Open-label Clinical Trial of Niraparib Combined With Pembrolizumab for Treatment of Advanced or Metastatic Triple-Negative Breast Cancer

Abstract

Importance: Poly(adenosine diphosphate-ribose) polymerase inhibitor and anti-programmed death receptor-1 inhibitor monotherapy have shown limited clinical activity in patients with advanced triple-negative breast cancer (TNBC).

Objective: To evaluate the clinical activity (primary) and safety (secondary) of combination treatment with niraparib and pembrolizumab in patients with advanced or metastatic TNBC.

Design, setting, and participants: This open-label, single-arm, phase 2 study enrolled 55 eligible patients with advanced or metastatic TNBC irrespective of BRCA mutation status or programmed death-ligand 1 (PD-L1) expression at 34 US sites. Data were collected from January 3, 2017, through October 29, 2018, and analyzed from October 29, 2018, through February 27, 2019.

Interventions: Patients were administered 200 mg of oral niraparib once daily in combination with 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle.

Main outcomes and measures: The primary end point was objective response rate (ORR) per the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points were safety, disease control rate (DCR; complete response plus partial response plus stable disease), duration of response (DOR), progression-free survival (PFS), and overall survival.

Results: Within the full study population of 55 women (median age, 54 years [range, 32-90 years]), 5 patients had confirmed complete responses, 5 had confirmed partial responses, 13 had stable disease, and 24 had progressive disease. In the efficacy-evaluable population (n = 47), ORR included 10 patients (21%; 90% CI, 12%-33%) and DCR included 23 (49%; 90% CI, 36%-62%). Median DOR was not reached at the time of the data cutoff, with 7 patients still receiving treatment at the time of analysis. In 15 evaluable patients with tumor BRCA mutations, ORR included 7 patients(47%; 90% CI, 24%-70%), DCR included 12 (80%; 90% CI, 56%-94%), and median PFS was 8.3 months (95% CI, 2.1 months to not estimable). In 27 evaluable patients with BRCA wild-type tumors, ORR included 3 patients (11%; 90% CI, 3%-26%), DCR included 9 (33%; 90% CI, 19%-51%), and median PFS was 2.1 months (95% CI, 1.4-2.5 months). The most common treatment-related adverse events of grade 3 or higher were anemia (10 [18%]), thrombocytopenia (8 [15%]), and fatigue (4 [7%]). Immune-related adverse events were reported in 8 patients (15%) and were grade 3 in 2 patients (4%); no new safety signals were detected.

Conclusions and relevance: Combination niraparib plus pembrolizumab provides promising antitumor activity in patients with advanced or metastatic TNBC, with numerically higher response rates in those with tumor BRCA mutations. The combination therapy was safe with a tolerable safety profile, warranting further investigation.

Trial registration: ClinicalTrials.gov identifier: NCT02657889.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Vinayak reported receiving clinical trial funding from TESARO; serving on an advisory board for TESARO; and serving on an advisory board for OncoSec Medical (uncompensated). Dr Tolaney reported receiving institutional research funding from Novartis, Genentech, Eli Lilly and Company, Pfizer, Merck & Co, Exelixis, Eisai Co, Inc, Bristol-Myers Squibb, AstraZeneca, Cyclacel Pharmaceuticals, Inc, and Nektar and serving as an advisor/consultant to Novartis, Eli Lilly and Company, Pfizer, Merck & Co, AstraZeneca, Eisai Co, Inc, Puma Biotechnology, Genentech, Immunomedics, Nektar, TESARO, and NanoString Technologies. Dr Schwartzberg reported receiving institutional grants from Amgen, GlaxoSmithKline, Spectrum Pharmaceuticals, Medivation, Bayer, Genentech, Pfizer, Sanofi, Bristol-Myers Squibb, Novartis, and MedImmune; serving as a consultant to Helsinn, Pfizer, Amgen, NanoString Technologies, Napo Pharmaceuticals, Inc, Taiho Pharmaceutical, Genentech/Roche, Bristol-Myers Squibb, Genomic Health, Myriad Genetics, and AstraZeneca; and receiving nonfinancial support from AbbVie, AstraZeneca, Helsinn, Merck & Co, Novartis, Bayer, Celgene, Eli Lilly and Company, Bristol-Myers Squibb, Genentech, and Pfizer. Dr Tan reported receiving clinical trial funding from TESARO, and institutional grants from Merck & Co. Dr Forero reported receiving speaker fees from Seattle Genetics and institutional grants from TESARO, Seattle Genetics, Pfizer, Novartis, Genentech, Incyte Corp, TRACON Pharmaceuticals, Inc, Forty Seven, Inc, and Affimed NV. Dr Anders reported receiving clinical trial funding and funding for preclinical work from TESARO; receiving research support from Novartis, Merrimack Pharmaceuticals, Puma Biotechnology, Eli Lilly and Company, Merck & Co, Seattle Genetics, Nektar, and G1 Therapeutics, Inc; serving as an uncompensated advisor to Novartis, Merrimack Pharmaceuticals, Puma Biotechnology, Eli Lilly and Company, Seattle Genetics, Nektar, and Genentech; and receiving royalties from UpToDate and Jones and Bartlett Learning. Dr Wulf reported receiving grants from Stand Up to Cancer, Mary Kay Ash Foundation, Ovarian Cancer Research Foundation, Breast Cancer Alliance, Breast Cancer Research Foundation, the National Institutes of Health, and Merck & Co and having a patent licensed to Cell Signaling and R&D Systems. Dr Dillon reported receiving clinical trial funding from TESARO, and Merck & Co. Dr Lynce reported receiving grants from Bristol-Myers Squibb, Pfizer, and Regeneron Pharmaceuticals, Inc, and serving on an advisory board for AstraZeneca. Dr Zarwan reported financial relationships with Perceptive Informatics and Revere Pharmaceuticals. Dr Erban reported research support from TESARO, MacroGenics, Inc, and Hoosier Cancer Research Network and serving on an advisory board for TESARO. Drs Zhou, Graham, and Dezube, Ms Arora, and Mr Buerstatte are employees of TESARO. Dr Telli reported receiving institutional funding from Genentech, Pfizer, Merck & Co, AstraZeneca, Vertex Pharmaceuticals, PharmaMar, Medivation, and OncoSec Medical; serving as an advisor to Genentech, Aduro Biotech, Celldex, Pfizer, Merck & Co, Immunomedics, AstraZeneca, Vertex, and PharmaMar; and serving on a Data Safety and Monitoring Committee for G1 Therapeutics, Inc. No other disclosures were reported.

Figures

Figure 1.. Flow Diagram of Study Enrollment, Treatment, and Outcomes

TNBC indicates triple-negative breast cancer.

Figure 2.. Antitumor Activity of Niraparib in Combination With Pembrolizumab by Biomarker Status

A, Change is stratified by biomarker status as tumor BRCA mutation (tBRCAmut), homologous recombination repair mutation (HRRmut, including tBRCA wild type [tBRCAwt]), HRR wild type (HRRwt), or unknown (UNK). The broken line indicates a 30% decrease. Four patients with progressive disease due to a new lesion did not have target lesion measurements available and are not included in the plot. B, Overall response was determined using Response Evaluation Criteria in Solid Tumors, version 1.1, as confirmed complete response (CR), partial response (PR), progressive disease (PD), or stable disease (SD) and stratified by biomarker status. C, Progression-free survival was stratified by tBRCAmut or tBRCAwt biomarker status or UNK. NE indicates not evaluable; PD-L1, programmed death-ligand 1; minus sign, negative; and plus sign, positive. aIncludes 1 patient with germline BRCAmut and unknown tBRCA status. bPatient had a PR that was not confirmed by a subsequent scan and was therefore classified as SD.