July 15, 2025: A Big Ten CRC study, BTCRC-BRE18-337, led by Sneha Phadke, DO, MPH, of the University of Iowa Holden Comprehensive Cancer Center, was published in Breast Cancer Research and Treatment on June 5, 2025. The article is titled, “Phase I/II trial investigating gedatolisib plus talazoparib in advanced triple negative or BRCA1/2 positive, HER2 negative breast cancers.”
Congratulations to all co-authors and study teams whose hard work led to this publication.
Abstract Highlights:
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.
Authors:
Sneha Phadke (University of Iowa Holden Comprehensive Cancer Center), Kathy D. Miller (Indiana University Melvin and Bren Simon Comprehensive Cancer Center), Ami Shah (University of Wisconsin Carbone Cancer Center), Oana C. Danciu (University of Illinois Cancer Center), Yi Chen (University of Wisconsin), Menggang Yu (University of Wisconsin), Mark E. Burkard (University of Wisconsin Carbone Cancer Center), Kari B. Wisinski (University of Wisconsin Carbone Cancer Center)
About the Big Ten Cancer Research Consortium: The Big Ten Cancer Research Consortium was created in 2013 to transform the conduct of cancer research through collaborative clinical trials and observational studies that seek to improve the lives of cancer patients in the diverse communities we serve by leveraging the scientific and clinical expertise of Big Ten universities. The Big Ten Cancer Research Consortium creates a unique team research culture to drive science rapidly from ideas to treatment and prevention. Within this innovative environment, today’s research leaders collaborate with and mentor the research leaders of tomorrow. Since its founding, the Big Ten CRC has activated nearly 40 clinical trials across a wide range of cancer types, more than 1,000 participants have enrolled in Big Ten CRC studies, and more than 500 researchers have joined Big Ten CRC Clinical Trial Working Groups.
About the Big Ten Conference: The Big Ten Conference is an association of world-class universities whose member institutions share a common mission of research, graduate, professional and undergraduate teaching and public service. Founded in 1896, the Big Ten has sustained a comprehensive set of shared practices and policies that enforce the priority of academics in the lives of students competing in intercollegiate athletics and emphasize the values of integrity, fairness and competitiveness. The broad-based programs of the 18 Big Ten institutions provide direct financial support for more than 11,000 participation opportunities on 350 teams in 42 different sports. The Big Ten sponsors 28 official conference sports, 14 for men and 14 for women. For more information, visit www.bigten.org.
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