HRR mutation status prognostic for survival
Results of a biomarker analysis from the NRG Oncology NRG-GY004 trial were presented in a seminal session at the Society for Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer in March 2022. The analysis, which took place as part of a pre-planned translational endpoint for the study, concluded that homologous recombination repair mutant type (HRRmt) was prognostic for progression-free survival and predictive of olaparib activity compared to standard of care, platinum-based chemotherapy for women with relapsed platinum-responsive ovarian cancer.
The NRG-GY004 trial did not achieve its primary objective of improving progression-free survival in this patient population by treating with olaparib alone or a combination of olaparib and cediranib compared to usual chemotherapy. However, data collected from the trial suggested that study participants with BRCA the mutations showed clinically significant activity in a prespecified assay when treated with the investigational drugs.
The status of homologous recombination deficiency (HRD) was successfully measured by the BROCA-HR test for 470 of the 565 patients included in the trial. BROCA-HR is a next-generation targeted sequencing platform including all known gynecological cancer susceptibility genes and other DNA repair or related genes, as well as a 3100 single nucleotide polymorphism panel for the loss of heterozygosity (LOH) analysis. The genes included as HRD were ATM, BARD1, BRCA1, BRCA2, NBN, PALB2, RAD51C, and RAD51D. BRCA1 and BRCA2 mutations composed of 90% of the HRR mutations in the analysis.
“This analysis let us know that a subset of the population of women treated in the trial experienced significant clinical benefit from olaparib or the combination of olaparib and cediranib,” Joyce said. F. Liu, MD, MPH of the Dana-Farber Cancer Institute and study chair for the NRG-GY004 trial. “Due to the potential complications of repeated exposure to platinum-based chemotherapy in women with relapsed platinum-sensitive ovarian cancer, it is critically important to continue testing less burdensome treatment alternatives for the patient with the same efficiency. More personalized and targeted approaches could benefit some patients depending on the biomarker subset.
Although LOH status was also explored, LOH was not prognostic for progression-free survival independent of BRCA status. LOH was also not predictive of the activity of either experimental treatment arm compared to chemotherapy.
This study was supported by grants from the National Cancer Institutes of Health to NRG Oncology SDMC (1U10 CA180822), NRG Operations (U10CA180868), and U24CA180803 (IROC). Additionally, the participation of the Canadian Cancer Trials Group (CCTG) in this trial is supported by its grant from the National Cancer Institute of the United States National Institutes of Health under award CA180863. Additional programmatic financial support for the CCTG is provided by the Canadian Cancer Society (#704970) and the Canada Foundation for Innovation. The NCI’s National Clinical Trials Network participated in the study. Funding and support was also received from AstraZeneca under a cooperative research and development agreement with NCI.
Swisher E, Miller A, Kohn EC, Brady MF, Radke MR, Pennil CC, Khasvanis N, Buscema J, Tew WP, Muller C, Hill EK, Moore RG, Michelin D, Wagoner S, Geller M, Fujiwara K, D’ Andrew S. Liu J.F., Birrer M. (2022, March). Association of Homologous Recombination Deficiency (HRD) with Clinical Outcomes in a Phase 3 Study of Olaparib or Cediranib and Olaparib Versus Platinum-Based Chemotherapy in Recurrent Platinum-Responsive Ovarian Cancer (PSOC): biomarker analyzes of NRG-GY004. Paper presented at the Women’s Cancer Annual Meeting for the Society of Gynecologic Oncology. Chicago, AZ.
About NRG Oncology
NRG Oncology conducts practice-changing, multi-institutional clinical and translational research to improve the lives of cancer patients. Founded in 2012, NRG Oncology is a Pennsylvania-based nonprofit company that incorporates research from the former National Surgical Adjuvant Breast and Bowel Project (NSABP), Radiation Therapy Oncology Group (RTOG), and Gynecologic Oncology Group (GOG) programs. The research network seeks to conduct clinical trials with an emphasis on gender-specific malignancies, including gynecological, breast and prostate cancers, and localized or locally advanced cancers of all types. NRG Oncology’s extensive research organization includes multidisciplinary researchers, including medical oncologists, radiation oncologists, surgeons, physicists, pathologists and statisticians, and encompasses more than 1,300 research sites located worldwide, with a predominance in the United States and Canada. NRG Oncology is supported primarily by grants from the National Cancer Institute (NCI) and is one of five research groups in the NCI’s National Clinical Trials Network.
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