Researchers Continue to Explore Optimal Use of Radium-223

Tanya B. Dorff, MD

Limited data exist regarding optimal patient selection and sequencing of radium-223 relative to other approved treatments for patients with metastatic castration-resistant prostate cancer (mCRPC).¹ In a presentation given at the 2015 ASCO Annual Meeting, Tanya B. Dorff, MD, Keck School of Medicine of USC, discussed the available research on the radiopharmaceutical agent.

Patient Selection

Radium-223 was approved in 2013 for the treatment of patients with metastatic CRPC and bone metastases,¹ based on data from the phase III ALSYMPCA trial in patients with metastatic CRPC who received radium-223.²

The ALSYMPCA trial randomized 928 men with bone pain from metastatic CRPC who had either progressed on docetaxel or who were not candidates for docetaxel, to radium-223 or placebo (each given monthly for 6 total doses) plus standard care.²

Data reported at an interim analysis showed a median overall survival of 14 months versus 11.2 months with radium-223 versus placebo, respectively (HR = 0.70; P = .00185). The time to the first skeletal-related event was a median of 15.6 months in the radium-223 arm compared with 9.8 months with placebo (HR = 0.658; P = .00037).

There was no clear distinction regarding radium-223 benefit according to the extent of disease (as defined by the number of bone lesions). Subgroup analyses did not provide definitive information on which patients may benefit, as the numbers of patients were small.2 There was no difference in median time to PSA progression between the radium-223 and placebo arms.²

These results confirm the need for further studies to define patient groups most likely to benefit from radium-223 treatment. “I would contend that there is really no clinical marker as of now that can help us to say, ‘This is a patient who shouldn’t get radium or who wouldn’t benefit.’ There is limited utility in these subgroup analyses,” concluded Dorff.

Sequencing

Determining the treatment sequence of radium-223 relative to other therapies is challenging for clinicians. Because of the potential for additive myelosuppression from radiopharmaceuticals and cytotoxic chemotherapy, most studies have focused on the timing of radium-223 either before or after docetaxel-based chemotherapy.¹ Retrospective analysis from ALSYMPCA found somewhat higher rates of hematologic toxicity and packed red blood cell transfusions in patients receiving radium-223 who previously received docetaxel compared with those who did not.³

“But you will see that the grade 3 and 4 numbers remain relatively low, and I would argue that there’s nothing here that tells me it’s not safe to use this. So you can really choose to use this before or after docetaxel,” said Dorff.

“Similarly, when you look at transfusions, there are more transfusions, but you will see that they are for both the radium and the placebo group in the docetaxel pretreated cohort, suggesting that maybe some of this is related to disease burden…but again, I don’t think this is prohibitive in terms of choosing to use this before or after docetaxel,” she continued.

In addition, subgroup analysis of ALSYMPCA revealed that, although symptomatic skeletal events were not delayed in docetaxel-naïve patients, there was a substantial delay in these events in patients who were pretreated with docetaxel. “This gets back to that concept that maybe earlier on, patients are just not at as much risk, so they will stand perhaps greater benefit to using radium-223 later, after docetaxel,” commented Dorff.

The number of included patients was small; however, cautious interpretation suggests that docetaxel-pretreated patients may represent a group in which bone-targeting therapy may produce a greater effect.¹

“Speaking to that, they found that there were actually about 5 fewer hospital days per patient per year in the docetaxel-naïve cohort that was treated with radium compared to placebo, and about 8 fewer hospital days per patient per year for docetaxel-pretreated patients treated with radium-223, suggesting that there is really a palliative benefit here,” Dorff noted.

“In patients who have received radium-223, they may require less palliative external beam radiotherapy down the road…if you are faced with a patient who is in pain, it might be reasonable to try the radium-223 first, and then if they are not experiencing pain palliation add the external beam radiation, but some patients may end up not needing it.”

Although there are no data regarding tolerability of chemotherapy after radium-223, the increased need for blood transfusions throughout the 13 weeks following completion of radium-223 therapy is suggestive that hematologic effects of chemotherapy may be additive, at least for a short while.¹ Therefore, the choice involves balancing the potential for more hematologic toxicity during radium-223 treatment with docetaxel pretreatment with the possibility that radium-223 may provide fewer benefits when administered before docetaxel.

Studies evaluating the combination of docetaxel and radium-223 are ongoing.¹ A phase I study of radium-223 and docetaxel revealed considerable hematologic toxicity with full doses; therefore, future combination studies will utilize a reduced docetaxel dose (60 mg/m2).⁴

The risk of secondary myelodysplasia is also a significant concern when considering the potential for earlier administration.¹ Very few long-term data are available, and to date, no differences between radium-223 and placebo in incidence of myelodysplastic syndrome or acute myeloid leukemia have been reported.⁵ Longer-term studies are needed to address this potential issue.¹

No data are available regarding the timing and interaction of radium-223 and newer antiandrogen agents such as abiraterone and enzalutamide. The safety and efficacy of these combinations is currently being studied.¹

“Finally, the argument for early use…when patients are more heavily pretreated they are less likely to get all 6 doses of radium-223…that could raise a question about sequencing if we were to learn that it’s important to receive all 6 doses,” stated Dr Dorff.

References

1. Dorff TB and Gross ME. ASCO 2015 Educational Book. Radium 223: How Can We Optimize This New Tool for Metastatic Castration-Resistant Prostate Cancer? Available at: http://meetinglibrary.asco.org/content/11500270-156. Accessed June 27, 2015.
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(3):213-223.
3. Hoskin P, Sartor O, O'Sullivan JM, et al. Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial. Lancet Oncol. 2014;15(12):1397-1406.
4. Morris MJ, Hammers HJ, Sweeney CJ, et al. Safety of radium-223 (ra-223) with docetaxel (D) in patients with bone metastases from castration-resistant prostate cancer (CRPC). A Phase 1 Clinical Trials Prostate Cancer Consortium Study. J Clin Oncol. 2013;31 (suppl; abstract 5021).
5. Nilsson S, Vogelzang NJ, Sartor AO, et al. 1.5 year post-treatment follow-up of radium-223 (Ra-223) dichloride in patients with castration-resistant prostate cancer (CRPC) and bone metastases from the phase 3 ALSYMPCA study. J Clin Oncol. 2014; 32 (suppl 4; abstr 9).