From the Desk of the Associate Editor: Radium-223 Radiographic Response

Radium-223 is a novel alpha emitting radiopharmaceutical with bone tropism, now FDA approved for men with symptomatic bone-metastatic castration-resistant prostate cancer.  Approval was based on the survival benefit observed in the phase 3 ALSYMPCA trial over best supportive care, which included oral steroids or hormonal therapies, bone anti-resorptive therapy, and palliative radiation.

Notably, patients in each treatment group received this best supportive care, and radium-223 was placebo controlled every month over the 6 month treatment period. In this trial, delays in symptomatic skeletal related events such as spinal cord compression were notable secondary endpoints. One of the main limitations of the phase 3 trial, however, was the lack of regular radiographic imaging over time and the lack of patient reported outcomes, such as pain responses, which are of critical importance in patient management.

Keizman and colleagues recently reported on their large multicenter experience with radium-223 following regulatory approval for men with metastatic prostate cancer.  In their study, which was conducted across Switzerland, Denmark, and Israel, patients were treated similarly to ALSYMPCA but many men received concurrent enzalutamide or abiraterone acetate, which were not available during the ALSYMPCA trial. In addition, pain responses and opiate use was recorded and CT and bone scan imaging was performed at baseline and every 3 months. The 130 men included in this analysis were largely Caucasian, had good functional status (only 20% with ECOG PS of 2 or worse), 65% had prior docetaxel chemotherapy, 35% had lymph node metastases in addition to bone metastases, and the median PSA was 97. Nearly 75% received concurrent denosumab, and 34% received concurrent abiraterone/enzalutamide. Thus, this represents a contemporary large series similar to those men treated in the United States.

The authors describe several key findings. The first is that only 54% of patients received the full 6 doses of radium-223, largely due to disease progression (65%) and less commonly due to bone marrow toxicity (23%).  Second, disease progression was commonly observed in soft tissue metastases (37%, including visceral and brain metastases) or in the epidural space (10%), where radium-223 cannot reach. Third, pain responses were observed in approximately half of men; however, a transient increase in pain was seen in 27% of men.  While PSA declines were seen in a surprisingly high number of men (20%), this may be due to concurrent abiraterone or enzalutamide. The vast majority of men had PSA increases as their best response to radium-223.  Alkaline phosphatase responses were more common (50% had a 30% or greater decline, an arbitrary threshold).  Finally, the mode of bone progression on radium-223 was reported. While the majority of patients had stable bone metastases after 6 months, new bone lesions after 3 months were observed in 26% of men, with a further 6% having additional new lesions at 6 months.  This may represent bone scan flare or simply slow disease progression in the bones during radium-223 therapy.

My key takeaways from this study are that radium-223 is best used early, prior to extensive soft tissue metastases, and when the risk of spinal cord compression is low. Because soft tissue disease goes essentially untreated during radium-223 therapy, concurrent use of effective systemic therapies should be considered in such patients with extra-skeletal metastases. Ongoing trials of radium-223 with enzalutamide, abiraterone, sipuleucel-T, atezolizumab, PARP inhibitors, docetaxel, and other combinations should clarify the optimal combination approaches to controlling bone and soft tissue/visceral metastases. Finally, patients should be followed carefully by providers for pain flare and are likely to need opiate dose titration during therapy.  Concurrent care by a palliative care specialist should be strongly considered, given the limited life expectancy and palliative needs for these patients.  

Written by: Andrew Armstrong, MD, ScM, FACP, USA

Dr. Armstrong is Associate Professor of Medicine, Surgery, Pharmacology and Cancer Biology and Associate Director of the Duke Cancer Institute Genitourinary Clinical Research Program. He is a medical oncologist and internationally recognized expert in experimental therapeutics and biomarker development in genitourinary cancers, particularly in prostate cancer

Full Text Article: Imaging response during therapy with radium-223 for castration-resistant prostate cancer with bone metastases
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