Neoadjuvant Talazoparib in Patients With Germline BRCA1/2 Mutation-Positive, Early-Stage Triple-Negative Breast Cancer: Results of a Phase II Study.
Humans
BRCA1 Protein
/ genetics
Neoadjuvant Therapy
Triple Negative Breast Neoplasms
/ drug therapy
BRCA2 Protein
/ genetics
Quality of Life
Antineoplastic Combined Chemotherapy Protocols
/ adverse effects
Poly(ADP-ribose) Polymerase Inhibitors
/ adverse effects
Germ-Line Mutation
Anthracyclines
/ therapeutic use
antineoplastic agents
neoadjuvant therapy
poly(ADP-ribose) polymerase inhibitors
triple-negative breast neoplasms
Journal
The oncologist
ISSN: 1549-490X
Titre abrégé: Oncologist
Pays: England
ID NLM: 9607837
Informations de publication
Date de publication:
03 10 2023
03 10 2023
Historique:
received:
27
12
2022
accepted:
14
04
2023
medline:
4
10
2023
pubmed:
15
6
2023
entrez:
15
6
2023
Statut:
ppublish
Résumé
The undetermined efficacy of the current standard-of-care neoadjuvant treatment, anthracycline/platinum-based chemotherapy, in patients with early-stage triple-negative breast cancer (TNBC) and germline BRCA mutations emphasizes the need for biomarker-targeted treatment, such as poly(ADP-ribose) polymerase inhibitors, in this setting. This phase II, single-arm, open-label study evaluated the efficacy and safety of neoadjuvant talazoparib in patients with germline BRCA1/2-mutated early-stage TNBC. Patients with germline BRCA1/2-mutated early-stage TNBC received talazoparib 1 mg once daily for 24 weeks (0.75 mg for moderate renal impairment) followed by surgery. The primary endpoint was pathologic complete response (pCR) by independent central review (ICR). Secondary endpoints included residual cancer burden (RCB) by ICR. Safety and tolerability of talazoparib and patient-reported outcomes were assessed. Of 61 patients, 48 received ≥80% talazoparib doses, underwent surgery, and were assessed for pCR or progressed before pCR assessment and considered nonresponders. pCR rate was 45.8% (95% confidence interval [CI], 32.0%-60.6%) and 49.2% (95% CI, 36.7%-61.6%) in the evaluable and intent-to-treat (ITT) population, respectively. RCB 0/I rate was 45.8% (95% CI, 29.4%-63.2%) and 50.8% (95% CI, 35.5%-66.0%) in the evaluable and ITT population, respectively. Treatment-related adverse events (TRAE) were reported in 58 (95.1%) patients. Most common grade 3 and 4 TRAEs were anemia (39.3%) and neutropenia (9.8%). There was no clinically meaningful detriment in quality of life. No deaths occurred during the reporting period; 2 deaths due to progressive disease occurred during long-term follow-up (>400 days after first dose). Neoadjuvant talazoparib monotherapy was active despite pCR rates not meeting the prespecified threshold; these rates were comparable to those observed with combination anthracycline- and taxane-based chemotherapy regimens. Talazoparib was generally well tolerated. NCT03499353.
Sections du résumé
BACKGROUND
The undetermined efficacy of the current standard-of-care neoadjuvant treatment, anthracycline/platinum-based chemotherapy, in patients with early-stage triple-negative breast cancer (TNBC) and germline BRCA mutations emphasizes the need for biomarker-targeted treatment, such as poly(ADP-ribose) polymerase inhibitors, in this setting. This phase II, single-arm, open-label study evaluated the efficacy and safety of neoadjuvant talazoparib in patients with germline BRCA1/2-mutated early-stage TNBC.
PATIENTS AND METHODS
Patients with germline BRCA1/2-mutated early-stage TNBC received talazoparib 1 mg once daily for 24 weeks (0.75 mg for moderate renal impairment) followed by surgery. The primary endpoint was pathologic complete response (pCR) by independent central review (ICR). Secondary endpoints included residual cancer burden (RCB) by ICR. Safety and tolerability of talazoparib and patient-reported outcomes were assessed.
RESULTS
Of 61 patients, 48 received ≥80% talazoparib doses, underwent surgery, and were assessed for pCR or progressed before pCR assessment and considered nonresponders. pCR rate was 45.8% (95% confidence interval [CI], 32.0%-60.6%) and 49.2% (95% CI, 36.7%-61.6%) in the evaluable and intent-to-treat (ITT) population, respectively. RCB 0/I rate was 45.8% (95% CI, 29.4%-63.2%) and 50.8% (95% CI, 35.5%-66.0%) in the evaluable and ITT population, respectively. Treatment-related adverse events (TRAE) were reported in 58 (95.1%) patients. Most common grade 3 and 4 TRAEs were anemia (39.3%) and neutropenia (9.8%). There was no clinically meaningful detriment in quality of life. No deaths occurred during the reporting period; 2 deaths due to progressive disease occurred during long-term follow-up (>400 days after first dose).
CONCLUSIONS
Neoadjuvant talazoparib monotherapy was active despite pCR rates not meeting the prespecified threshold; these rates were comparable to those observed with combination anthracycline- and taxane-based chemotherapy regimens. Talazoparib was generally well tolerated.
CLINICALTRIALS.GOV IDENTIFIER
NCT03499353.
Identifiants
pubmed: 37318349
pii: 7198523
doi: 10.1093/oncolo/oyad139
pmc: PMC10546823
doi:
Substances chimiques
BRCA1 protein, human
0
BRCA1 Protein
0
talazoparib
9QHX048FRV
BRCA2 protein, human
0
BRCA2 Protein
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Anthracyclines
0
Banques de données
ClinicalTrials.gov
['NCT03499353']
Types de publication
Clinical Trial, Phase II
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
845-855Informations de copyright
© The Author(s) 2023. Published by Oxford University Press.
Références
Ther Adv Med Oncol. 2011 Nov;3(6):257-67
pubmed: 22084640
J Clin Oncol. 2020 May 10;38(14):1539-1548
pubmed: 32097092
Lancet Oncol. 2018 Apr;19(4):497-509
pubmed: 29501363
Ann Oncol. 2021 Feb;32(2):240-249
pubmed: 33242536
J Clin Oncol. 2015 Jan 1;33(1):13-21
pubmed: 25092775
Cancer Treat Rev. 2015 Jan;41(1):1-8
pubmed: 25467110
J Pathol. 2013 Feb;229(3):422-9
pubmed: 23165508
Cancers (Basel). 2020 May 29;12(6):
pubmed: 32486021
Clin Cancer Res. 2019 May 1;25(9):2717-2724
pubmed: 30563931
Front Oncol. 2020 Nov 09;10:592998
pubmed: 33304851
Curr Breast Cancer Rep. 2019 Dec;11(4):303-310
pubmed: 33312344
Mol Cancer. 2020 Jun 20;19(1):107
pubmed: 32563252
J Clin Oncol. 2017 Apr 1;35(10):1049-1060
pubmed: 28135148
Oncologist. 2020 Mar;25(3):e439-e450
pubmed: 32162822
Ann Oncol. 2021 Jan;32(1):49-57
pubmed: 33098995
Hum Genet. 2008 Aug;124(1):31-42
pubmed: 18575892
Science. 2017 Mar 17;355(6330):1152-1158
pubmed: 28302823
Ann Oncol. 2018 Dec 1;29(12):2341-2347
pubmed: 30335131
J Clin Oncol. 2020 Feb 10;38(5):388-394
pubmed: 31461380
JAMA. 2017 Jun 20;317(23):2402-2416
pubmed: 28632866
Cancers (Basel). 2020 Jul 25;12(8):
pubmed: 32722408
Nat Cancer. 2022 Aug;3(8):927-931
pubmed: 35788722
Lancet Oncol. 2014 Jun;15(7):747-56
pubmed: 24794243
Cancers (Basel). 2020 May 27;12(6):
pubmed: 32471249
Oncologist. 2021 Sep;26(9):e1609-e1618
pubmed: 33973301
N Engl J Med. 2020 Feb 27;382(9):810-821
pubmed: 32101663
Health Qual Life Outcomes. 2007 Dec 21;5:70
pubmed: 18154669
Cancer Epidemiol Biomarkers Prev. 2012 Jan;21(1):134-47
pubmed: 22144499
N Engl J Med. 2021 Jun 24;384(25):2394-2405
pubmed: 34081848
Med Care. 1997 Nov;35(11):1095-108
pubmed: 9366889
Qual Life Res. 2015 May;24(5):1207-16
pubmed: 25398495