Abstract OT2-09-01: TBCRC-055: A Phase II Study of NirAparib, Dostarlimab, and Radiotherapy in Metastatic, PD-L1 Negative or Immunotherapy-Refractory Triple-Negative Breast Cancer (NADiR) – NCT04837209
Authors: Scott Elizabeth , Isakoff Steven J. , Taghian Alphonse G. , Wright Jean , Santa-Maria Cesar Augusto , Shah Payal , Taunk Neil , Anders Carey , Blitzblau Rachel , Gupta Gaorav , Ho Alice 
Published: March 2023

Abstract
Background: Metastatic triple negative breast cancer (mTNBC) is associated with high recurrence and mortality rates. Prior studies have shown an immune checkpoint inhibitor (ICI) + chemotherapy improves progression-free survival for patients with PD-L1 positive mTNBC. There remains a need for treatment options in patients who do not respond to ICI or are PD-L1 negative. Preclinical data suggests that a PARP inhibitor (PARPi) may promote innate immune signaling, and combination with an ICI has shown a positive response in patients with mTNBC. Radiotherapy (RT) is a potent immune stimulator and used for local control in the setting of metastatic breast cancer. This phase II study (NCT04837209) proposes combination of PARPi, ICI, and RT to combat ICI resistance and improve response rates in patients with mTNBC who are PD-L1 negative or who have progressed on prior ICI. Methods: 32 patients with mTNBC defined as ER&lt; 1%, PR&lt; 1%, HER-2-neu 0-1+ by IHC or non-FISH-amplified or patients with metastatic HR+/HER2- breast cancer are anticipated to participate. Eligibility criteria for mTNBC patients includes those who are PD-L1 negative or have progressed on prior ICI. Eligibility criteria for HR+/HER2- patients is specific to those who harbor a deleterious BRCA1 or BRCA2 mutation with or without high tumor mutational burden (TMB). All trial patients should have at least 1 lesion amenable to RT and at least 1 measurable lesion that will not be radiated. Study treatment consists of 3-week cycles, with 500mg dostarlimab given on day 1 of each cycle through cycle 5, then 1000mg given every 6 weeks. RT (24 Gy) is delivered in 3 consecutive fractions starting day 1 of cycle 1. Niraparib (200mg) is dosed orally daily. Tumor biopsies are taken within 28 days pre-treatment, and at C3D1-8. Blood samples are taken at baseline and every odd cycle for cfDNA and PBMC analysis. The primary endpoint is to assess overall response rate as measured by RECIST v1.1 of the combination of niraparib, dostarlimab, and RT. Secondary objectives include assessing safety and toxicity, overall survival, progression free survival, and quality of life. Results: To date, this study has accrued 4 subjects, including 3 with mTNBC, and 1 with HR+/HER2-/BRCA mutant + TMB high mBC. The study is currently open at MGH and Sibley, and the addition of UPenn, Johns Hopkins, and Duke are in progress. Funding for this study was provided by GSK. GSK was provided the opportunity to review a preliminary version of this abstract for factual accuracy, but the authors are solely responsible for final content and interpretation. People with specific interest in the trial should reach out to Elizabeth Scott, Clinical Research Coordinator, at ecscott@mgh.harvard.edu.
Citation Format: Elizabeth Scott, Steven J. Isakoff, Alphonse G. Taghian, Jean Wright, Cesar Augusto Santa-Maria, Payal Shah, Neil Taunk, Carey Anders, Rachel Blitzblau, Gaorav Gupta, Alice Ho. TBCRC-055: A Phase II Study of NirAparib, Dostarlimab, and Radiotherapy in Metastatic, PD-L1 Negative or Immunotherapy-Refractory Triple-Negative Breast Cancer (NADiR) – NCT04837209 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-09-01.