(1) What is the utility of linking alpha particles to other antibody targets?
Dr. de Bono noted that this is a relevant question considering there are tumors which are PSMA negative. As such, he feels there are investigator opportunities in this disease space. Secondly, Dr. de Bono remarked that this also potentially opens the door for combinatorial treatment options, targeting several molecules. Indeed, resistance to targeted alpha therapy may hinge on these tumors being PSMA negative, according to Dr. de Bono.
(2) What specifically are the implications of these resistance mechanisms to targeted alpha therapy?
Dr. O’Sullivan believes that true resistance to targeted alpha therapy should actually be quite low, considering the specificity and short radius of the alpha particle. In his opinion, there is very little that could withstand the local, DNA damaging effects of this therapy. In his opinion, this is the future for the thorium conjugate targeted therapy.
(3) What happens when after 3 cycles of radium-223 there is increasing PSA and/or ALP with a concomitant bone-scan still demonstrating a “hot-spot” in the affected area? Would one consider intervening with local therapy the specific location and/or continue with the full treatment of radium-223?
Dr. O’Sullivan stated that he fully supports local external beam radiation therapy to these sites noting that it likely will help with symptoms, and in his experience, is safe. Furthermore, if there are soft tissue concomitant metastases, Dr. O’Sullivan advocates for local external beam radiation therapy to these lesions while still treating the bone lesions with radium-223.
(4) When is the appropriate time to stop radium-223?
Dr. James notes that when he has patients on radium-223, he is not a big believer in tracking PSA and ALP levels, but rather he’s an advocate of close and more frequent imaging. His criteria for stopping radium-223 usually comes down to worsening disease progression on imaging. The specific imaging that Dr. James uses is CT abdomen/pelvis and bone scintigraphy.
(5) How should one use bone-targeted agents (such as zoledronic acid and denosumab) in the current era of radium-223 and particularly in the early disease state?
Dr. O’Sullivan states that he has been a keen endorser of zoledronic acid. In his opinion, despite the data not being extremely convincing in the clinical trials for preventing skeletal-related events, he states that he is much more of an advocate of zoledronic acid in real-world clinical practice because of the bone stabilizing properties and that he truly believes it works.
(6) One of the concerns is that patients with soft tissue disease may progress while they are on radium-223 for their bone-specific lesions. However, one of the theories is that if you target the bone, which may be the root of the problem, this may actually improve the soft tissue and/or lymph node lesions?
Dr. Omlin deftly notes that in ALSYMPCA  patients were not excluded if they had lymph node metastases up to 3 cm. In his opinion, he doesn’t exclude patients based on lymph node size or status, unless they are large/obstructing and/or causing pain symptoms. The panel notes, however, that in their experience, there is very little evidence (even anecdotal) that lymph nodes shrink in the setting of primary radium-223 therapy.
(7) Would you consider adding dexamethasone for soft tissue progression while on radium-223?
Dr. Omlin responded by saying that this is indeed an excellent question and that this may be an option for a subset of patients who may benefit from soft-tissue control with dexamethasone. Dr. James notes that he would also consider concomitant dexamethasone in the appropriate patient.
Speaker: Johann de Bono, Institute of Cancer Research and Royal Marsden, London, United Kingdom
Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the European Society for Medical Oncology Annual Congress - September 8 - 12, 2017 - Madrid, Spain
1. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013;369(3):213-223.