Sneha Phadke, Kathy D Miller, Ami Shah, Oana C Danciu, Yi Chen, Menggang Yu, Mark E Burkard, Kari B Wisinski
{"title":"Phase I/II trial investigating gedatolisib plus talazoparib in advanced triple negative or BRCA1/2 positive, HER2 negative breast cancers.","authors":"Sneha Phadke, Kathy D Miller, Ami Shah, Oana C Danciu, Yi Chen, Menggang Yu, Mark E Burkard, Kari B Wisinski","doi":"10.1007/s10549-025-07747-x","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov ID: NCT03911973, Date of registration: 2019-04-11.</p>","PeriodicalId":9133,"journal":{"name":"Breast Cancer Research and Treatment","volume":" ","pages":""},"PeriodicalIF":3.0000,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Breast Cancer Research and Treatment","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s10549-025-07747-x","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Purpose: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
Trial registration: ClinicalTrials.gov ID: NCT03911973, Date of registration: 2019-04-11.
期刊介绍：
Breast Cancer Research and Treatment provides the surgeon, radiotherapist, medical oncologist, endocrinologist, epidemiologist, immunologist or cell biologist investigating problems in breast cancer a single forum for communication. The journal creates a "market place" for breast cancer topics which cuts across all the usual lines of disciplines, providing a site for presenting pertinent investigations, and for discussing critical questions relevant to the entire field. It seeks to develop a new focus and new perspectives for all those concerned with breast cancer.
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