Abstract Background: Current guidelines recommend bone modifying agents (BMAs), such as bisphosphonates and denosumab, every 4 to 12 weeks to reduce the incidence of and delay the onset of symptomatic skeletal events (SSEs) in patients with bone metastases from breast cancer and castration-resistant prostate cancer (CRPC). Given the absence of level one evidence, the optimal frequency and duration of BMAs after 2 years of treatment is unknown. This is an important clinical question as the risk of SSEs decreases with time, while the risk of treatment-related toxicities increases. Methods: Patients with bone metastases from breast cancer or CRPC who have received ≥ two years of BMA treatment will be approached for this pragmatic, multicenter, open-label RCT. Using the Rethinking Clinical Trials (REaCT) methodology that incorporates the integrated oral consent model, eligible and consented patients will be randomized to either continue standard schedule BMA (every 4 or 12 weeks) or de-escalated BMA (every 24 weeks). This is a non-inferiority study. The co-primary endpoints are the physical functioning subscale of EORTC-QLQ-C30 and functional interference subscale of EORTC-QLQ-BM22. Secondary endpoints include number of patients with ≥ 1 SSE, time to development of SSE, SSE-free survival, skeletal morbidity rate, EORTC-QLQ-C30 and BM22 scores, BMA-related toxicity, and treatment adherence. To achieve 80% power for both co-primary endpoints and assuming a 10% non-compliance and 20% death rate, the planned sample size is 240 patients (120 per arm). Randomization (1:1 ratio) will be stratified by cancer type (breast vs prostate) and treatment schedule prior to randomization (Q4weeks vs. Q12weeks). A subgroup analysis comparing patients with 2-3 years vs. > 3 years of prior BMA treatment will be conducted. Results: The study has been open for enrollment since Oct 2020. As of July 5, 2021, the study has opened at 2 sites, 48 patients have been randomized and 8 are in screening. The study needs 60 patients randomized by September 2021 to continue to receive funding. There is a plan to open the study at two other academic centers in Ontario, Canada. Conclusion: This will be the first RCT providing level one evidence regarding the optimal frequency of BMA treatment that accounts for health-related quality of life after ≥ two years of prior BMA in this patient population. Citation Format: Terry L. Ng, Gregory R. Pond, Marta Sienkiewicz, Kednapa Thavorn, Mark Clemons. A randomised trial comparing continuation or de-escalation of bone modifying agents (BMA) in patients treated for over 2 years for bone metastases from either breast or castration-resistant prostate cancer (REaCT-HOLD BMA) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-06-01.