Safety of concomitant therapy with radium‐223 and abiraterone or enzalutamide in a real‐world population

Hanson Zhao MD1, Lauren E. Howard MB2,3, Amanda M. De Hoedt MS3 |Martha K. Terris MD4,5, Christopher L. Amling MD6, Christopher J. Kane MD7, Matthew R. Cooperberg MD, MPH8, William J. Aronson MD9,10, Zachary Klaassen MD5, Thomas J. Polascik MD2,3 , Adriana C. Vidal PhD1

Abstract

Background: Real‐world utilization and outcomes of combination therapy for men with metastatic castrate‐resistant prostate cancer (mCRPC) are largely unknown. We evaluated the overall survival (OS) and skeletal‐related events (SREs) among men who received radium‐223 with or without concomitant abiraterone or enzalutamide in the Veterans Affairs (VA) Health System.
Methods: We reviewed charts of all mCRPC patients who received radium‐223 in the VA from January 2013 to September 2017. We used Cox models to test the association between concomitant therapy versus radium‐223 alone on OS and SRE. Sensitivity analyses were performed for concomitant use of denosumab/ bisphosphonates.
Results: Three hundred and eighteen patients treated with radium‐223 were identified; 116/318 (37%) received concomitant abiraterone/enzalutamide. Two hundred and seventy‐seven (87%) patients died during follow‐up. Patients who received concomitant therapy were younger at radium‐223 initiation (median age 68 vs. 70, p = .027) and had a longer follow‐up (median 29.5 vs. 17.9 months, p = .030). There was no OS benefit for those on concomitant therapy (hazard ratio [HR]: 0.87, 95% confidence interval [CI]: 0.67–1.12, p = .28). There was a trend for an increased SRE risk for patients on concomitant therapy (HR: 1.87, 95% CI: 0.96–3.61, p = .066), but this was not significant. When analyses were limited to men using bone heath agents, similar results were seen for OS (HR: 0.86, 95% CI 0.64–1.15, p = .30) and SRE (HR: 2.36, 95% CI: 0.94–5.94, p = .068).
Conclusions: Despite the common use of concomitant therapy in this real‐world study, there was no difference in OS among mCRPC patients. A nonsignificant increased SRE risk was observed. Further work needs to evaluate the optimal sequence, timing, and safety of combination therapies.

K E Y W O R D S
abiraterone, concomitant therapy, enzalutamide, metastatic prostate cancer, radium‐223

1,INTRODUCTION

Radium‐223 is a calcium mimetic that emits cytotoxic alpha particles. Once injected, radium‐223 preferentially goes to areas of rapid bone turnover such as osteoblastic or sclerotic metastases.1−3 In the ALSYMPCA trial, among men with symptomatic metastatic castrateresistant prostate cancer (mCRPC), radium‐223 increased overall survival (OS) (hazard ratio [HR]: 0.70, 95% confidence interval [CI]: 0.58–0.83; p < .001), and delayed time to first skeletal‐related event (SRE) (HR: 0.66, 95% CI: 0.52–0.83; p < .001).1 Based on these data, radium‐223 was Food and Drug Administration (FDA) approved in 2013.4,5
In an international, open‐label, phase 3b trial, patients with mCRPC treated with radium‐223 combined with abiraterone or enzalutamide had longer OS than those who received radium‐223 alone.6 Whether combination therapy leads to improved OS was formally tested in the ERA‐223 trial.7 In this double‐blind, placebo‐controlled study, 806 patients with asymptomatic or mildly symptomatic bone mCRPC were randomized to receive abiraterone and prednisone with radium‐223 or abiraterone and prednisone alone. This trial was unblinded prematurely by the independent data monitoring committee due to more fractures and deaths in the combination group.7 In the published results of this study, there was no difference in OS between the two groups but the combination group had an increased risk of fractures (29% vs. 11%).7
The interim results of ERA‐223 led to the mandatory use of bone protective agents in the PEACE III trial, which is an ongoing phase III trial comparing enzalutamide to radium‐223 plus enzalutamide for men with asymptomatic or mildly symptomatic mCRPC.8,9 Among patients not on bone health agents, early PEACE III data mirrored ERA‐223 data (increased fracture in the combination arm), but after implementing mandatory bone health agents, the risk of bone fractures in both arms was extremely low.8
Real‐world utilization and outcomes of combination therapy with radium‐223 and abiraterone or enzalutamide are largely unknown. In this study, we identified men with mCRPC treated with radium‐223 in the Veterans Affairs (VA) Health System and compared the differences in OS and SRE between those who did and did not receive concomitant therapy with abiraterone or enzalutamide. We stratified by the use of abiraterone or enzalutamide and use of bone protective agents to better understand how these factors affect OS and SRE.

2,PATIENTS AND METHODS

2.1,Data source/ascertainment of study cohort

This study was approved by the institutional review board at the Durham VA Medical Center. Our study cohort has been previously described.10 We identified all men (n = 318) in the entire nationwide VA Healthcare System who received radium‐223 between January 2013 and September 2017. These men were identified with radiotherapy current procedural terminology code (A9606, A9699, or 79101) and had “Xofigo,” “Zofigo,” “Ra‐223,” or “Radium‐223” keywords in their progress notes. Each patient’s medical record was reviewed to confirm radium‐223 treatment and treatment dates. Other mCRPC therapies and duration for each therapy were also abstracted.
All patients were confirmed to have bone mCRPC at radium‐223 initiation. CPRC status was determined by the Prostate Cancer Working Group 2 criteria: ≥25% increase in prostate specific antigen (PSA) and an absolute increase of ≥2 ng/ml above the PSA nadir while castrate.11 Castration was defined as testosterone < 50 ng/dl, bilateral orchiectomy, or continuous receipt of hormone agonists or antagonists. We reviewed progress notes and imaging reports to identify cancer metastasis locations. Bone pain was abstracted from medical notes within 2 months before or after the development of bone metastases. Patients were followed until the date of death determined from the medical records or last follow‐up. SREs were defined as pathologic bone fracture, spinal cord compression, radiation to the bone, or surgery to the bone. The first incidence of an SRE after bone metastases was abstracted using imaging reports and medical records. Ten percent of all the collected data were randomly selected for a secondary review.

2.2,Statistical analysis

PSA doubling time (PSADT) was calculated by the natural log of two divided by the slope of the linear regression of the natural log of PSA over time in months. All available PSAs within 2 years before the first bone metastasis diagnosis but after CRPC diagnosis were used to calculate PSADT. To calculate PSADT, subjects had to have ≥2 PSAs over ≥3 months.
Kaplan–Meier curves were used to compare OS and SREs in men who did and did not receive concomitant abiraterone or enzalutamide. OS was considered the primary outcome and SRE as a secondary outcome. Concomitant abiraterone or enzalutamide was defined as patients filling abiraterone or enzalutamide prescriptions in the same time interval while receiving radium‐223 injections. Cox models were used to test the association between receiving concomitant therapy and OS. Similar models were done for testing time to SRE. Time zero was the initiation of radium‐223. Patients who developed an SRE before initiating radium‐223 were excluded from the time to SRE model. Covariables for each outcome were chosen using backwards stepwise selection with α = .05 for entry and 0.1 for removal. Candidate covariables included age at radium‐223 initiation (continuous), year of radium‐223 initiation (continuous), biopsy grade group (1 vs. 2–3 vs. 4–5 vs. unknown), primary localized treatment (none vs. radical prostatectomy and/or radiation vs. radiation alone), PSA at radium‐223 initiation (continuous, log‐transformed), PSADT at metastases (<9 months vs. ≥9 months vs. not calculable), months from ADT to CRPC (continuous), months from CRPC to first bone metastasis (continuous), docetaxel before radium (no vs. yes), presence of bone pain at metastasis diagnosis (no vs. yes vs. unknown), SRE before radium‐223 (no vs. yes; OS model only) and the number of bone metastases at initial diagnosis of bone metastases (1 vs. 2 vs. 3–9 vs. ≥ 10 vs. unknown).
Sensitivity analyses were performed for patients with at least 30 days of treatment overlap with radium‐223 and abiraterone or enzalutamide, patients with at least 60 days of treatment overlap, patients who received at least an average of 0.8 shots/injections of radium per month (to account for men who were receiving radium intermittently), patients treated with radium‐223 and abiraterone alone or enzalutamide alone, patients on docetaxel before radium223, and patients using denosumab or bisphosphonates at radium223 initiation.
Analyses were conducted using Stata 15.0 (Stata Corp.). p < .05 was considered statistically significant.

3,RESULTS

We identified 318 patients in the entire VA Health System who received radium‐223, all of whom had bone mCRPC (Table 1). Median follow‐up after radium‐223 initiation among men who did not die was 25.3 months (IQR: 13.8–37.1 months). During this time, 217 (68%) patients developed an SRE, of which 41 (19%) had SRE after radium‐223 initiation. Two hundred and seventyseven (87%) patients died during the study. Median survival was 11 months (95% CI: 9.7–12.5). One hundred and sixteen (37%) patients took abiraterone or enzalutamide at the same time as radium‐223. The median overlap time was 112 days (IQR: 37–153) days. Forty three (14%) patients received concurrent abiraterone, and 77 (24%) patients received concurrent enzalutamide. There were 193 (61%) patients who received docetaxel before radium.
Patients who received concomitant radium‐223 with abiraterone or enzalutamide were younger at radium‐223 initiation (median age 68 vs. 70, p = .027) and had longer follow‐up (median 29.5 vs. 17.9 months, p = .030) versus those without overlapping treatment, but otherwise, characteristics were similar between groups (Table 1). There was no difference in the number of radium injections received between groups (median 5 vs. 4 injections, p = .150).
OS was similar among men who received concomitant therapy and those who did not (Figure 1, p = .11). On multivariable analysis, there was no significant difference in OS between patients who did and did not receive concomitant abiraterone or enzalutamide while on radium‐223 (HR: 0.87, 95% CI: 0.67–1.12, p = .33; Table 2).
One hundred and forty‐two men did not have an SRE before radium‐223 initiation. For these patients, the median time to SRE was 30.6 months. Patients who received concomitant abiraterone or enzalutamide had a higher risk of SRE, although this was not significant (Figure 2, p = .069). On multivariable analysis, there was a trend to an increased SRE risk between patients who received concomitant abiraterone or enzalutamide while on radium‐223, though this was not statistically significant (HR: 1.86, 95% CI: 0.96–3.61, p = .066; Table 2).
There was no increased risk of mortality for any of the subgroups (Table 2) including patients treated with radium‐223 with concomitant abiraterone alone (HR: 0.90, 95% CI: 0.62–1.31, p = .59) or enzalutamide alone (HR: 0.84, 95% CI: 0.63–1.11, p = .22). Patients who had ≥60 days of overlap with the two therapies had improved OS (HR: 0.70, 95% CI: 0.52–0.94, p = .016).
Although there was no increased risk of SRE with concomitant abiraterone (HR: 0.91, 95% CI: 0.28–2.89, p = .86), there was an increased risk of SRE with concomitant enzalutamide (HR: 1.97, 95% CI: 1.0–3.88, p = .049). Analysis of several other of the subgroups including patients with ≥30 days of treatment overlap, patients who received radium consistently, and patients who did not receive docetaxel before radium‐223 also found a significantly increased risk of SRE for those on concomitant therapy, although this was limited by a small number of events (Table 2).
There was a total of 249 (78%) patients taking denosumab or bisphosphonate. There was no difference in mortality risk for patients on concomitant therapy whether or not they were taking denosumab or bisphosphonate (HR: 0.86, 95% CI: 0.64–1.15, p = .30 and HR: 0.77, 95% CI: 0.43–1.41, p = .40, respectively). For patients taking denosumab or bisphosphonate, there was a trend of an increased risk of SRE for patients on concomitant therapy (HR: 2.36, 95% CI: 0.94–5.94, p = .068).

4,DISCUSSION

Despite the numerous treatment options approved for mCRPC, little is known about the outcomes of concomitant therapy. Herein, we identified mCRPC patients from the national VA Health System who received radium‐223 from January 2013 until September 2017. We found concomitant therapy with abiraterone or enzalutamide was common in this real‐world cohort (37%). On multivariable analysis, there was no increased risk of mortality between the two groups although there was a trend to an increased SRE risk for those who received concurrent treatment. These real‐world results are consistent with findings from the ERA‐223 trial and reinforce the importance of having a better understanding of biological effects of combination therapy before implementation in clinical practice.
In this VA cohort, the median PSA upon initiating radium‐223 was 102.2 ng/ml and median alkaline phosphatase was 143 U/L. Based on these characteristics, our patients had more advanced disease than those in the ERA‐223 trial where median PSA and alkaline phosphatase in the combination group were 30 ng/ml and 129 U/L, respectively.7 Importantly, 176 men (55%) in our cohort had an SRE before initiating radium‐223. Due to this, our analysis of new SREs after radium‐223 was limited by small numbers. Nevertheless, our real‐world study found a suggestion of increased SRE risk with concomitant therapy of radium‐223 and abiraterone or enzalutamide, and this association persisted on various subset analyses. In the ERA‐223 trial, the combination of radium‐223 and abiraterone plus prednisone had more bone fractures than the abiraterone plus prednisone group alone (29% vs. 11%).7 Thus, though bone fractures and SREs are not identical, there appears to be some consistency with our results, suggesting the combination of androgen receptortargeted therapy plus radium‐223 may have adverse effects on the bone.
In our real‐world study, combination therapy was not associated with adverse effects on mortality. In fact, patients with ≥60 days of therapy overlap had improved survival, although this may likely represent survivor bias in that they lived at least 2 months and were still receiving anticancer therapy.
The exact biologic mechanism to explain increased bone fractures from combination therapy seen in ERA‐223 is unknown but there are several possible hypotheses. Bone health is maintained by a delicate balance between osteoblastic and osteoclastic activity. Androgens and estrogens help maintain osteoblastic activity to promote bone mass and integrity.12 Iuliani et al.13 found abiraterone can actually promote osteoblastic differentiation and inhibit osteoclastic differentiation to have a direct anabolic and anti‐resorptive activity on the bone. Radium‐223 could then be deposited within these weakened sites of active remodeling and lead to an increased risk of fractures.14,15 Murine xenograft models found that radium223 typically deposits near activated osteoblasts and has an effect on not just tumor cells but also adjacent osteoblasts and osteoclasts.16 This imbalance of osteoblastic and osteoclastic activity may be responsible for the osteoporotic fractures in ERA‐223.
Ultimately, bone health is clearly vital in this patient population. In the posthoc analysis of ERA‐223, patients taking bone health agents had fracture rates of 15% and 7% in the combination and placebo group, and patients not taking bone health agents had fracture rates of 37% and 15%, respectively.7 Combination therapy in our study was associated with higher SRE risk in men whether they were also on denosumab or bisphosphonate or not, though neither result was statistically significant. In the PEACE III interim safety results, adding radium‐223 to enzalutamide without bone protective agents increased the risk of fracture from 13% to 33%.8 However, the addition of bone protective agents to the combination group decreased that risk to just 3%.8 In a recent phase II trial investigating bone metabolic markers for patients treated with enzalutamide alone or radium‐223 plus enzalutamide, 47 of the 49 patients received concomitant zoledronic acid or denosumab with no pathologic fractures observed in either group.17
There is clearly a need to continue further investigation. Our study joins several others that evaluated the real‐world safety of combination radium‐223 and enzalutamide or abiraterone.6,18 Saad et al.6 reported on 696 mCRPC patients treated with radium‐223, of which 189 (27%) received concomitant therapy with abiraterone and/or enzalutamide. They found no difference in the rate of treatment‐emergent adverse events between those who did and did not receive concomitant therapy, and patients who received concomitant therapy had improved OS (13 months vs. not reached).6 In another open‐label trial of 184 patients with mCRPC receiving radium‐223, 40 (22%) received concomitant abiraterone or enzalutamide, which was considered to be well‐tolerated.18 Given all the available agents for mCRPC, the optimal combination and timing of therapies are largely unknown and further studies should focus not only on the efficacy but also the safety profile of combination therapy. We eagerly await the final results of the PEACE III trial.9
Our study has several limitations. This is a retrospective study with inherent selection bias as the treatments were decided by the primary physician. As this cohort was identified after the FDA approval of radium‐223, patients may have received other therapies before radium‐223. Some patients may not have been captured in this study if they received radium‐223 treatment outside of the VA Health System and some may have received enzalutamide or abiraterone outside of the VA as well. In addition, not all patients may have been compliant with their medication. As this is a veterans‐only population, this study may have limited generalizability to other populations. Nevertheless, this is a representative and diverse realworld cohort of patients from around the country in an equal access setting. These results add to the growing literature on mCRPC combination therapies. Further prospective studies are required to confirm our findings.

5,CONCLUSION

Among men with mCRPC in the national VA Health system who were treated with radium‐223, we found that there was no difference in mortality among patients who received concomitant radium‐223 with abiraterone or enzalutamide or radium‐223 alone. There was a trend toward an increased risk of SRE for patients with concomitant therapy. Further studies are needed to investigate the benefits, safety, and optimal timing of combination therapy for mCRPC.

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.
2. Nilsson S, Larsen RH, Fosså SD, et al. First clinical experience with alpha‐emitting radium‐223 in the treatment of skeletal metastases.Clin Cancer Res Off J Am Assoc Cancer Res. 2005;11(12):4451‐4459.
3. Nilsson S, Franzén L, Parker C, et al. Bone‐targeted radium‐223 in symptomatic, hormone‐refractory prostate cancer: a randomised, multicentre, placebo‐controlled phase II study. Lancet Oncol. 2007; 8(7):587‐594.
4. Nuhn P, De Bono JS, Fizazi K, et al. Update on systemic prostate cancer therapies: management of metastatic castration‐resistant prostate cancer in the era of precision oncology. Eur Urol. 2019; 75(1):88‐99.
5. Sartor O, de Bono JS. Metastatic prostate cancer. N Engl J Med.2018 15;378(7):645‐657.
6. Saad F, Carles J, Gillessen S, et al. Radium‐223 and concomitant therapies in patients with metastatic castration‐resistant prostate cancer: an international, early access, open‐label, single‐arm phase 3b trial. Lancet Oncol. 2016;17(9):1306‐1316.
7. 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.Lancet Oncol. 2019;20(3):408‐419.
8. 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.
9. Phase III Radium 223 mCRPC‐PEACE III ‐ Full Text View ‐ Clinical-Trials.gov. 2019. https://clinicaltrials.gov/ct2/show/NCT02194842
10. Zhao H, Howard L, De Hoedt A, et al. Racial discrepancies in overall survival among men treated with 223Radium. J Urol. 2019. https://doi.org/10.1097/JU.0000000000000524
11. Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol Off J Am Soc Clin Oncol.2008;26(7):1148‐1159.
12. Vanderschueren D, Vandenput L, Boonen S, Lindberg MK, Bouillon R, Ohlsson C. Androgens and bone. Endocr Rev. 2004;25(3):389‐425.
13. Iuliani M, Pantano F, Buttigliero C, et al. Biological and clinical effects of abiraterone on anti‐resorptive and anabolic activity in bone microenvironment. Oncotarget. 2015;6(14):12520‐12528.
14. Cursano MC, Santini D, Iuliani M, Paganelli G, Giorgi UD. Early use of abiraterone and radium‐223 in metastatic prostate cancer. Lancet Oncol. 2019;20(5):e228.
15. Morris MJ, Corey E, Guise TA, et al. Radium‐223 mechanism of action: implications for use in treatment combinations. Nat Rev Urol. 2019;16:745‐756.
16. Suominen MI, Fagerlund KM, Rissanen JP, et al. Radium‐223 inhibits osseous prostate cancer growth by dual targeting of cancer cells and bone microenvironment in mouse models. Clin Cancer Res Off J Am Assoc Cancer Res. 2017;23(15):4335‐4346.
17. Agarwal N, Nussenzveig R, Hahn AW, et al. Prospective evaluation of bone metabolic markers as surrogate markers of response to radium‐223 therapy in metastatic castrationresistant prostate cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2020;26:2104‐2110.
18. Sartor O, Vogelzang NJ, Sweeney C, et al. 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.