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. Interpretation: 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. Funding: Tesaro.

Original languageEnglish (US)
Pages (from-to)636-648
Number of pages13
JournalThe Lancet Oncology
Volume20
Issue number5
DOIs
StatePublished - May 2019

Bibliographical note

Funding Information:
KNM reports honoraria or advisory board fees from Tesaro, Genentech, Roche, Clovis Oncology, AstraZeneca, ImmunoGen, VBL Therapeutics, and Janssen, outside the submitted work. AAS reports research funding and honoraria or advisory board fees from Tesaro during the conduct of the study; and research funding from AbbVie, Amgen, Astex Pharmaceuticals, AstraZeneca, Clovis, Astellas Pharma, Boehringer Ingelheim, Bristol-Myers Squibb, Eisai, Endocyte, Exelixis, Incyte, Merck, PharmaMar, Immutep, Roche, Genentech, Seattle Genetics, and TapImmune, and honoraria or advisory board fees from Alexion, Aravive, Astex Pharmaceuticals, AstraZeneca, Clovis, Janssen, Johnson & Johnson, Merck, Mersana, Myriad, Oncoquest, Roche, and Genentech, outside the submitted work. MAG reports consulting fees, speaker's bureau fees, and research funding from Tesaro, outside the submitted work. DSM reports consulting fees, speakers' bureau fees, and research funding from Genentech; consulting fees and research funding from Tesaro, ImmunoGen, and AstraZeneca; consulting and speakers' bureau fees from Clovis Oncology; consulting fees from Eisai, Guardant Health, and Alexion Pharmaceuticals; and research funding from TRACON Pharmaceuticals, Janssen, Aeterna Zentaris, Pfizer, Aprea Therapeutics, Takeda, and Xenetic Biosciences, all outside the submitted work. NC reports research funding from Tesaro, and employment by Texas Oncology, outside the submitted work. GFF reports financial relationships with Aeterna Zentaris outside the submitted work. PD reports consulting fees and research funding from Tesaro and AstraZeneca, and research funding from AbbVie, Genentech, Roche, and Janssen, outside the submitted work. AMO reports consulting and advisory fees from Clovis Oncology; honoraria from WebRX and Intas Oncology, and travel and expenses payments from AstraZeneca, outside the submitted work. MC reports research funding from TrovaGene outside the submitted work. JKC reports consulting fees, speakers' bureau fees, and honoraria from Genentech, Roche, AstraZeneca, and Tesaro; speakers' bureau fees and honoraria from Clovis Oncology; and consulting for Janssen Oncology, Mateon Therapeutics, and Biodesix, all outside the submitted work. BJR reports advisory board participation with Tesaro, AstraZeneca, Genentech, and Clovis Oncology outside the submitted work. DEM reports personal fees from AstraZeneca, Roche, Tesaro, The European Commission, Clovis, and Astex, outside the submitted work. YL, KS, and KL are employees and stockholders of Tesaro. UAM reports consulting and advisory fees from Merck, Clovis Oncology, Geneos, Eli Lilly, and 2X Oncology outside the submitted work. BJM reports honoraria, and consultancy and speaker fees from AstraZeneca, Clovis Oncology, Janssen, Johnson & Johnson, Roche, Genentech, and Tesaro; honoraria and consultancy fees from AbbVie, Advaxis, Amgen, Biodesix, Genmab, Gradalis, ImmunoGen, Immunomedics, Incyte, Mateon (formerly Oxigene), Merck, Myriad, Perthera, Pfizer, Precision Oncology, Puma Biotechnology, Samumed, Takeda, and VBL Therapeutics, all outside the submitted work. All other authors report no competing interests.

Publisher Copyright:
© 2019 Elsevier Ltd

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