Why are real-world efficacy and safety data for radium-223 in mCRPC important?
Radium-223 was approved in 2013 in the United States for the treatment of metastatic castration-resistant prostate cancer (mCRPC) with bone metastases. At that time, the only other approved treatment for mCRPC was chemotherapy; however, in the intervening decade, the treatment landscape has radically changed. There are now multiple additional options available for men with mCRPC, including androgen-receptor pathway inhibitors (ARPIs), immunotherapy, poly adenosine diphosphate-ribose polymerase inhibitors (PARPIs), and radioligand therapy. Furthermore, some agents approved for mCRPC have now been indicated for the management of earlier stage disease.
With this shifting treatment landscape and potentially changing use of radium-223, a comprehensive understanding of the real-world outcomes associated with radium-223 was needed.
What was the study methodology?
Searches were performed using Embase, MEDLINE, and the Cochrane Library from 2014–2024. Registry searches were also performed to identify noninterventional studies, and relevant conference proceedings were analyzed.
Studies of interest were prospective, retrospective, and cross-sectional observational studies in adults with mCRPC treated with radium-223, regardless of treatment line. Studies had to include over 100 patients and report at least one clinical, safety, or health-related quality of life outcome of interest. Primary outcomes of interest were the number of radium-223 cycles, overall survival (OS), progression-free survival (PFS), skeletal-related events (SREs), and safety.
A total of 1,085 citations were identified, with 48 distinct studies meeting predefined inclusion criteria. In total, the studies included a population of 15,368 men treated with radium-223.
What were the key findings?
Completion of radium-223 cycles
- On average, completion rates for ≥5 cycles were 65% (range 45–80%), with an average completion rate of 55% for 6 cycles
- Factors associated with completing ≥5 cycles were low alkaline phosphatase (ALP) level and hemoglobin equal to or above lower levels of normal
Overall survival
- Median OS ranged from 9 – 23.5 months, with more than 80% of studies showing ≥ 12 months.
- Completion of radium-223 cycles was associated with a 2- to 5-fold increase in OS (Figure 1)
Figure 1: Real-world survival in men treated with radium-223 by cycle. HR, hazard ratio; OS, overall survival.
Progression-free survival
- Median PFS (seven studies) ranged from 4.3 to 7.3 months in participants with a median of two prior lines of therapy
- In 12 studies reporting pain outcomes, nearly half of the participants reported pain control or improvement in pain following radium-223 treatment, irrespective of pain scale used
- A reduction in ALP or prostate-specific antigen (PSA) level was reported in 27 studies
- Five studies reported that 66–80% of participants had any level of decline in ALP from baseline. Almost half of the participants had ≥25% declines (3 studies) and ≥30% declines (8 studies) in ALP level
- Seven studies found that 13–28% of participants had any decline in PSA level. Declines of ≥30% and ≥50% from baseline occurred in 4–29% of participants
- A total of 21 studies reported SRE outcomes, with the incidence of any SRE occurring in ≤25% of participants in most studies
- Median time to SRE was not estimable in five studies, and ranged from 3–33.9 months in the six studies in which it was reached
- SREs occurred sooner and more frequently in participants who were not receiving concomitant bone protective agents (BPAs)
- Prior BPA use was associated with a lower incidence of SREs (0.34 vs. 0.37 per person-year), bone fractures (2–4% vs. 5–7%), and, a lower risk of SREs (hazard ratio: 0.49) in a multivariate regression analysis
- Sixteen studies reported myelosuppression adverse events
- Incidence of any grade events was <15%, and 1–5% for grade 3/4 events
- High rates of low-grade anemia were reported in two studies (>50%), although rates of grade 3/4 anemia were <10%
To our knowledge, this is the first systematic review that has been conducted on the real-world evidence for radium-223; thus, it provides the most up-to-date and comprehensive collection of real-world outcomes available.
Our findings are complementary to those of prospective clinical trial data and highlight the efficacy and safety benefits associated with the completion of radium-223. Notable findings related to radium-223 utilization and outcomes include:
- Radium-223 was used mainly as a second and third-line therapy. ARPIs and chemotherapy were the most common prior lines of therapy
- Nearly two-thirds of men treated with radium-223 completed five or more cycles, and this was associated with improved OS. Fewer prior lines of treatment and no prior chemotherapy were also associated with improved survival
- There was a clear trend toward a reduction of pain from baseline in participants treated with radium-223 throughout the studies
- Declines in ALP following radium-223 treatment occurred in a significant number of the studies included, suggesting a potential role for both as biomarkers to predict clinical outcomes
- Radium-223 was well-tolerated, with a safety profile consistent with clinical trial experience. BPA use lowered the risk of SREs
The results of this systematic literature review show that radium-223 is associated with positive real-world outcomes in the management of mCRPC. However, they also highlight a need for further research into how radium-223 can be more effectively utilized within the continuously evolving treatment landscape.
Written by: Michaela Lunan-Taylor,1 Amit D. Raval,2 Nguyen Thi Nhan Phan,1 Matthew J. Korn,2 Vanessa Quintero,2 Rana R. McKay3
- RTI Health Solutions, Manchester, UK.
- Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA.
- Division of Hematology-Oncology, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.