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      Single-Arm Phases 1 and 2 Trial of Niraparib in Combination With Pembrolizumab in Patients With Recurrent Platinum-Resistant Ovarian Carcinoma

      research-article
      Author(s): , MD, PhD 1 , 2 , , , MD 3 , , MD 4 , , MD 5 , , MD 6 , , MD 7 , 8 , , MD 9 , , MD 10 , 11 , , MD 12 , , MD 13 , , MD 14 , , MD 15 , , MD 16 , , MD 17 , 18 , , MD 19 , , MD 20 , , MD 21 , , MD 22 , , PhD 23 , , MPH 24 , , MS 25 , , PhD 26 , , MD 26 , , MD 26 , , MD 27
      Publication date (Electronic):
      Journal: JAMA Oncology
      Publisher: American Medical Association

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          Key Points

          Question

          What is the clinical activity and safety of combination therapy of niraparib plus pembrolizumab in patients with platinum-based chemotherapy–resistant ovarian carcinoma or those not eligible for retreatment with a platinum-based chemotherapy?

          Findings

          Sixty-two patients with ovarian carcinoma were enrolled in this open-label, single-arm phases 1 and 2 study. Among the 60 evaluable patients, 3 had complete responses, 8 had partial responses, and 28 had stable disease.

          Meaning

          Combination niraparib plus pembrolizumab therapy showed promising antitumor activity in patients with ovarian carcinoma, warranting further investigation.

          Abstract

          This open-label, single-arm, phases 1 and 2 study evaluates the poly(adenosine diphosphate–ribose) polymerase inhibitor niraparib combined with pembrolizumab in patients with recurrent ovarian carcinoma.

          Abstract

          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.

          Trial Registration

          ClinicalTrials.gov identifier: NCT02657889

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          Most cited references12

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          Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study.

          Karen Gelmon, Marc Tischkowitz, Helen Mackay … (2011)
          Olaparib (AZD2281) is a small-molecule, potent oral poly(ADP-ribose) polymerase (PARP) inhibitor. We aimed to assess the safety and tolerability of this drug in patients without BRCA1 or BRCA2 mutations with advanced triple-negative breast cancer or high-grade serous and/or undifferentiated ovarian cancer. In this phase 2, multicentre, open-label, non-randomised study, women with advanced high-grade serous and/or undifferentiated ovarian carcinoma or triple-negative breast cancer were enrolled and received olaparib 400 mg twice a day. Patients were stratified according to whether they had a BRCA1 or BRCA2 mutation or not. The primary endpoint was objective response rate by Response Evaluation Criteria In Solid Tumors (RECIST). All patients who received treatment were included in the analysis of toxic effects, and patients who had measurable lesions at baseline were included in the primary efficacy analysis. This trial is registered at ClinicalTrials.gov, number NCT00679783. 91 patients were enrolled (65 with ovarian cancer and 26 breast cancer) and 90 were treated between July 8, 2008, and Sept 24, 2009. In the ovarian cancer cohorts, 64 patients received treatment. 63 patients had target lesions and therefore were evaluable for objective response as per RECIST. In these patients, confirmed objective responses were seen in seven (41%; 95% CI 22-64) of 17 patients with BRCA1 or BRCA2 mutations and 11 (24%; 14-38) of 46 without mutations. No confirmed objective responses were reported in patients with breast cancer. The most common adverse events were fatigue (45 [70%] of patients with ovarian cancer, 13 [50%] of patients with breast cancer), nausea (42 [66%] and 16 [62%]), vomiting (25 [39%] and nine [35%]), and decreased appetite (23 [36%] and seven [27%]). Our study suggests that olaparib is a promising treatment for women with ovarian cancer and further assessment of the drug in clinical trials is needed. AstraZeneca. Copyright © 2011 Elsevier Ltd. All rights reserved.
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            Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval.

            Peter C Fong, Timothy Yap, David Boss … (2010)
            Selective tumor cell cytotoxicity can be achieved through a synthetic lethal strategy using poly(ADP)-ribose polymerase (PARP) inhibitor therapy in BRCA1/2 mutation carriers in whom tumor cells have defective homologous recombination (HR) DNA repair. Platinum-based chemotherapy responses correlate with HR DNA repair capacity. Olaparib is a potent, oral PARP inhibitor that is well tolerated, with antitumor activity in BRCA1/2 mutation carriers. Patients with BRCA1/2-mutated ovarian cancer were treated with olaparib within a dose-escalation and single-stage expansion of a phase I trial. Antitumor activity was subsequently correlated with platinum sensitivity. Fifty patients were treated: 48 had germline BRCA1/2 mutations; one had a BRCA2 germline sequence change of unknown significance, and another had a strong family history of BRCA1/2-associated cancers who declined mutation testing. Of the 50 patients, 13 had platinum-sensitive disease, 24 had platinum-resistant disease, and 13 had platinum-refractory disease (according to platinum-free interval). Twenty (40%; 95% CI, 26% to 55%) achieved Response Evaluation Criteria in Solid Tumors (RECIST) complete or partial responses and/or tumor marker (CA125) responses, and three (6.0%) maintained RECIST disease stabilization for more than 4 months, giving an overall clinical benefit rate of 46% (95% CI, 32% to 61%). Median response duration was 28 weeks. There was a significant association between the clinical benefit rate and platinum-free interval across the platinum-sensitive, resistant, and refractory subgroups (69%, 45%, and 23%, respectively). Post hoc analyses indicated associations between platinum sensitivity and extent of olaparib response (radiologic change, P = .001; CA125 change, P = .002). Olaparib has antitumor activity in BRCA1/2 mutation ovarian cancer, which is associated with platinum sensitivity.
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              PARPi Triggers the STING-Dependent Immune Response and Enhances the Therapeutic Efficacy of Immune Checkpoint Blockade Independent of BRCAness

              Jianfeng Shen, Wei Zhao, Zhenlin Ju … (2019)
              Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPi) have shown remarkable therapeutic efficacy against BRCA1/2 mutant cancers through a synthetic lethal interaction. PARPi exert their therapeutic effects mainly through the blockade of single-stranded DNA damage repair, which leads to the accumulation of toxic DNA double-strand breaks specifically in cancer cells with DNA repair deficiency (BCRAness), including those harboring BRCA1/2 mutations. Here we show that PARPi-mediated modulation of the immune response contributes to their therapeutic effects independently of BRCA1/2 mutations. PARPi promoted accumulation of cytosolic DNA fragments due to unresolved DNA lesions, which in turn activated the DNA sensing cGAS-STING pathway and stimulated production of type I interferons to induce antitumor immunity independent of BRCAness. These effects of PARPi were further enhanced by immune checkpoint blockade. Overall, these results provide a mechanistic rationale for using PARPi as immunomodulatory agents to harness the therapeutic efficacy of immune checkpoint blockade.
              Article 0 comments Cited 230 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): JAMA Oncol
                Journal ID (iso-abbrev): JAMA Oncol
                Journal ID (pmc): JAMA Oncol
                Title: JAMA Oncology
                Publisher: American Medical Association
                ISSN (Print): 2374-2437
                ISSN (Electronic): 2374-2445
                Publication date (Electronic): 13 June 2019
                Publication date (Print): August 2019
                Publication date PMC-release: 13 June 2019
                Volume: 5
                Issue: 8
                Pages: 1141-1149
                Affiliations
                [1 ]Division of Gynecologic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
                [2 ]Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
                [3 ]Department of Reproductive Medicine, Case Western Reserve University School of Medicine, University Hospitals of Cleveland, Cleveland, Ohio
                [4 ]Division of Medical Oncology, West Cancer Center, Memphis, Tennessee
                [5 ]Department of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, California
                [6 ]Section of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of Chicago Medicine, Chicago, Illinois
                [7 ]Division of Gynecologic Oncology, Florida Hospital Gynecologic Oncology, Florida Hospital Cancer Institute, Orlando
                [8 ]Global Robotics Institute, Orlando, Florida
                [9 ]Department of Obstetrics & Gynecology, University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill
                [10 ]Division of Hematology and Oncology, Virginia G. Piper Cancer Center Clinical Trials, HonorHealth Research Institute, Scottsdale, Arizona
                [11 ]Translational Genomics Research Institute, Scottsdale, Arizona
                [12 ]Weill Cornell Medicine, Department of Obstetrics and Gynecology, Cornell University, New York, New York
                [13 ]Department of Internal Medicine, Mayo Clinic, Jacksonville, Florida
                [14 ]Division of Hematology-Oncology, Department of Medicine, Massachusetts General Hospital, Boston
                [15 ]Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
                [16 ]Department of Obstetrics and Gynecology, Tufts Medical Center, Boston, Massachusetts
                [17 ]Stephenson Cancer Center, Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City
                [18 ]Sarah Cannon Research Institute, Nashville, Tennessee
                [19 ]Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, Seattle
                [20 ]Department of Obstetrics and Gynaecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
                [21 ]Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
                [22 ]Division of Hematology/Oncology, Department of Medicine, The University of Alabama at Birmingham
                [23 ]Department of Research & Early Development, TESARO: A GSK Company, Waltham, Massachusetts
                [24 ]Department of Clinical Operations, TESARO: A GSK Company, Waltham, Massachusetts
                [25 ]Department of Biostatistics, TESARO: A GSK Company, Waltham, Massachusetts
                [26 ]Department of Clinical Science, TESARO: A GSK Company, Waltham, Massachusetts
                [27 ]Helen Diller Family Comprehensive Cancer Center, Department of Medicine, University of California, San Francisco, Medical Center at Mount Zion, San Francisco
                Author notes
                Article Information
                Accepted for Publication: March 5, 2019.
                Published Online: June 13, 2019. doi:10.1001/jamaoncol.2019.1048
                Open Access: This article is published under the JN-OA license and is free to read on the day of publication.
                Corresponding Author: Panagiotis A. Konstantinopoulos, MD, PhD, Division of Gynecologic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave, YC Room 1424, Boston, MA 02215 ( panagiotis_konstantinopoulos@ 123456dfci.harvard.edu ).
                Author Contributions: Dr Konstantinopoulos and Ms Arora had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
                Concept and design: Konstantinopoulos, Sachdev, Matulonis, Swisher, Wang, Arora, Bobilev, Dezube, Munster.
                Acquisition, analysis, or interpretation of data: Konstantinopoulos, Waggoner, Vidal, Mita, Moroney, Holloway, Van Le, Sachdev, Chapman-Davis, Colon-Otero, Penson, Matulonis, Kim, Moore, Swisher, Färkkilä, D'Andrea, Stringer-Reasor, Wang, Buerstatte, Arora, Graham, Munster.
                Drafting of the manuscript: Konstantinopoulos, Colon-Otero, Swisher, D'Andrea, Graham, Dezube, Munster.
                Critical revision of the manuscript for important intellectual content: Konstantinopoulos, Waggoner, Vidal, Mita, Moroney, Holloway, Van Le, Sachdev, Chapman-Davis, Colon-Otero, Penson, Matulonis, Kim, Moore, Swisher, Färkkilä, Stringer-Reasor, Wang, Buerstatte, Arora, Graham, Bobilev, Dezube, Munster.
                Statistical analysis: Wang, Arora, Dezube.
                Obtained funding: D'Andrea, Bobilev, Dezube.
                Administrative, technical, or material support: Konstantinopoulos, Waggoner, Mita, Moroney, Penson, Matulonis, Swisher, Färkkilä, Wang, Buerstatte, Graham, Bobilev, Dezube.
                Supervision: Konstantinopoulos, Moroney, Sachdev, Colon-Otero, Matulonis, Moore, Wang, Dezube, Munster.
                Conflict of Interest Disclosures: 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/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.
                Role of the Funder/Sponsor: The manuscript was 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.
                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.
                Article
                Accession ID: PMC6567832 Pmcid ID: PMC6567832 Pmc-uid ID: 6567832 Publisher ID: coi190029
                DOI: 10.1001/jamaoncol.2019.1048
                PMC ID: 6567832
                PubMed ID: 31194228
                SO-VID: 55f3e832-46cf-4e9d-a92e-430e3a31d7e1
                Copyright © Copyright 2019 American Medical Association. All Rights Reserved.
                License:

                This article is published under the JN-OA license and is free to read on the day of publication.

                History
                Date received : 14 December 2018
                Date: 1 March 2019
                Date accepted : 5 March 2019
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                Categories
                Subject: Research
                Subject: Research
                Subject: Original Investigation
                Subject: Online First

                Data availability:

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