Journal article
Phase I/II trial investigating gedatolisib plus talazoparib in advanced triple negative or BRCA1/2 positive, HER2 negative breast cancers
Breast cancer research and treatment, Vol.212, pp.521-530
06/05/2025
DOI: 10.1007/s10549-025-07747-x
PMCID: PMC12208992
PMID: 40471518
Appears in UI Libraries Support Open Access
Abstract
Metastatic triple negative breast cancer has a poor prognosis with limited targeted treatment options. In preclinical studies PI3K inhibition led to increased DNA damage and subsequent sensitization to PARP inhibition. This study aimed to investigate the safety and efficacy of the combination of an mTOR/pan-PI3K inhibitor, gedatolisib, with the PARP inhibitor, talazoparib, in patients with advanced triple negative breast cancer or advanced HER2 negative breast cancer and a germline BRCA1/2 mutation.
The primary objective of the safety run-in was safety and tolerability of the combination and for dose escalation to find the maximum tolerated dose. A 3 + 3 design was utilized for dose escalation. The primary objective of the phase II study was objective response rate (ORR) in the patients with wildtype germline BRCA1/2. The prespecified efficacy threshold was 20%. Secondary objectives included progression-free (PFS) and overall survival (OS) as well as correlative testing, examining homologous recombination deficiency (HRD) status.
The combination of gedatolisib and talazoparib carried manageable toxicities with a low incidence of grade 3 adverse events. The most common adverse events of all grades were anemia, fatigue, and oral mucositis. The ORR in the phase II study was 12%. There were no new safety signals identified in the phase II study. mPFS was 2.5 months (95% CI 1.71, 9.89), and mOS was 7 months (95% CI 4.3, NA) in the full phase II cohort. HRD status was analyzed by high (≥ 33) or low (< 33) genomic instability score, and there was no difference in response rate between the groups.
The combination of gedatolisib and talazoparib is safe but did not meet the prespecified efficacy threshold for objective response rate. Additional preclinical studies of these pathways are warranted prior to future clinical trials of the combination.
ClinicalTrials.gov ID: NCT03911973, Date of registration: 2019-04-11.
Details
- Title: Subtitle
- Phase I/II trial investigating gedatolisib plus talazoparib in advanced triple negative or BRCA1/2 positive, HER2 negative breast cancers
- Creators
- Sneha Phadke - University of IowaKathy D Miller - Indiana University HealthAmi Shah - Northwestern UniversityOana C Danciu - University of Illinois Urbana-ChampaignYi Chen - University of Wisconsin–MadisonMenggang Yu - University of MichiganMark E Burkard - University of IowaKari B Wisinski - University of Wisconsin–Madison
- Resource Type
- Journal article
- Publication Details
- Breast cancer research and treatment, Vol.212, pp.521-530
- DOI
- 10.1007/s10549-025-07747-x
- PMID
- 40471518
- PMCID
- PMC12208992
- NLM abbreviation
- Breast Cancer Res Treat
- ISSN
- 1573-7217
- eISSN
- 1573-7217
- Publisher
- Springer Nature; NEW YORK
- Grant note
- Pfizer
This research was funded by a grant from Pfizer. Gedatolisib was provided by Celcuity.
- Language
- English
- Date published
- 06/05/2025
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984826341002771
Metrics
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