Observational Study of Radium-223 Reveals Safety and Pain Response in mCRPC

Short and longterm safety and a meaningful reduction in worst pain were reported in patients with metastatic castration-resistant prostate cancer (mCRPC), based on results from the REASSURE trial (NCT02141438), which evaluated radium-223 dichloride (Ra-223; Xofigo) over a 7-year period. The findings were presented at the Society of Nuclear Medicine and Molecular Imaging 2020 Annual Meeting Virtual Edition.¹

“These analyses of the REASSURE study of Ra-223 used in routine clinical practice as part of standard treatment schedules for [patients with] mCRPC revealed that radiotherapy can be safely administered concomitantly with Ra-223, as demonstrated by the low incidence of second primary malignancy and low rates of hematologic toxicities,” Peter S. Conti, MD, PhD, professor of radiology and director of the Molecular and PET Imaging Centers at Keck School of Medicine of the University of California in Los Angeles, said during his presentation of the data.

In the overall population for this global perspective, single-arm trial of 1465 patients, there was a 1% incidence of secondary primary malignancy. It was less than 1% for those with prior or concomitant radiotherapy. There were 160 patients who received concomitant radiotherapy and 1305 who did not. In these groups, the rates of grade 3/4 bone marrow suppression were 17% and 14%, respectively.

Among all participants, 12% had hematologic adverse effects (AEs) related to Ra-223 that were associated with bone marrow suppression, and 5% had fractures.Forty-eight percent of patients experienced AEs, and just 5% of these patients had Ra-223−related serious AEs.

The investigators observed that the 182 patients who received chemotherapy after Ra-223 did not have increased risk of febrile neutropenia or hemorrhage. In this group, 8 patients (4.4%) had any-grade toxicities; 2 (1.1%) had any-grade febrile neutropenia. Epistaxis (1.6%), hematochezia (1.1%), hematuria (0.5%), and rectal hemorrhage (0.5%) were observed.

The agent also reduced worst pain in some patients, including those who did not receive concomitant radiotherapy. There was a meaningful improvement in Brief Pain Inventory−Short Form (BPI-SF) worst pain for 34% of all patients who completed the BPI-SF and had a score at baseline and at treatment visit 6 (n = 657). For patients who received Ra-223 and radiotherapy (n = 75), 44% showed meaningful improvement in worst pain. Of those receiving Ra-223 without radiotherapy (n = 582), 32% had clinically meaningful improvement.

There was a consistent improvement of the mean BPISF pain score observed with therapy of Ra-223 versus baseline (FIGURE).1

“The mechanism of action of Ra-223, which is an a particle emitter…mimics calcium and forms complexes with bone mineral hydroxyapatite in areas of increased bone turnover such as metastatic sites,” Conti explained. “The particle emission leads to double-strand DNA breaks in adjacent cells, including tumor cells, osteoblasts, and osteoclasts, resulting in an antitumor effect on bone metastases. Importantly, the range of activity is short—less than 10-cell diameters—which limits damage to surrounding normal tissue.”

Ra-223 showed significant survival advantage in the ALSYMPCA trial (NCT00699751) for patients with mCRPC, which was the background for this study.² There was an improved overall survival (OS), as well as improved quality of life, a significantly delayed time to first opioid use, and an acceptable safety profile in this randomized, double-blind phase 3 trial.

In ALSYMPCA, 921 patients received either Ra-223 or placebo. The median OS for the patients receiving Ra-223 was 14.9 months; for patients who got placebo, 11.3 months (HR, 0.70; 95% CI, 0.58-0.83; P < .001). The median OS for the observational trial was 15.6 months (95% CI, 14.6-16.5).

There was a median follow-up of 11.5 months (range, 0-46.9) in this second interim analysis.

Of the total population, 59% had completed 6 Ra-223 injections. The median age at baseline was 73 years (range, 44-94). Most patients had an ECOG performance status of 0 or 1 and a Gleason score of 7 to 10 at initial diagnosis. The median time from diagnosis with CRPC to study entry was 13 months (range, 0-147), and median time from bone metastasis diagnosis was 23 months (range, 0-236). For almost half the patients (47%), the extent of disease was 6 to 20 lesions.

Most patients who received concomitant radiotherapy were given external beam radiation therapy (73%). Other types of radiotherapy given included brachytherapy, gamma knife, stereotactic, and radiofrequency ablation.

Twelve percent of patients received taxane chemotherapy of docetaxel or cabazitaxel (Jevtana). The other most frequent subsequent systemic anticancer therapies for these patients were enzalutamide (Xtandi), abiraterone acetate (Zytiga), and sipuleucel-T (Provenge).

The trial’s primary end points were incidence of second primary malignancies, short- and long-term safety, and bone marrow suppression. Secondary end points were pain severity and pain assessment over time with the BPI-SF, the number of bone-associated events and incidence of fractures, and OS.

“This second interim analysis of REASSURE confirms that, in routine clinical practice, Ra-223 has an acceptable safety profile with no new safety signals,” Conti said.

_References:

_{1. Conti P, George S, Tomaszewski J, et al. Safety outcomes and pain responses in the REASSURE observational study of radium-223 (Ra-223) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Nucl Med. 2020;61(suppl 1):185. https://bit.ly/39eLyxd}

_{2. Parker C, Nilsson S, Heinrich D, et al; ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213223. doi:10.1056/NEJMoa1213755}