clinical topic updates
Therapeutic Radiopharmaceuticals: Past, Present, and Future
Clinical trials promise to shape the future of prostate cancer care: alpha-emitting therapy might be successfully combined or sequenced with other agents, including chemotherapy, androgen receptor–targeting agents, DNA damage repair inhibitors, or immunotherapy. Additionally, trials of prostate-specific membrane antigen (PSMA)–targeted radioligands are showing promise.
Professor of Medicine (Medical Oncology) and Urology
“In addition to radium-223, PSMA-based treatments are also showing promise.”
Therapeutic radiopharmaceuticals are classified by the type of particles they emit. Alpha particles have the advantages of high potency and localized energy deposition compared with beta particles. In fact, this localization is thought to have a sparing effect on the bone marrow, which results in less bone marrow toxicity; we no longer use beta-emitting strontium-89 and samarium-153 in clinical practice for that reason. Alpha-emitting radium-223 was developed and approved for castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastases. Post hoc analyses of the phase 3 ALSYMPCA trial suggested that radium-223 was safe regardless of concurrent abiraterone or enzalutamide. However, the concomitant use of radium-223 with abiraterone plus prednisone/prednisolone in the ERA 223 trial did not improve symptomatic skeletal event-free survival and increased the risk of osteoporotic fractures.
One could hypothesize that sequential therapy would allow time for the bone to recover from the effects of hormonal treatment, and the administration of radium-223 would not produce an additive effect on bone irradiation. Antiresorptive agents may be effective at mitigating the risk of fractures in this patient population. Preliminary results from the PEACE III trial demonstrated that, while enzalutamide combined with radium-223 increased the risk of fractures, starting zoledronic acid or denosumab at least 6 weeks before the first injection of radium-223 nearly eliminated that risk.
Oncologists and urologists typically share the responsibility of managing the use of antiresorptive agents in their patients with prostate cancer. While I would like to use radium-223 up front, especially in patients with symptomatic bone metastases who do not want or are ineligible for chemotherapy, we need more research to understand the optimal timing of administration. Nevertheless, there is the possibility that a delay in initiating therapy would reduce the benefits of treatment.
In addition to radium-223, PSMA-based treatments are also showing promise. Further studies are needed to investigate their role, but PSMA radioligands they may provide an option for both the imaging and treatment of advanced prostate cancer (ie, theranostics). When compared with radium-223, PSMA-based therapy has the conceptual advantage of being more targeted, with the additional capacity to treat soft-tissue disease. However, a fundamental limitation with PSMA-based therapy would be its lack of activity against tumors that have little or no PSMA expression.
De Vincentis G, Gerritsen W, Gschwend JE, et al. Advances in targeted alpha therapy for prostate cancer. Ann Oncol. 2019;30(11):1728-1739. doi:10.1093/annonc/mdz270
Fendler WP, Calais J, Eiber M, et al. Assessment of 68Ga-PSMA-11 PET accuracy in localizing recurrent prostate cancer: a prospective single-arm clinical trial. JAMA Oncol. 2019;5(6):856‐863. doi:10.1001/jamaoncol.2019.0096
Hoffmann MA, Wieler HJ, Baues C, Kuntz NJ, Richardsen I, Schreckenberger M. The impact of 68Ga-PSMA PET/CT and PET/MRI on the management of prostate cancer. Urology. 2019;130:1‐12. doi:10.1016/j.urology.2019.04.004
Nilsson S, Cislo P, Sartor O, et al. Patient-reported quality-of-life analysis of radium-223 dichloride from the phase III ALSYMPCA study. Ann Oncol. 2016;27(5):868-874. doi:10.1093/annonc/mdw065
Parker C, Nilsson S, Heinrich D, et al; ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223. doi:10.1056/NEJMoa1213755
Sartor O, Vogelzang NJ, Sweeney C, et al; U.S. Expanded Access Program Investigators. Radium-223 safety, efficacy, and concurrent use with abiraterone or enzalutamide: first U.S. experience from an expanded access program. Oncologist. 2018;23(2):193-202. doi:10.1634/theoncologist.2017-0413.
Smith M, Parker C, Saad F, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial [published correction appears in Lancet Oncol. 2019;20(10):e559]. Lancet Oncol. 2019;20(3):408-419. doi:10.1016/S1470-2045(18)30860-X
Terrisse S, Karamouza E, Parker CC, et al; MORPHEP Collaborative Group. Overall survival in men with bone metastases from castration-resistant prostate cancer treated with bone-targeting radioisotopes: a meta-analysis of individual patient data from randomized clinical trials. JAMA Oncol. 2020;6(2):206-216. doi:10.1001/jamaoncol.2019.4097.
Tombal BF, Loriot Y, Saad F, et al. Decreased fracture rate by mandating bone-protecting agents in the EORTC 1333/PEACE III trial comparing enzalutamide and Ra223 versus enzalutamide alone: an interim safety analysis. J Clin Oncol. 2019;37(15 suppl):5007. doi:10.1200/JCO.2019.37.15_suppl.5007
Werner RA, Derlin T, Lapa C, et al. 18F-labeled, PSMA-targeted radiotracers: leveraging the advantages of radiofluorination for prostate cancer molecular imaging. Theranostics. 2020;10(1):1-16. doi:10.7150/thno.37894
Zimmerman ME, Meyer AR, Rowe SP, Gorin MA. Imaging of prostate cancer with positron emission tomography. Clin Adv Hematol Oncol. 2019;17(8):455‐463.