Real-world utilization patterns and survival in men with metastatic prostate cancer treated with Radium-223 in the United States | Prostate Cancer and Prostatic Diseases
Study Shows Benefits of Radium-223 Treatment for Men with Metastatic Prostate Cancer
Breaking News for IPCSG Members
A significant new study published in the journal Prostate Cancer and Prostatic Diseases reveals important findings about Radium-223 (Ra-223) treatment for men with metastatic castration-resistant prostate cancer (mCRPC).
The research, led by Dr. Rana R. McKay from the University of California, San Diego, analyzed data from 1,376 men treated with Ra-223 between 2017 and 2022. This extensive real-world study offers valuable insights that could influence treatment decisions for many prostate cancer patients.
Key Findings
The study demonstrated that men who received Ra-223 had a median overall survival of 22.9 months, which is longer than the 14.9 months observed in the original ALSYMPCA clinical trial that led to Ra-223's approval in 2013.
Several factors were associated with improved survival:
- Earlier treatment: Men who received Ra-223 as a first-line treatment had a median survival of 37.6 months, compared to just 14.1 months when used as a fourth-line or later treatment.
- Combination therapy: Using Ra-223 alongside other treatments (particularly enzalutamide) showed a median survival of 26.6 months, versus 20.5 months with Ra-223 alone.
- Completing treatment: Men who completed 5 or more cycles of Ra-223 had significantly better outcomes (30.3 months median survival) than those who completed fewer cycles (15.3 months).
"Significant real-world overall survival benefits were identified in men who received Ra-223 as an earlier line of therapy, received Ra-223 in combination with another therapy, and completed ≥5 Ra-223 cycles, underscoring the importance of Ra-223 in the current treatment landscape," the researchers concluded.
Recent Supportive Research
These findings align with several other recent studies that highlight the benefits of Ra-223:
The PEACE III trial recently demonstrated that combining Ra-223 with enzalutamide significantly prolongs both radiological progression-free survival (19.4 vs. 16.4 months) and overall survival (42.3 vs. 35.0 months) compared to enzalutamide alone for men with mCRPC. This randomized Phase 3 trial showed that when bone-protective agents were used, the combination therapy was safe and effective.
A meta-analysis published in BMC Cancer evaluated Ra-223 efficacy across multiple studies and found it consistently improved overall survival in men with bone-predominant mCRPC. The analysis emphasized that Ra-223's effectiveness is enhanced when given earlier in the disease course.
Researchers at Memorial Sloan Kettering Cancer Center found that biomarkers such as alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) levels can help predict which patients are likely to benefit most from Ra-223 therapy, potentially helping doctors select candidates for earlier treatment.
A retrospective analysis from Johns Hopkins suggested that patients with lower tumor burden and better baseline performance status experienced greater benefits from Ra-223, supporting the case for earlier intervention in appropriate patients.
What This Means for Patients
These collective findings suggest that discussing Radium-223 earlier in your treatment journey with your healthcare provider could be beneficial. The research indicates that Ra-223 may be most effective when:
- Used earlier in the treatment sequence
- Combined with other therapies (especially enzalutamide)
- Completed for the full recommended course of treatment
- Administered with bone-protective agents to reduce fracture risk
According to the McKay study, Ra-223 was most commonly administered as a second-line (35%) or third-line (25%) treatment, with only 17% of men receiving it as first-line therapy. This suggests many patients might benefit from earlier consideration of this treatment option.
For patients currently on Ra-223 therapy, completing the full course of treatment (at least 5 cycles) appears to be particularly important for maximizing survival benefits.
About Radium-223
Radium-223 (brand name Xofigo) is an alpha-emitting radiopharmaceutical approved in 2013 for treating mCRPC with bone metastases and no known visceral involvement. It targets bone metastases while limiting damage to surrounding tissues.
For more information about this study or Radium-223 treatment, speak with your healthcare provider or visit the websites in our references section below.
SIDEBAR: Understanding the Pharmaceutical Connection with Xofigo
About Xofigo and Bayer
Radium-223 dichloride is marketed under the brand name Xofigo by Bayer HealthCare Pharmaceuticals. The drug received FDA approval in May 2013 and European Medicines Agency approval in November 2013 for the treatment of patients with mCRPC, symptomatic bone metastases, and no known visceral metastatic disease.
Industry Funding and Research
It's important to note that the main study highlighted in this article was funded by Bayer, and three of the five authors (Amit D. Raval, Yiqiao Zhang, Matthew Korn, and Niculae Constantinovici) are Bayer employees and stockholders. Dr. Rana R. McKay, the senior author, reported consulting relationships with multiple pharmaceutical companies, including Bayer.
This industry connection is common in medical research but warrants transparency. The Komodo Health dataset used in the study is a verified, adjudicated, and de-identified administrative claims dataset covering over 140 million individuals from more than 150 US private insurance providers.
Ongoing Research
Bayer continues to invest in research exploring Xofigo's effectiveness in various treatment combinations. The PEACE III trial, examining Ra-223 with enzalutamide, is one such example of ongoing research aimed at optimizing treatment protocols.
Cost Considerations
A full course of Xofigo treatment (six injections) can cost upwards of $69,000 before insurance coverage. Most insurance plans, including Medicare, cover Xofigo when medically necessary, though co-pays and out-of-pocket costs vary. Bayer offers patient assistance programs that may help eligible patients with financial support.
Patient Perspective
When evaluating research on cancer treatments, it's always valuable to consider the source of funding and potential conflicts of interest while weighing the evidence presented. Patients should discuss the potential benefits, risks, and costs of Xofigo with their healthcare providers to make informed treatment decisions.
References
- Raval, A.D., Zhang, Y., Korn, M., Constantinovici, N., & McKay, R.R. (2025). Real-world utilization patterns and survival in men with metastatic prostate cancer treated with Radium-223 in the United States. Prostate Cancer and Prostatic Diseases. https://doi.org/10.1038/s41391-025-00969-6
- Parker, C., Nilsson, S., Heinrich, D., Helle, S.I., O'Sullivan, J.M., Fosså, S.D., et al. (2013). Alpha emitter radium-223 and survival in metastatic prostate cancer. New England Journal of Medicine, 369, 213-223. https://www.nejm.org/doi/full/10.1056/nejmoa1213755
- Gillessen, S., et al. (2024). PEACE III: A randomized multicenter open-label phase III trial comparing enzalutamide vs a combination of radium-223 and enzalutamide in asymptomatic or mildly symptomatic patients with bone metastatic mCRPC. Annals of Oncology, 35, S1254. https://doi.org/10.1016/j.annonc.2024.05.1929
- Gillessen, S., Tombal, B., Turco, F., et al. (2025). Decrease in Fracture Rate with Mandatory Bone-protecting Agents in the EORTC 1333/PEACE-3 Trial Comparing Radium-223 Combined with Enzalutamide Versus Enzalutamide Alone: A Safety Analysis. European Urology, 87, 285-288. https://doi.org/10.1016/j.eururo.2024.12.019
- Wu, S., Zhang, J., Huang, J., et al. (2023). Efficacy and safety of radium-223 for patients with metastatic castration-resistant prostate cancer: a systematic review and meta-analysis. BMC Cancer, 23, 966. https://bmccancer.biomedcentral.com/articles/10.1186/s12885-023-11108-6
- Saylor, P.J., Otani, K., Balza, R., et al. (2024). Circulating and Imaging Biomarkers of Radium-223 Response in Metastatic Castration-Resistant Prostate Cancer. JCO Precision Oncology, 8, e2300230. https://ascopubs.org/doi/10.1200/PO.23.00230
- National Comprehensive Cancer Network (NCCN) Guidelines for Prostate Cancer. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf
- FDA Approval Information for Xofigo (Radium-223). https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/203971s016lbl.pdf
- Bayer Patient Assistance and Resources for Xofigo. https://www.xofigo-us.com/patient-support/
Real-world utilization patterns and survival in men with metastatic prostate cancer treated with Radium-223 in the United States | Prostate Cancer and Prostatic Diseases
Background The treatment landscape for metastatic castration-resistant prostate cancer (mCRPC) has evolved since radium-223 (Ra-223) was approved in the United States (2013). We examined treatment patterns and real-world overall survival (rwOS) of men with mCRPC treated with Ra-223 in the modern treatment era.
Methods A retrospective cohort of men treated with Ra-223 was derived using private insurance data from the Komodo Health dataset from January 1, 2017 to June 30, 2022. Cox-regression analyses examined associations between Ra-223 use and rwOS with adjustment for covariates.
Results Of 1376 men, the median age was 68 years, 51% were White, and 89% had bone-only metastases. Overall, 17%, 35%, and 25% of men received Ra-223 as first-line, second-line, or third-line treatment for mCRPC, respectively. Thirty-six percent received Ra-223 as combination/layered therapy, mainly with enzalutamide, and 46% completed ≥5 cycles. Overall, median rwOS was 22.9 months. Median rwOS was longer in men who completed ≥5 Ra-223 cycles versus 1–4 cycles (30.3 versus 15.3 months) and combination/layered therapy versus monotherapy (26.6 versus 20.5 months). Combination/layered therapy and completion of ≥5 Ra-223 cycles were associated with 22% and 55% reductions in risk of death in adjusted analyses, respectively. Limitations include some clinical information not captured by claims databases.
Conclusions Significant rwOS benefits were identified in men who received Ra-223 as an earlier line of therapy, received Ra-223 in combination with another therapy, and completed ≥5 Ra-223 cycles, underscoring the importance of Ra-223 in the current treatment landscape.
This study examined the treatment patterns and real-world overall survival (rwOS) of men with metastatic castration-resistant prostate cancer (mCRPC) who were treated with radium-223 (Ra-223) in the United States (US) from January 2017 to June 2022.
Research objectives and hypotheses:
The study aimed to comprehensively examine the current treatment patterns and rwOS in men with mCRPC treated with Ra-223 in the US. The researchers hypothesized that using Ra-223 as an earlier line of therapy, in combination with another therapy, and completing at least 5 cycles of Ra-223 would be associated with improved survival outcomes.
Methodology:
This was a retrospective cohort study using private insurance data from the Komodo Health dataset. The researchers identified men with mCRPC who received Ra-223 during the study period and examined their treatment patterns, including the completion of at least 5 Ra-223 cycles, the use of combination or layered therapy, and the sequence of prostate cancer therapies. They also calculated the rwOS and used Cox-regression analyses to examine the associations between Ra-223 use and rwOS, adjusting for various covariates.
Results and findings:
The study included 1,376 men with mCRPC. Overall, 17%, 35%, and 25% of men received Ra-223 as first-line, second-line, or third-line treatment, respectively. Thirty-six percent received Ra-223 as combination or layered therapy, mainly with enzalutamide. Forty-six percent of men completed at least 5 Ra-223 cycles. The median rwOS was 22.9 months. Median rwOS was longer in men who completed at least 5 Ra-223 cycles versus 1-4 cycles (30.3 versus 15.3 months) and in men who received Ra-223 as combination or layered therapy versus monotherapy (26.6 versus 20.5 months). Completing at least 5 Ra-223 cycles and receiving Ra-223 as combination or layered therapy were associated with a 55% and 22% reduction in the risk of death, respectively, in the adjusted analyses.
Discussion and interpretation:
The researchers found significant rwOS benefits in men who received Ra-223 as an earlier line of therapy, in combination with another therapy, and who completed at least 5 Ra-223 cycles. These findings suggest the importance of Ra-223 in the current treatment landscape for mCRPC and support the use of Ra-223 in earlier lines of therapy and in combination with other therapies.
Contributions to the field:
This study provides valuable real-world evidence on the utilization patterns and survival outcomes associated with Ra-223 treatment in men with mCRPC in the US, which can help guide clinical decision-making and inform future research.
Achievements and significance:
The study is the largest analysis of a real-world cohort of men treated with Ra-223 in the US, addressing the utilization of Ra-223 in the current mCRPC treatment landscape. The findings support the use of Ra-223 as an earlier line of therapy, in combination with another life-prolonging therapy, and the importance of completing at least 5 cycles to improve survival outcomes.
Limitations and future work:
Limitations include the lack of capture of some clinical information, such as pain, disease severity, and specific laboratory values, which may have influenced treatment decisions and outcomes. Additionally, the findings may not be generalizable to public insurance-only beneficiaries. Future research could further explore the optimal sequencing and combination of Ra-223 with other therapies in the evolving mCRPC treatment landscape.
Introduction
Radium-223 dichloride (Ra-223), an alpha-emitting radiopharmaceutical, has been an approved treatment for metastatic castration-resistant prostate cancer (mCRPC) with bone metastases and no known visceral involvement since 2013 [1]. Approval was based on the findings of the pivotal phase 3 ALSYMPCA trial where Ra-223 significantly prolonged overall survival (OS) and had quality of life benefits versus placebo [2, 3].
Since the approval of Ra-223, the treatment landscape for prostate cancer (PC) has evolved substantially. Changes include treatment intensification for metastatic hormone-sensitive prostate cancer (mHSPC), shifting from androgen deprivation therapy alone to in combination with androgen-receptor pathway inhibitors (ARPIs; i.e., enzalutamide, apalutamide, darolutamide, and abiraterone), with or without docetaxel [4,5,6,7], and the approval of ARPIs (enzalutamide, apalutamide, and darolutamide) for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC) [8,9,10,11,12,13,14]. As such, men with PC may receive more life-prolonging therapies prior to an mCRPC diagnosis.
Given the changes in PC treatment, recent real-world evidence of Ra-223 utilization patterns and outcomes may inform clinicians on when Ra-223 should be used and whether it is feasible to combine it with other agents. While numerous real-world studies of Ra-223 use in the United States (US) have been published, these are limited to only a few centers [15,16,17,18], have small sample sizes (n < 350) [15,16,17,18,19,20,21], or analyze data prior to the approval of ARPIs for nmCRPC/mHSPC or docetaxel for mHSPC [15, 16, 19, 21]. Consequently, existing data may not provide a complete picture of current Ra-223 treatment patterns and outcomes in the US. Therefore, there is a need for larger, more robust real-world studies evaluating Ra-223 use and associated clinical outcomes at a national level that integrate the current PC treatment paradigm. We aimed to comprehensively examine current treatment patterns and real-world OS (rwOS) in men with mCRPC treated with Ra-223 in clinical practice using data from a large US administrative claims dataset covering private health insurance.
Subjects and methods
Study design
We conducted a retrospective cohort analysis of men with PC who initiated Ra-223 (assumed, therefore, to be men with mCRPC) among private insurance beneficiaries, identified from claims made for Ra-223 from January 1, 2017 to June 30, 2022 (identification period). The index date was defined as the date of earliest Ra-223 administration; all individuals required a baseline period of ≥12 months prior to the index date and a follow-up period of ≥6 months, or until death if they died within 6 months from the index date. The end of follow-up was the last date of continuous enrollment, death, or the end of the study period (December 31, 2022). Study design details are shown in Supplementary Fig. S1.
Ethics approval and consent to participate
This retrospective analysis of real-world data was conducted in accordance with the RECORD and STROBE statements [22, 23]. Due to the de-identified nature of the dataset, informed consent was not required; data were also considered exempt from Institutional Review Board review.
Data source
The Komodo Health dataset is a verified, adjudicated, and de-identified administrative claims dataset covering >140 million individuals from >150 US private insurance providers. We utilized data from privately insured and Medicare Advantage Plan populations, representing individuals aged <65 years covered through employer-sponsored plans, health insurance exchange, or Medicaid managed care, as well as supplementary private insurance plans for individuals aged ≥65 years.
Inclusion and exclusion criteria
We identified men with PC who received Ra-223 during the identification period using the selection process detailed in Supplementary Table S1.
Ra-223 utilization patterns
We examined the completion of ≥5 Ra-223 cycles, the use of combination or layered therapy, and the sequence of PC therapies pre- and post-Ra-223. Ra-223 therapy completion was defined as completing ≥5 cycles without a gap of ≥56 days between two subsequent administrations. Combination therapy was considered the administration of other life-prolonging mCRPC medications within 30 days of starting Ra-223, and layered therapy was considered as starting Ra-223 after using another therapy for ≥30 days; these definitions are consistent with those of other studies [17, 24, 25].
The index line of therapy (LOT) was the use of Ra-223, as monotherapy or with any other mCRPC agent within 30 days of the index date. Change in LOT was defined as initiating a new PC non-index therapy or having a ≥90-day gap in the current LOT. Using these parameters, we also identified pre- and post-index LOTs during the baseline and follow-up periods, respectively.
Real-world overall survival
The Komodo Health dataset contains mortality data from several sources, including claims or other mortality data sources, with 92% matching the death data reported by the Centers for Disease Control and Prevention in the year following 2017 (Komodo Health in-house resources). RwOS was calculated as the time from index date to date of death. Men whose follow-up end date was not due to death were censored at the end of follow-up.
Study variables
Demographics at the index date, clinical characteristics, and PC treatments during the baseline period were analyzed; these covariates are defined in Supplementary Table S2.
Statistical analyses
Descriptive statistics are reported for independent measures by overall population and study groups of interest. Logistic regression analyzed factors associated with completion of ≥5 Ra-223 cycles, including demographic, clinical, and medication-related characteristics. Odds ratios (ORs) were calculated to indicate baseline characteristics associated with completion of ≥5 Ra-223 cycles versus 1–4 cycles. Statistically significant differences in baseline characteristics between the Ra-223 monotherapy and combination/layered therapy groups were estimated using the chi-square or Fisher-exact tests for categorical variables and t-tests, Mann–Whitney or ANOVA tests for continuous variables. Median rwOS was calculated using Kaplan–Meier methodology. Cox-regression analyses examined associations between Ra-223 use and rwOS with adjustment for covariates, such as baseline demographics, clinical characteristics, treatments, and healthcare resource use.
Results
Patient demographics and baseline characteristics
During the sample identification process (Supplementary Table S1), of 556,610 men with metastatic prostate cancer, 11,069 (2%) had evidence of Ra-223 treatment initiation between 2017 to 2022. After applying further inclusion and exclusion criteria, 1376 men with mCRPC were included in this analysis (Supplementary Table S1). Demographic and baseline characteristics are summarized in Table 1. The median age was 68 years and 51% of men were White. On average, it took 2 years from the first observed metastasis or ADT use to initiate Ra-223. The majority of men (89%) had bone-only metastases and a Charlson Comorbidity Index (CCI) score ≥1 (76%). The most common pre-existing comorbidities were diabetes (34%), peripheral vascular disease (30%), pulmonary disease (26%), mild liver disease (25%), renal disease (20%), cerebral vascular accident (15%), and congestive heart failure (14%). Overall, 73%, 32%, 83%, and 74% of men had received prior ARPIs, chemotherapy, opioids and bone health agents (BHAs), respectively (Table 1).
Ra-223 utilization patterns
Sequence of Ra-223 use
Ra-223 was most commonly received as a second (35%) or third (25%) LOT; 17% of men received Ra-223 as a first LOT (Fig. 1, Table 1). Few men received Ra-223 as a fourth (11%) or fifth (12%) LOT. For men who received Ra-223 as a second LOT, ARPIs (abiraterone [13%]; enzalutamide [12%]), docetaxel (5%), and sipuleucel-T (2%) were the most common first LOTs. When Ra-223 was given as a third LOT, back-to-back ARPIs (abiraterone-enzalutamide [5%]; enzalutamide-abiraterone [3%]) and docetaxel-ARPIs (docetaxel-abiraterone [3%]; docetaxel-enzalutamide [3%]) were common prior therapy sequences (Fig. 1). Post Ra-223 initiation, 45%, 19%, and 9% of men received one, two, or three subsequent LOTs, respectively, with chemo-ARPI and ARPI-chemo being the most common LOT sequences. The most common first subsequent LOTs were chemotherapy (docetaxel [31%]; cabazitaxel [15%]), ARPI (enzalutamide [22%]; abiraterone [21%]), and poly (ADP-ribose) polymerase inhibitor (olaparib [4%]). Similar trends were observed for second and third subsequent LOTs. Lutetium-177 vipivotide tetraxetan was used in <1% of subsequent LOTs.
ARPI androgen receptor pathway inhibitor, CHEMO taxane-based chemotherapy, IMMU immunotherapy (sipuleucel-T or pembrolizumab), PARP poly (ADP-ribose) polymerase, LU Lutetium-177 vipivotide tetraxetan.
Ra-223 monotherapy, layered, and combination therapy
Ra-223 was given as monotherapy, layered, or combination therapy in 64%, 28%, and 8% of men, respectively (Fig. 2A; baseline characteristics for these groups are in Supplementary Table S3). ARIs (most commonly enzalutamide) and abiraterone were the most commonly used agents in combination/layered Ra-223 therapy (21% and 12%, respectively) (Fig. 2B).
The proportion of men who A received Ra-223 as combination, layered or monotherapy, B received Ra-223 in combination/layered regimens with the specified agents, C completed the stated number of Ra-223 cycles, and D completed 1–4 or ≥5 Ra-223 cycles. aOf the 289 men who received an ARI as combination/layered therapy, 275 (95%) received enzalutamide, 9 (3%) received apalutamide, and 5 (2%) received darolutamide. bTaxane-based chemotherapy. cSipuleucel-T or pembrolizumab. ARI androgen receptor inhibitor, PARPi poly (ADP-ribose) polymerase inhibitor.
In a multinomial logistic regression analysis, factors associated with a significantly higher likelihood of receiving layered Ra-223 therapy were pulmonary disease (OR 1.47; 95% confidence interval [CI] 1.07–2.03) and baseline BHA use (OR 1.47; 95% CI 1.08–1.99) (Supplementary Table S4). A lower likelihood of receiving layered Ra-223 therapy was associated with some older age groups (75–79 years [OR 0.58; 95% CI 0.33–0.99]; ≥85 years [OR 0.32; 95% CI 0.12–0.85]), a lower number of prior therapies (<2 [OR 0.58; 95% CI 0.42–0.80]) and pain medication use (OR 0.70; 95% CI 0.50–0.99). A higher likelihood of receiving Ra-223 combination therapy was associated with a lower number of prior therapies (<2 [OR 2.08; 95% CI 1.21–3.61]) and higher number of office visits (>17 [OR 1.58; 95% CI 1.03–2.42]) (Supplementary Table S4).
Completion of ≥5 Ra-223 cycles
Overall, 46% of men completed ≥5 Ra-223 cycles (Fig. 2C, D). In univariable analyses, men more likely to complete ≥5 Ra-223 cycles included those who had bone-only metastases, received Ra-223 as combination or layered therapy, received Ra-223 as first or second LOT, or had no prior abiraterone, chemotherapy or opioid use (Supplementary Table S5). In multivariable analyses, men who received Ra-223 as combination therapy had a higher likelihood of completing ≥5 Ra-223 cycles than those who received Ra-223 monotherapy (OR 1.59; 95% CI 1.01–2.50) (Supplementary Table S5).
Real-world overall survival
The median rwOS of the overall cohort was 22.9 months (Fig. 3A). Median rwOS was longer in men who completed ≥5 versus 1–4 Ra-223 cycles (30.3 versus 15.3 months) and in men who received Ra-223 as layered/combination therapy versus Ra-223 monotherapy (26.6 versus 20.5 months) (Table 2). Similar trends were seen irrespective of whether Ra-223 was the first, second, third or fourth LOT (Fig. 3B, C). In multivariable Cox-regression analyses, the risk of death was 55% lower in those completing ≥5 versus 1–4 Ra-223 cycles, and 22% lower when Ra-223 was used as combination/layered therapy versus monotherapy (Table 2, Supplementary Tables S6 and S7).
Data are shown for A the overall cohort, B by completion of 1–4 versus ≥5 Ra-223 cycles and LOT, C by use of Ra-223 monotherapy versus combination/layered and LOT, and D by LOT. CI confidence interval, LOT line of therapy, rwOS real-world overall survival.
Median rwOS was longest in men who received Ra-223 as their first LOT (37.6 months) and decreased incrementally in subsequent LOTs (26.0, 20.0, and 14.1 months in second, third, or fourth or later LOT, respectively) (Fig. 3D). Compared with Ra-223 as fourth or later LOT, use as first, second, or third LOT was associated with a 58%, 42%, or 25% lower risk of death, respectively, when adjusted for other baseline variables (Table 2). In multivariable analysis, prior hospitalization and BHA use at baseline were associated with a higher risk of death; whereas African American race was associated with a lower risk of death (Supplementary Table S7).
Discussion
Using a large US claims dataset of men with mCRPC treated with Ra-223 between January 2017 and June 2022, we describe how Ra-223 can impact survival. Our large cohort allowed us to analyze outcomes of numerous subgroups while maintaining sufficient sample sizes. Although Ra-223 is underutilized in the current mCRPC treatment landscape, our findings support its benefits as an established life-prolonging therapy.
Survival of the overall cohort was longer than in the ALSYMPCA trial (22.9 vs 14.9 months, respectively) [2], but remained within median ranges reported in other real-world studies (10.5–23.5 months [15,16,17, 20, 21, 26,27,28,29,30,31,32,33,34,35,36]). OS differences may be due to recent changes in the PC treatment landscape, such as the approval of ARPIs and chemotherapy for the treatment of nmCRPC and mHSPC [4,5,6,7]. Few life-prolonging therapies were available as standard treatments for mCRPC at the time of ALSYMPCA, although 57% of patients had received prior docetaxel; in a pre-specified subgroup analysis, Ra-223 prolonged OS versus placebo irrespective of prior docetaxel use [37]. In our study, 30% and 73% of men received prior docetaxel and ARPIs, respectively. Moreover, our study population was slightly younger than that of ALSYMPCA, due to high representation of younger (<65 years) private insurance beneficiaries, which may also have contributed to the prolonged rwOS observed in our study.
Real-world studies assessing if combining Ra-223 with other agents results in an observed improvement in survival versus Ra-223 monotherapy are limited and have not demonstrated significant findings [15, 19, 35]. However, these studies were limited by small cohorts (monotherapy and combination therapy groups: N = 128 and N = 92 [15]; N = 202 and N = 116 [19]; N = 32 and N = 19 [35]). By contrast, in our larger analysis, men in the combination/layered Ra-223 group (N = 492) had longer rwOS than those in the Ra-223 monotherapy group (N = 884). Among men who received combination/layered therapy, the agent most commonly given with Ra-223 was enzalutamide.
Several ongoing studies are assessing Ra-223 in combination with other mCRPC medications, including PEACE III (NCT02194842), DORA (NCT03574571), COMRADE (NCT03317392), and Rad2Nivo (NCT04109729). Notably, the phase 3 PEACE III trial recently demonstrated the significant clinical benefits of first-line combination therapy for mCRPC, with enzalutamide plus Ra-223 significantly prolonging both radiological progression-free survival (19.4 vs 16.4 months; p = 0.0009) and OS (42.3 vs 35.0 months; p = 0.0031) relative to enzalutamide alone [38]. Safety data from PEACE III indicate that concomitant BHA use mitigates the fracture risk of therapy, with the cumulative incidence of fractures at 1 year in men treated with enzalutamide plus Ra-223 being 2.7% (95% CI 0.5–8.5) with BHAs versus 37.1% (95% CI 21.3–53.0%) without BHAs; the corresponding values with enzalutamide were 2.6% (95% CI 0.5–8.3%) versus 15.6% (95% CI 5.6–30.3%) [39]. According to European [40, 41] and US [7] guidance, BHAs should be considered for all men with mCRPC [40] with bone metastases [7, 41] in order to prevent/delay skeletal-related events such as osteoporotic fragility fractures. Advanced prostate cancer carries an increased risk of osteoporosis [42] (which can be exacerbated by the use of ADT [40, 43]), with this poor bone health leading to bone fragility and fractures in some patients [44], including those treated with Ra-223 [45].
In our study, most men received Ra-223 after one or two LOT. Consistent with many drugs, Ra-223 may provide a greater survival benefit when provided as a first versus second or later LOT. Similar findings have been seen in other real-world studies [31, 46]. As patients progress through several lines of therapy, their general health can deteriorate (e.g., declining performance status, disease or symptomatic progression, or cytopenia), potentially leading to early treatment discontinuation. In our study, men who completed ≥5 Ra-223 cycles were observed to live longer than men who only completed 1–4 cycles, consistent with findings of other real-world studies [15, 27, 29]. We found that completing ≥5 Ra-223 cycles was more likely when Ra-223 was used as combination therapy than when used as layered therapy or monotherapy, supporting a previous real-world finding that men receive more cycles when Ra-223 is given as combination therapy versus monotherapy [15]. Prior studies have shown poor performance status and high tumor markers may be associated with lower ability to complete Ra-223 treatment [27, 47]. Due to data limitations, we were unable to capture such information. Nevertheless, our findings support the importance of identifying the population that will be able to adhere to the full treatment course and receive the optimal benefits of Ra-223 therapy. Currently, there are no validated markers for predicting which men with mCRPC are likely to respond the best to Ra-223, although several have shown promise including automated bone scan index, circulating tumor cells, alkaline phosphatase, lactate dehydrogenase, and bone metabolic markers [46, 48,49,50].
With respect to race, there was no significant difference in completion of ≥5 Ra-223 cycles between Whites and African Americans. Furthermore, with respect to survival, African Americans had a lower risk of death compared to Whites. Our findings are consistent with a large systematic literature review showing no difference or favorable outcomes for African American men versus White men with mCRPC when they were treated with specific therapies, including Ra-223, in real-world practice [51].
Despite the strengths of the study, it is not without limitations. First, while we were able to capture opioid and BHA use, we were not able to capture pain or disease severity with number of metastases and prostate-specific antigen or alkaline phosphatase levels. Second, it is possible that some of the prior LOTs for mCRPC could have been utilized for mHSPC, which might have led to a misclassification of second- and third-line Ra-223 LOT. However, when comparing these data with those of a chart review [21], we found relative consistency in the distribution of index Ra-223 LOTs. Therefore, the degree of misclassification for second- and third LOTs is likely negligible. Third, the findings may not be generalizable to public insurance-only beneficiaries. Fourth, we were unable to evaluate how approval of lutetium (177Lu) vipivotide tetraxetan (a beta-emitter) for men with mCRPC may have impacted Ra-223 treatment patterns, as its approval was 3 months prior to our data cutoff, and its usage was therefore low.
Conclusions
To our knowledge, this is the largest analysis of a real-world cohort of men treated with Ra-223 in the US. Our analysis addresses the utilization of Ra-223 in the current mCRPC treatment landscape. Our findings support using Ra-223 as an earlier LOT, giving Ra-223 in combination with another life-prolonging therapy, and the importance of completing ≥5 cycles to improve survival outcomes. Real-world evidence can provide information pertaining to treatment patterns and associated survival outcomes in men with mCRPC, which may be used to guide clinical decisions.
Data availability
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Acknowledgements
Medical writing support was provided by Dr Chris Guise and Victoria Lord, Bioscript Group, Macclesfield, UK, in accordance with Good Publication Practice guidelines, and funded by Bayer. Dr Orsolya Lunacsek (Bayer) provided assistance with the analyses.
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AR, YZ, MK and NC are employees and stockholders of Bayer. RM reports consulting fees for Ambrx, Arcus, AstraZeneca, Aveo, Bayer, Bristol-Myers Squibb, Calithera, Caris, Dendreon, Eisai, Exelixis, Johnson & Johnson, Lilly, Merck, Myovant, NeoMorph, Novartis, Pfizer, Sanofi, SeaGen, Sorrento Therapeutics, Telix, Tempus; and institutional research support for Artera, AstraZeneca, Bayer, Tempus, Oncternal, Bristol-Myers Squibb, Exelixis.
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Raval, A.D., Zhang, Y., Korn, M. et al. Real-world utilization patterns and survival in men with metastatic prostate cancer treated with Radium-223 in the United States. Prostate Cancer Prostatic Dis (2025). https://doi.org/10.1038/s41391-025-00969-6
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DOI: https://doi.org/10.1038/s41391-025-00969-6
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