TY - JOUR
T1 - Single-Arm Phases 1 and 2 Trial of Niraparib in Combination with Pembrolizumab in Patients with Recurrent Platinum-Resistant Ovarian Carcinoma
AU - Konstantinopoulos, Panagiotis A.
AU - Waggoner, Steven
AU - Vidal, Gregory A.
AU - Mita, Monica
AU - Moroney, John W.
AU - Holloway, Robert
AU - Van Le, Linda
AU - Sachdev, Jasgit C.
AU - Chapman-Davis, Eloise
AU - Colon-Otero, Gerardo
AU - Penson, Richard T.
AU - Matulonis, Ursula A.
AU - Kim, Young Bae
AU - Moore, Kathleen N.
AU - Swisher, Elizabeth M.
AU - Färkkilä, Anniina
AU - D'Andrea, Alan
AU - Stringer-Reasor, Erica
AU - Wang, Jing
AU - Buerstatte, Nathan
AU - Arora, Sujata
AU - Graham, Julie R.
AU - Bobilev, Dmitri
AU - Dezube, Bruce J.
AU - Munster, Pamela
N1 - Funding Information:
Dr Konstantinopoulos reported serving on advisory boards for AstraZeneca, Pfizer, and Merck & Co. Dr Vidal reported consulting for Pfizer and Eli Lilly and Company and received research funding from Eli Lilly and Company, Genentech, AstraZeneca, Merck Serono, TESARO, Puma Biotechnology, and Bristol-Myers Squibb. Dr Holloway reported serving on a speaker bureau for TESARO. Dr Sachdev reported receiving research funding from Celgene and Pfizer; advisory board honoraria from Celgene and TapImmune, Inc; drug-only support for an investigator-sponsored trial from Genentech; and travel support from Celgene. Dr Colon-Otero reported receiving research funding from Novartis. Dr Penson reported serving on scientific advisory boards for Merck & Co and TESARO. Dr Matulonis reported serving in consulting/advisory roles for Merck KGaA, Clovis Oncology, Geneos Therapeutics, Eli Lilly and Company, and 2X Oncology. Dr Moore reported receiving fees from AstraZeneca, Clovis Oncology, TESARO, Genentech/Roche, ImmunoGen, Inc, Merck & Co, VBL Therapeutics, Janssen Pharmaceuticals, and OncoMed Pharmaceuticals, Inc. Dr Swisher reported receiving fees from IDEAYA Biosciences, SAB-Pharma, Inc, and Johnson & Johnson. Dr D’Andrea reported receiving funding from Stand Up to Cancer. Dr Stringer-Reasor reported serving as an investigator on an investigator-sponsored trial using niraparib and trastuzumab (Herceptin) in the treatment of metastatic HER2-positive breast cancer sponsored by TESARO. Drs Wang, Graham, Bobilev, and Dezube, Mr Buerstatte, and Ms Arora are employees of TESARO. Dr Munster reported receiving fees from Merck & Co, Pfizer, Novartis, GlaxoSmithKline, OncoMed Pharmaceuticals, Inc, Celgene, Intellikine, OncoNova Therapeutics, Nektar, Sanofi, Merrimack Pharmaceuticals, Genentech/Roche, OncoSec Medical Incorporated, Bristol-Myers Squibb, Plexxikon, Piramal Life Science, Andes Biotechnologies, Immune Design, BioMarin Pharmaceuticals, HUYA Bioscience International, and Threshold Pharmaceuticals outside the submitted work. No other disclosures were reported.
Funding Information:
Funding/Support: This study was supported by TESARO: A GSK Company, and Merck & Co and in part by grant SU2C-AACR-DT16-15 from Stand Up to Cancer (a program of the Entertainment Industry Foundation), Ovarian Cancer Research Fund Alliance, and National Ovarian Cancer Coalition Dream Team Translational Research, with research grants administered by the American Association for Cancer Research, the scientific partner of Stand Up to Cancer.
Funding Information:
written by the authors with medical writing assistance funded by TESARO. The funding sources had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The funders collaborated with the investigators in designing the trial, provided the study drug, coordinated the management of the study sites, funded the statistical analysis, and provided medical writing support. Authors employed by TESARO, in coordination with all authors, were involved in preparation, review, approval, and decision to submit the manuscript.
Funding Information:
Additional Contributions: We thank the patients and their families for their participation in this study, as well as the study teams at each of the study sites. Geoffrey Shapiro, MD, PhD, Dana-Farber Cancer Institute, Harvard Medical School, provided helpful discussions and feedback during the initial design of this study. Yinghui Zhou, PhD, TESARO, served as lead translational scientist; Deepali Gupta, BS, TESARO, as lead statistical programmer; Chuan Zhu, BS, TESARO, as lead data manager; and Cynthia Rouser, CCDM, TESARO, as data manager. Michael Stillman, PhD, and Ashujit Tagde, PhD, TESARO, coordinated medical writing and editing funded by TESARO. Nicole Renner, PhD, Jeremy Kennard, PhD, and Dena McWain, BA, Ashfield Healthcare Communications, and Adrienne M. Schreiber, BA, TESARO, provided medical writing and editing. All acknowledged individuals provided input as part of their regular employment, and no compensation was received beyond normal salary and benefits.
Publisher Copyright:
© 2019 American Medical Association. All rights reserved.
PY - 2019/8
Y1 - 2019/8
N2 - Importance: Patients with recurrent ovarian carcinoma frequently develop resistance to platinum-based chemotherapy, at which time treatment options become limited. Objective: To evaluate the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor niraparib combined with pembrolizumab in patients with recurrent ovarian carcinoma. Design, Setting, and Participants: The TOPACIO/KEYNOTE-162 (Niraparib in Combination With Pembrolizumab in Patients With Triple-Negative Breast Cancer or Ovarian Cancer) trial, an open-label, single-arm phases 1 and 2 study enrolled women with advanced or metastatic triple-negative breast cancer (TNBC) or recurrent ovarian carcinoma, irrespective of BRCA mutation status. Median follow-up was 12.4 months (range, 1.2 to ≥23.0 months). Data were collected from April 15, 2016, through September 4, 2018, with September 4, 2018, as a data cutoff, and analyzed from September 4, 2018, through January 30, 2019. Interventions: The recommended phase 2 dose (RP2D) was 200 mg of oral niraparib once daily and 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle. Main Outcomes and Measures: The primary objectives of phase 1 were to evaluate dose-limiting toxic effects and establish the RP2D and dosing schedule. The primary objective of phase 2 was to assess objective response rate (ORR; complete plus partial responses). Results from the phase 1 ovarian carcinoma and TNBC cohorts and phase 2 ovarian carcinoma cohort are reported. Because of the similarity in the phase 1 and 2 ovarian carcinoma populations, the data were pooled to perform an integrated efficacy analysis. Results: Fourteen patients (9 with ovarian carcinoma and 5 with TNBC) in phase 1 and 53 patients with ovarian carcinoma in phase 2 were enrolled, for a pooled ovarian carcinoma cohort of 62 patients (median age, 60 years [range, 46-83 years]). In the integrated efficacy phases 1 and 2 ovarian carcinoma population (60 of 62 evaluable patients), ORR was 18% (90% CI, 11%-29%), with a disease control rate of 65% (90% CI, 54%-75%), including 3 (5%) with confirmed complete responses, 8 (13%) with confirmed partial responses, 28 (47%) with stable disease, and 20 (33%) with progressive disease. The ORRs were consistent across subgroups based on platinum-based chemotherapy sensitivity, previous bevacizumab treatment, or tumor BRCA or homologous recombination deficiency (HRD) biomarker status. Median duration of response was not reached (range, 4.2 to ≥14.5 months). At data cutoff, 2 patients with a response and 1 patient with stable disease continued to receive treatment. Conclusions and Relevance: Niraparib in combination with pembrolizumab is tolerable, with promising antitumor activity for patients with ovarian carcinoma who have limited treatment options regardless of platinum status, biomarker status, or prior treatment with bevacizumab. Responses in patients without tumor BRCA mutations or non-HRD cancers were higher than expected with either agent as monotherapy.
AB - Importance: Patients with recurrent ovarian carcinoma frequently develop resistance to platinum-based chemotherapy, at which time treatment options become limited. Objective: To evaluate the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor niraparib combined with pembrolizumab in patients with recurrent ovarian carcinoma. Design, Setting, and Participants: The TOPACIO/KEYNOTE-162 (Niraparib in Combination With Pembrolizumab in Patients With Triple-Negative Breast Cancer or Ovarian Cancer) trial, an open-label, single-arm phases 1 and 2 study enrolled women with advanced or metastatic triple-negative breast cancer (TNBC) or recurrent ovarian carcinoma, irrespective of BRCA mutation status. Median follow-up was 12.4 months (range, 1.2 to ≥23.0 months). Data were collected from April 15, 2016, through September 4, 2018, with September 4, 2018, as a data cutoff, and analyzed from September 4, 2018, through January 30, 2019. Interventions: The recommended phase 2 dose (RP2D) was 200 mg of oral niraparib once daily and 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle. Main Outcomes and Measures: The primary objectives of phase 1 were to evaluate dose-limiting toxic effects and establish the RP2D and dosing schedule. The primary objective of phase 2 was to assess objective response rate (ORR; complete plus partial responses). Results from the phase 1 ovarian carcinoma and TNBC cohorts and phase 2 ovarian carcinoma cohort are reported. Because of the similarity in the phase 1 and 2 ovarian carcinoma populations, the data were pooled to perform an integrated efficacy analysis. Results: Fourteen patients (9 with ovarian carcinoma and 5 with TNBC) in phase 1 and 53 patients with ovarian carcinoma in phase 2 were enrolled, for a pooled ovarian carcinoma cohort of 62 patients (median age, 60 years [range, 46-83 years]). In the integrated efficacy phases 1 and 2 ovarian carcinoma population (60 of 62 evaluable patients), ORR was 18% (90% CI, 11%-29%), with a disease control rate of 65% (90% CI, 54%-75%), including 3 (5%) with confirmed complete responses, 8 (13%) with confirmed partial responses, 28 (47%) with stable disease, and 20 (33%) with progressive disease. The ORRs were consistent across subgroups based on platinum-based chemotherapy sensitivity, previous bevacizumab treatment, or tumor BRCA or homologous recombination deficiency (HRD) biomarker status. Median duration of response was not reached (range, 4.2 to ≥14.5 months). At data cutoff, 2 patients with a response and 1 patient with stable disease continued to receive treatment. Conclusions and Relevance: Niraparib in combination with pembrolizumab is tolerable, with promising antitumor activity for patients with ovarian carcinoma who have limited treatment options regardless of platinum status, biomarker status, or prior treatment with bevacizumab. Responses in patients without tumor BRCA mutations or non-HRD cancers were higher than expected with either agent as monotherapy.
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U2 - 10.1001/jamaoncol.2019.1048
DO - 10.1001/jamaoncol.2019.1048
M3 - Article
C2 - 31194228
AN - SCOPUS:85067339055
SN - 2374-2437
VL - 5
SP - 1141
EP - 1149
JO - JAMA Oncology
JF - JAMA Oncology
IS - 8
ER -