ABSTRACT
Background: The poly(ADP-ribose) polymerase inhibitor niraparib showed clinical activity in advanced gBRCAm ovarian and breast cancers. LUZERN aims to assess the effectiveness of niraparib plus AI in HR+/HER2–, AI-resistant ABC with a pathogenic variant in homologous recombination-related genes. Here we report findings from the stage 1 interim analysis. Methods: This open-label, single-arm, Simon’s 2-stage, phase II trial is enrolling HR+/HER2– ABC patients (pts) with gBRCAm (cohort A;n=6 in stage 1, n=7 in stage 2) and gBRCA wild-type/HRd (cohort B;n=9 in stage 2). Pts had to have received ≤1 prior line of chemotherapy for ABC, 1–2 prior lines of endocrine therapy for early or ABC with secondary endocrine resistance to the last AI regimen. Pts receive niraparib (200/300mg daily orally) plus AI (same agent given with the prior regimen) on each 28-day cycle. Primary endpoint: clinical benefit rate (CBR) as per RECIST 1.1. Secondary endpoints: overall response rate, progression-free survival (PFS), and safety per CTCAE 5.0. If ≥1/6 pts experienced clinical benefit, the trial should proceed to stage 2. Results: Six pts were enrolled in stage 1. Median age was 46 years (range 32–76), 66.7% of pts had visceral disease, and 83.3% had received prior CDK4/6 inhibitor-containing regimen for ABC. At data cut-off, 50.0% of pts were ongoing and median duration of treatment was 4.6 months (range 2.4–5.7). One patient achieved complete response, meeting the criterion to proceed to stage 2. Median investigator-assessed PFS was 5.3 months (95%CI 3.9–NA). The most frequent adverse events (AEs) of any grade (G) were nausea (3 [50.0%]), neutropenia (2 [33.3%];16.7% G3), constipation (2 [33.3%]), and vomiting (1 [16.7%]). Serious AEs occurred in 3 pts (50.0%;G3 COVID-19 pneumonia;G3 pseudomonal bacteriemia;G2 sacral pain). No treatment-related discontinuations/deaths were reported. Conclusions: Niraparib plus AI showed preliminary activity with a tolerable safety profile in gBRCAm HR+/HER2– AI-resistant ABC pts. Based on the steering committee recommendation, enrolment in cohorts A and B is ongoing. Clinical trial identification: ClinicalTrials.gov identifier: NCT04240106. Legal entity responsible for the study: MEDSIR. Funding: GlaxoSmithKline. Disclosure: J.Á. García Saenz: Financial Interests, Personal, Advisory Board: Seagen, Gilead;Financial Interests, Personal, Invited Speaker: Novartis, Celgene, Eli Lilly, Eisai, AstraZeneca, Daiichi Sankyo, MSD, Exact Sciences;Financial Interests, Institutional, Funding: AstraZeneca. J. De la Haba Rodriguez: Financial Interests, Personal, Other, Consultant and Advisory Role, Research Funding and Speaking: Pfizer, Novartis, Roche, Lilly;Financial Interests, Personal, Other, grant support: Pfizer. J.E. Ales Martínez: Financial Interests, Personal, Other, travel grant: Pfizer;Financial Interests, Personal, Research Grant: MEDSIR. E. Alba Conejo: Financial Interests, Personal, Advisory Role: Roche, Novartis, Pfizer, Lilly, BMS, Astrazeneca, Pierre Fabre, Daiichi, Exact Sciences;Financial Interests, Personal, Research Grant: Pfizer. J. Balmaña: Financial Interests, Personal, Advisory Role: AstraZeneca, Pfizer;Financial Interests, Institutional, Other, Steering committee member: AstraZeneca;Financial Interests, Institutional, Principal Investigator: Medsir, Pfizer. J.M. Perez Garcia: Financial Interests, Personal, Advisory Role: Lilly,Roche, Eisai, Daichii Sankyo, AstraZeneca, Seattle Genetics, Medsir;Financial Interests, Personal, Other, travel expenses: Roche. M. Sampayo-Cordero: Financial Interests, Personal, Other, honoraria: Medsir, Syntax for Science, Optimapharm, and Ability pharma;Financial Interests, Personal, Research Grant: Medsir;Financial Interests, Personal, Other, travel expenses: Medsir, Syntax for Science, Optimapharm, and Roche;Financial Interests, Personal, Other, consultant: Medsir, Syntax for Science, and Optimapharm;Financial Interests, Personal, Speaker’s Bureau: Medsir;Financial Interests, Personal, Full or part-time Employment: Me sir. A. Malfettone: Non-Financial Interests, Personal, Full or part-time Employment: MEDSIR. J. Cortés: Financial Interests, Personal, Advisory Role: Roche, Celgene, Cellestia, Astrazeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp&Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks;Financial Interests, Personal, Other, honoraria: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp&Dohme, Daiichi Sankyo;Financial Interests, Institutional, Research Grant: Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London.;Financial Interests, Personal, Stocks/Shares: MEDSIR, Nektar Pharmaceuticals, Leuko (relative);Financial Interests, Personal, Other, travel, accomodation: Roche, Novartis, Eisai, pfizer, Daiichi Sankyo, Astrazeneca. A. Llombart Cussac: Financial Interests, Personal, Leadership Role: Eisai, Celgene, Lilly, Pfizer, Roche, Novartis, and MSD;Financial Interests, Personal, Stocks/Shares: MEDSIR and Initia-Research;Financial Interests, Personal, Advisory Role: Lilly, Roche, Pfizer, Novartis, Pierre-Fabre, GenomicHealth, GSK;Financial Interests, Personal, Speaker’s Bureau: Lilly, AstraZeneca, and MSD;Financial Interests, Personal, Research Grant: Roche, Foundation Medicine, Pierre-Fabre, and Agendia;Financial Interests, Personal, Other, travel compensation: Roche, Lilly, Novartis, Pfizer, and AstraZeneca. All other authors have declared no conflicts of interest.