Radium 223 Option Hinges on Bony Disease Burden in mCRPC

Oliver A. Sartor, MD

As with other new therapies that have been approved in recent years for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC), researchers are not entirely certain about how best to fit radium Ra 223 dichloride (Xofigo) into the emerging paradigm, according to Oliver A. Sartor, MD.

Yet, after nearly a year of clinical use, the optimal setting for radium 223 appears to be in combination with new hormonal therapies as a treatment for patients with mCRPC who have a significant burden of bone-metastatic disease, even though they might not be considered symptomatic, Sartor said.

Sartor, who was the principal North American investigator for the clinical trial that led to the FDA approval for radium 223 last year, shared those insights about the drug during a presentation at the 7th Annual Interdisciplinary Prostate Cancer Congress™, which Physicians’ Education Resources, LLC (PER®) hosted March 15 in New York City. He is the Laborde Professor for Cancer Research and the medical director at Tulane Cancer Center in New Orleans, Louisiana.

Examining the “Symptomatic” Label

An alpha-emitting radiopharmaceutical that targets osteoblastic bone metastases, radium 223 gained the FDA’s approval in May 2013 after demonstrating a 30% improvement in median overall survival (OS) compared with placebo in the pivotal ALSYMPCA trial.¹ The next step in the drug’s clinical development is a large phase III trial that will evaluate whether radium 223 plus abiraterone (Zytiga) with prednisone or prednisolone is more effective than placebo plus that regimen in chemotherapy-naïve patients with bone-predominant mCRPC who are asymptomatic or mildly symptomatic.²The question of whether patients should be symptomatic to be considered candidates for the drug has arisen because of the FDA label indication. The drug was approved as treatment for patients with CRPC, symptomatic bone metastases, and no known visceral metastatic disease.³

However, Sartor said categorizing a patient as symptomatic is a “subjective assessment” with a wide variation among patients, even in ALYSMPCA.

“Symptomatic is a little bit of a tricky nomenclature here because you could be taking one acetaminophen a day and that was symptomatic,” Sartor said, referring to the ALSYMPCA criteria. “Or, you could have radiation in the previous 12 weeks and have no pain at all, but that was still symptomatic. Exactly what was symptomatic was not clearly defined, although there were a number of patients on opioids.”

In an interview, Sartor said he does not use the presence of pain as the determining factor when he weighs the radium 223 option. “I am thinking more about the burden of bone disease as opposed to whether or not the patient says ‘I have an ache in my back,’ ” he said. “Obviously, if a patient is on opioids and they have very significant pain, there is really no question that that’s a symptomatic patient. But there is a bit of a gray line in there.”

In addition to the extent of bony disease, Sartor said he also considers “how the ratio of tissue disease is distributed.” Since patients who receive radium 223 experience some myelosuppression, white blood cell and platelet counts also should be evaluated, Sartor said.

In summary, Sartor said during his presentation, “I am using radium 223 with the new hormones, and in those with a significant bony metastatic disease. That is what I am doing today in the clinic and it appears to be safe.”

As far as moving radium 223 forward in the treatment timeline is concerned, Sartor said no role for the drug has been established thus far in nonmetastatic or hormone-sensitive disease. He said large clinical trials would be needed to either prove or disprove those settings.

Key Clinical Trial Results

Sartor said certain unique characteristics of prostate cancer make radiation-emitting agents a rational approach to treatment. He noted that the bone/soft tissue ratios for metastases are high compared with other solid tumors, that prostate cancer is “exceptionally osteoblastic,” and that bone metastases “are frequently the only radiographically detected site of metastases” in patients with advanced disease.

In all, the FDA has approved three radiation-emitting particles for the treatment of prostate cancer. The agency approved two beta particles, strontium 89 and samarium 153, for pain reduction in 1993 and 1997, respectively. As an alpha particle, radium 223 emits a stronger, more targeted energy dosage than a beta particle, while inducing more lethal double-strand DNA breaks, Sartor noted.

In the phase III ALSYMPCA trial, the 614 patients who received radium 223 plus best standard of care experienced of median OS of 14.9 months compared with 11.3 months for the 307 patients in the placebo group (HR = 0.70; 95% CI, 0.58-0.83; P <.001).¹ During the trial, radium 223 was administered intravenously at 4-week intervals for 6 injections, which is the regimen recommended by the FDA. The approved dosage level is 50 kBq/kg body weight or 1.35 microcurie/kg body weight.² The safety profile for adverse events (AEs) of grade 3/4 severity is favorable, Sartor indicated. For hematologic AEs, the rate of grade 3/4 anemia was 13% in both trial arms. The rates of grade 3/4 neutropenia and thrombocytopenia were 2.2% and 6.3%, respectively, for the radium 223 group, compared with 0.7% and 2%, respectively, for the placebo group.

For nonhematologic AEs, the incidence of grade 3/4 bone pain was 21% among patients treated with radium 223, versus 26% for those who received the placebo. Rates of diarrhea, nausea, and vomiting were comparable in both arms at less than 2% for each AE.

Combinations and Sequencing

Another notable aspect of the ALSYMPCA trial is that radium 223 was evaluated along with best standard of care that could include hormonal therapy or external beam radiation. At the time, the hormones patients received were older agents such as ketoconazole and dexamethasone. Today, the newer hormonal agents abiraterone and/or enzalutamide (Xtandi) would be used instead, Sartor noted. Radium 223 fits in well with multitargeted therapy because it likely has an impact on the variety of cells that contribute to prostate cancer, such as osteoblast and stromal cells as well as tumor cells.

“Now we are really involved in what I call the stromal-based therapy,” said Sartor. “I think it has a bright future, and I think we need to figure out how best to put all these things together so we can have maximal benefit.”

References

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
2. NIH Clinical Trials Registry. www.ClinicalTrials.gov. NCT02043678.
3. Xofigo [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc; 2013.