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

Abstract

Purpose: Radium-223 is approved for metastatic castration-resistant 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 (BMMs) as surrogate markers of response to radium-223 in mCRPC.

Patients and methods: A prospective phase II trial of radium-223 plus enzalutamide (RE) versus enzalutamide alone was designed to assess surrogacy of BMMs with respect to response to radium-223. Enzalutamide 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.

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

Conclusions: 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 radium-223 in real-time.

Trial registration: ClinicalTrials.gov NCT02199197.

Conflict of interest statement

Conflict of Interest Statement

Neeraj Agarwal has consulted for Pfizer, Exelixis, Merck, Argos, EMD Serono, Eisai, Bayer, Novartis, Genentech, BMS, Astra Zeneca, Medivation, Clovis, Foundation One, Astellas, Eli Lilly, Nektar, Active Biotech, Bavarian Nordic, Calithera, Celldex, GlaxoSmithKline, Immunomedics, Janssen, Merck, New Link Genetics, Prometheus, Rexahn, Sanofi, Takeda, Tracon. Benjamin Maughan has consulted for Janssen Oncology, Exelixis, Tempus, Peloton Therapeutics and Astellas. John Hoffman has consulted for Blue Earth Diagnostics. Jared Thorley has consulted for Exelixis and Bristol Myers Squibb. Sumati Gupta reports her spouse has stock ownership in Salarius Pharmaceutical. Roberto Nussenzveig has consulted for Tempus. All authors declare this study was funded with support from Bayer Oncology. Additional support was provided by the Center for Quantitative Cancer Imaging at the Huntsman Cancer Institute, University of Utah.

©2020 American Association for Cancer Research.

Figures

Figure 1.

Kaplan-Meier plots for (A) PSA progression-free survival, (B) radiographic progression-free survival, (C) overall survival, and (D) bone alkaline phosphatase progression-free survival.