Up to 12 Doses of Radium-223 Proven Safe in Bone-Metastatic Prostate Cancer

Oliver Sartor, MD

Retreatment with radium-223 dichloride (Xofigo) after initial therapy and progression was determined to be safe in patients with bone-metastatic castration-resistant prostate cancer (CRPC), according to a recent prospective, open-label phase I/II trial.

In the small study, which was presented at the 2016 Genitourinary Cancers Symposium, no marked alterations in the incidence of treatment-emergent adverse event (TEAEs) were observed when 6 additional doses were added to the original 6-dose regimen, as compared with the ALSYMPCA trial, which first established the efficacy and safety of the standard radium-223 regimen.

The exploratory study also found that retreatment provided continuous control of disease progression in bone, with only 1 out of the 44 patients included in the study experiencing confirmed radiographic bone progression.

Of the remaining 12 patients who experienced a radiographic progression-free survival (rPFS) event, 8 had soft tissue tumor progression, 2 had radiographic progression from disposition but not documented in radiographic tumor assessment, and 2 died. Median time to radiographic bone progression was not reached. The median rPFS was 9.9 months and the median time to total alkaline phosphatase progression was not reached.

All patients in the trial had previously completed 6 initial radium-223 injections with no progression in the bone during the first course of treatment and radiographic or clinical progression after initial treatment. Although the trial is meant to be exploratory, the findings will influence the design of future more definitive studies, lead study author Oliver Sartor, MD, medical director of Tulane Cancer Center, said in an interview with OncLive.

“The most significant thing we learned from this trial was that there were really no new safety signals,” said Sartor. “Patients could receive 12 cycles of radium, which two-thirds of patients did, without any additional safety concerns. We don’t know if 12 cycles are better than 6 yet, but these findings do pave the way to planning additional studies that might provide some answers regarding efficacy.”

Of the 44 patients evaluated in the study, only 2 had grade 3 hematologic TEAEs and no grade 4 or 5 hematologic TEAEs were reported. Other grade 3/4 events reported included hypertension and nausea.

Two patients reported serious ocular TEAEs (uveitis and glaucoma), both of whom had prior history of these ocular events, diabetic retinopathy, and other risk factors. Five patients reported other less serious ocular TEAEs, including cataract, worsening of cataract, iritis with blurred vision, uveitis, glaucoma, and photopsia.

“In terms of side effects, there was nothing outside of the expected,” says Sartor. “There were no new side effects that we saw that differed from ALSYMPCA.”

MRI/CT and bone scans were performed every 3 months to try and determine where the progression was occurring. This was a novel method, explains Sartor.

“Even though it sounds simple, no one had ever done it that way before,” says Sartor. “What we found was the vast majority of patients with progressive disease on radium treatment, actually progressed in soft tissue, not the bone. That was really interesting and suggests that radium-223 does help control the disease of the bone, probably a little bit better than anticipated.”

Trials evaluating the use of radium-223 in combination with agents that control soft tissue progression are needed, says Sartor. There are ongoing clinical trial investigating the use of abiraterone acetate (Zytiga) or enzalutamide (Xtandi) in combination with the radiopharmaceutical.

Sixty-six percent of patients (n = 29) completed retreatment with all 6 injections. The majority of those who stopped did so due to disease progression, said Sartor. The median number of injections received was 6 and the median time from end of initial radium-223 treatment was 6 months. All patients had more than 2 prior hormonal regimens, 45% (20) had 1 prior chemotherapy regimen, and 73% (n = 32) had failed prior novel hormonal agents. Patients who received treatment with chemotherapy after their initial course of radium-223 were not included in the trial.

In the retreatment study, 16% (n= 7), 27% (n = 12), and 9% (n = 4) of patients had concurrent denosumab, abiraterone, and enzalutamide, respectively.

The concurrent therapy did not appear to impact results, said Sartor.

“These were patients who had some PSA progression but, nevertheless, I thought were good candidates for radium-223 so I just kept them on the abiraterone, enzalutamide, etc,” said Sartor. “From this data and other data, there has not been any safety signals with regard to combining radium-223 with abiraterone or enzalutamide, so from a safety perspective we were not too concerned about that. Patients were not able to start on these treatments during the trial, but they could already be on them.”

Future plans for this research include an ongoing study that will address expanded radium-223 dosing and duration of treatment to better understand the efficacy of 12 doses versus 6. Combination trials with radium-223 are another big area of interest in CRPC, said Sartor.

“I think that radium-223 is an excellent drug to combine with other drugs because it has relatively low toxicity. I see it moving into more combination strategies going forward and that is currently being tested in various ways,” said Sartor. “We are continuing to explore this agent. It is an interesting agent, a novel agent in terms of its mechanism, and we have more to learn.”

Sartor AO, Heinrich D, Mariados N, et al. Radium-223 (Ra-223) re-treatment (Re-tx): First experience from an international, multicenter, prospective study in patients (Pts) with castration-resistant prostate cancer and bone metastases (mCRPC). J Clin Oncol 34, 2016 (suppl 2S; abstr 197).