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

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 1 2019

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Ovarian Neoplasms
Therapeutics
niraparib
Homologous Recombination
Platinum
Thrombocytopenia
Mutation
Population
Safety
Survival

ASJC Scopus subject areas

  • Oncology

Cite this

Moore, K. N., Secord, A. A., Geller, M. A., Miller, D. S., Cloven, N., Fleming, G. F., ... Monk, B. J. (2019). Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial. The Lancet Oncology, 20(5), 636-648. https://doi.org/10.1016/S1470-2045(19)30029-4

Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA) : a multicentre, open-label, single-arm, phase 2 trial. / Moore, Kathleen N.; Secord, Angeles Alvarez; Geller, Melissa A.; Miller, David Scott; Cloven, Noelle; Fleming, Gini F.; Wahner Hendrickson, Andrea E; Azodi, Masoud; DiSilvestro, Paul; Oza, Amit M.; Cristea, Mihaela; Berek, Jonathan S.; Chan, John K.; Rimel, Bobbie J.; Matei, Daniela E.; Li, Yong; Sun, Kaiming; Luptakova, Katarina; Matulonis, Ursula A.; Monk, Bradley J.

In: The Lancet Oncology, Vol. 20, No. 5, 01.05.2019, p. 636-648.

Research output: Contribution to journalArticle

Moore, KN, Secord, AA, Geller, MA, Miller, DS, Cloven, N, Fleming, GF, Wahner Hendrickson, AE, Azodi, M, DiSilvestro, P, Oza, AM, Cristea, M, Berek, JS, Chan, JK, Rimel, BJ, Matei, DE, Li, Y, Sun, K, Luptakova, K, Matulonis, UA & Monk, BJ 2019, 'Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial', The Lancet Oncology, vol. 20, no. 5, pp. 636-648. https://doi.org/10.1016/S1470-2045(19)30029-4
Moore, Kathleen N. ; Secord, Angeles Alvarez ; Geller, Melissa A. ; Miller, David Scott ; Cloven, Noelle ; Fleming, Gini F. ; Wahner Hendrickson, Andrea E ; Azodi, Masoud ; DiSilvestro, Paul ; Oza, Amit M. ; Cristea, Mihaela ; Berek, Jonathan S. ; Chan, John K. ; Rimel, Bobbie J. ; Matei, Daniela E. ; Li, Yong ; Sun, Kaiming ; Luptakova, Katarina ; Matulonis, Ursula A. ; Monk, Bradley J. / Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA) : a multicentre, open-label, single-arm, phase 2 trial. In: The Lancet Oncology. 2019 ; Vol. 20, No. 5. pp. 636-648.
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T1 - Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA)

T2 - a multicentre, open-label, single-arm, phase 2 trial

AU - Moore, Kathleen N.

AU - Secord, Angeles Alvarez

AU - Geller, Melissa A.

AU - Miller, David Scott

AU - Cloven, Noelle

AU - Fleming, Gini F.

AU - Wahner Hendrickson, Andrea E

AU - Azodi, Masoud

AU - DiSilvestro, Paul

AU - Oza, Amit M.

AU - Cristea, Mihaela

AU - Berek, Jonathan S.

AU - Chan, John K.

AU - Rimel, Bobbie J.

AU - Matei, Daniela E.

AU - Li, Yong

AU - Sun, Kaiming

AU - Luptakova, Katarina

AU - Matulonis, Ursula A.

AU - Monk, Bradley J.

PY - 2019/5/1

Y1 - 2019/5/1

N2 - 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.

AB - 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.

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