Radium-223 in mCRPC: Where are we at in 2021?

At the 2021 New York GU 14th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies, Scott T. Tagawa, MD, discussed the latest developments with the alpha particle–emitting radioactive therapeutic agent radium-223 (Xofigo) in patients with castration-resistant prostate cancer (CRPC) and bone metastases.¹

ALSYMPCA trial

Based on the phase 3 ALSYMPCA trial, the FDA approved radium-223 in 2013 for the treatment of patients with CRPC, symptomatic bone metastases, and no known visceral metastatic disease.

The double-blind ALSYMPCA trial randomized 921 patients with CRPC and bone metastases in a 2:1 ratio to best standard of care plus either 6 doses of radium-223 or placebo.² Radium-223 reduced the risk of death by 30%, with median overall survival (OS) of 14.9 months compared with 11.3 months in the placebo arm (HR, 0.70; P <.001). The median time to first skeletal-related event was 15.6 months versus 9.8 months, respectively (HR, 0.66; P <.001).

Scott T. Tagawa, MD

“A 30% improvement [in overall survival] is right in line with the 20% to 30% improvement we typically see with successful agents, so this led to an FDA approval,” said Tagawa, professor of Medicine and Urology at Weill Cornell Medicine, and an attending physician at NewYork-Presbyterian/Weill Cornell Medical Center.

Radium-223 combinations

Following the ALSYMPCA study and prior to the FDA approval of radium-223, researchers conducted a phase 3b trial that was an early access, open-label, single-arm study of radium-223 in patients with CRPC with bone metastases.³

Among the findings from this non-prospective early access data set was that median OS was longer among patients treated with radium-223 plus abiraterone acetate (Zytiga), enzalutamide (Xtandi), or both agents, versus the median OS in patients not receiving these treatments. Combination therapy with radium-223 plus denosumab was also associated with a longer median OS compared to median OS in patients receiving radium-223 without denosumab.

“It looked like there was a fairly clear difference in overall survival for patients who got radium-223 with either abiraterone or enzalutamide at the same time, and similarly for those that received denosumab at the same time,” said Tagawa.

The subsequent ERA 223 trial randomized 806 patients with CRPC and bone metastases to abiraterone acetate and prednisone/prednisolone plus either radium-223 (n = 401) or placebo (n = 405).⁴ The primary results showed that the median symptomatic skeletal event-free survival was 22.3 months with radium-223 plus abiraterone compared with 26 months with placebo plus abiraterone (HR, 1.122; P = .2636).

“Surprisingly, to many of us, this was a flat, negative trial. The trends were actually in favor of placebo, both for the primary end point of symptomatic skeletal-related events, as well as overall survival,” said Tagawa.

Tagawa did note, however, that an unplanned analysis from ERA 223 underscored the importance of using bone health agents (BHAs) with radium-223. In both the intervention and control arms, frequency of fractures was lower when patients received BHAs along with their assigned therapy. In the radium-223/abiraterone/prednisone arm, the rate of symptomatic bone fracture was 15% in patients who did not receive accompanying BHAs versus 1.3% in those receiving BHAs. The rates were 4.7% versus 2.4%, respectively, in the placebo plus abiraterone/prednisone arm.

This finding “strengthened evidence and recommendations to use bone-protective agents when using radium-223,” said Tagawa.

Despite the setback of ERA 223, other combination regimens with radium-223 are currently being explored. The randomized phase 3 PEACE III trial (NCT02194842) is comparing radium-223 plus enzalutamide versus enzalutamide alone in patients with asymptomatic or mildly symptomatic CRPC metastatic to bone. The phase 3 DORA trial (NCT03574571) is randomizing patients with metastatic CRPC to radium-223 plus docetaxel or docetaxel alone.

Is radium-223 benefit enhanced with a higher dose?

A key question that emerged following the ALSYMPCA trial was whether higher doses of the radiopharmaceutical would produce a greater benefit. However, results from a phase 2 trial showed that symptomatic skeletal event-free survival was not improved in patients with bone-metastatic CRPC with either a higher dose of radium-223 than that used in the ALSYMPCA trial (HR, 1.06; P = .70), or an increase in the number of doses compared to the standard 6 doses used in the ALSYMPCA trial( HR, 1.26; P = .31)^.5

Conclusions

Wrapping up his discussion of radium-223, Tagawa said, “In summary, radium-223 will lead to an overall survival benefit in men with metastatic castration-resistant prostate cancer to the bone with limited extraosseous disease. We should not start abiraterone/prednisone and radium-223 at the same time, and we should use a bone health agent when we use this drug.”

Looking ahead, beyond the search for optimal radium-223 combinations, Tagawa said another key question concerns retreatment. “So someone who got treated a couple of years ago, did well, now has progressive disease/symptomatic disease restricted to bone and has been through all the other agents—can we retreat [with radium-223] safely? We do not know, at least not yet.”

References

1. Tagawa S. Therapeutic Radiopharmaceuticals: Past, Present, and Future. Presented at: 2021 New York GU 14th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies, hosted by Physicians’ Education Resource, LLC (PER®); Virtual.

2. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013; 369:213-223. doi: 10.1056/NEJMoa1213755

3. 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 Sep;17(9):1306-16.doi: 10.1016/S1470-2045(16)30173-5

4. 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: 408-419. doi: 10.1016/S1470-2045(18)30860-X

5. Sternberg CN, Saad F, Graff JN, et al. A randomised phase II trial of three dosing regimens of radium-223 in patients with bone metastatic castration-resistant prostate cancer. Ann Oncol. 2020;31(2):257-265. doi: 10.1016/j.annonc.2019.10.025