Prospective Evaluation of Bone Metabolic Markers as Surrogate Markers of Response to Radium-223 Therapy in Metastatic Castration Resistant Prostate Cancer.

Radium-223 is approved for metastatic castration-refractory prostate cancer (mCRPC) based on improved overall survival, and delay in skeletal related events. However, it is not associated with PSA or radiographic response, which poses a challenge in real-time assessment of its efficacy. Surrogate markers of treatment outcomes may facilitate tailoring treatment duration with radium-223, by limiting the duration of therapy with radium-223 in these patients. Here, we sought to investigate the utility of bone metabolic markers (BMM) as surrogate markers of response to radium-223 in mCRPC.

A prospective phase II trial of radium-223 plus enzalutamide (RE) versus enzalutamide (Enza) alone was designed to assess surrogacy of BMMs with respect to response to radium-223. Enza was used as a comparator in lieu of placebo due to the progressive disease. Co-primary endpoints were relative change in serum BMM N-telopeptide (NTP) levels from baseline to 6 months between the two arms and safety and feasibility of the combination.

Thirty-nine men were randomized to RE (n=27) or Enza (n=12). Combination was safe and feasible. Primary endpoint was met. A statistically significant relative change to NTP ratios between arms (0.64, 95% CI 0.51-0.81; P=0.00048) favored RE versus Enza. Overall, BMMs decreased with the RE therapy compared to Enza. Improved PSA response rate in RE versus Enza (P=0.024), correlated with decline in BMM.

BMMs declined significantly with combination therapy, and were associated with improved outcomes. Upon external validation, BMMs may emerge as surrogate markers to monitor treatment with radum-223 in real-time.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2020 Jan 14 [Epub ahead of print]

Neeraj Agarwal, Roberto H Nussenzveig, Andrew W Hahn, John M Hoffman, Kathryn Morton, Sumati Gupta, Julia Batten, Jared Thorley, Josiah L Hawks, Victor S Santos, Gayatri Nachaegari, Xuechen Wang, Kenneth M Boucher, Benjamin Haaland, Benjamin L Maughan

Medicine, University of Utah/Huntsman Cancer Institute ., Oncology, University of Utah/Huntsman Cancer Institute., Radiology Clinical, University of Utah., Radiology, University of Utah., Department of Medicine, University of Utah Huntsman Cancer Institute., Medicine, University of Utah/Huntsman Cancer Institute., Oncology, Complejo Hospitalario Universitario de A Coruña., Clinical Trials Office, University of Utah/Huntsman Cancer Institute., Population Health Sciences, University of Utah Health Care., Internal Medicine, University of Utah., Population Health Sciences, Huntsman Cancer Institute; University of Utah., Internal Medicine, University of Utah/Huntsman Cancer Institute.