Layered Treatment With Radium-223 and Abiraterone May Reduce Skeletal Events in mCRPC

Daniel J. George, MD

In a real-world setting, patients with metastatic castration-resistant prostate cancer (mCRPC) who received radium-223 dichloride (Xofigo) with abiraterone acetate (Zytiga) in a layered fashion experienced a lower rate of symptomatic skeletal events (SSEs) compared with those who received the treatments concurrently, according to retrospective findings presented during the 2019 Genitourinary Cancers Symposium.

Among patients with mCRPC who were enrolled in the Flatiron Health prostate cancer registry, the rate of SSEs was reduced from 0.46 per person-year in men who started radium-223 or abiraterone plus prednisone within 30 days of each other compared with 0.28 per person-year in those who initiated either therapy at least 30 days apart, reported Daniel J. George, MD, in a presentation during the meeting. The rate among all 625 men who received radium-223 was 0.35 per person-year.

In addition, the rate of pathologic fracture was nearly halved, from 0.17 per person-year in the patients who received concurrent therapy to 0.09 in those who received layered therapy. The overall rate of pathologic fracture among all patients treated with radium-223 was 0.11 per person-year.

Fracture seems to be a class effect with potent novel hormonal agents, such as abiraterone, and with agents that target osteoblasts, such as radium-223. SSEs are more likely as patients enter their final stages of disease, “so the rates seen in this study aren’t surprising,” said George, director of the GU Oncology Program at Duke Cancer Institute. “What’s encouraging is that these data tell me it’s okay to use radium-223 alone or layered with a hormonal agent. It’s only when they are used concomitantly that it looked worse, and that’s true of both fractures and skeletal events. That gives us peace of mind that we’re not making this disease worse by layering these agents.”

Radium-223 prolongs survival in mCRPC and has a unique mechanism of action. It accumulates in areas of increased bone turnover surrounding metastatic lesions. “If you don’t use radium-223 in a bone-dominant patient, you’re not going to make up that survival benefit with another treatment,” he continued. “When I see a patient with bone-dominant disease, the question is, ‘When can I use radium-223?,’ not ‘Should I use radium-223?’”

The Flatiron registry provides electronic health records from >245 US cancer clinics. From 1/1/2013 to 6/30/2017, 625 patients with a confirmed diagnosis of mCRPC who were treated with radium-223 formed the basis of this analysis. Of these, 136 patients received combination therapy with radium-223 and abiraterone: 97 (71%) who received layered treatment, defined as initiating one of the treatments at least 30 days after the start of the first treatment, and 39 (29%) who initiated radium-223 within 30 days of starting abiraterone as concurrent treatment. Approximately half of the patients treated with either combination approach had prior SSEs.

After a median follow-up of 13 months in those receiving combination treatment and 9.0 months in all 625 patients, overall survival (OS) from initiation of radium-223 was 22.1 months (95% CI, 14.7-not reached) in those undergoing concurrent treatment, 19.3 months (95% CI, 11.3-27.5) in those receiving layered treatment, and 15.2 months (95% CI, 13.2-16.3) in the overall population treated with radium-223. Median OS from the time of diagnosis was 28.3 months, 34.5 months, and 28.1 months in the 3 groups, respectively.

Any SSE occurred in 36% of patients receiving radium-223 and abiraterone concurrently compared with 23% in those receiving layered treatment and 27% of the overall 625-patient cohort treated with radium-223. The rates of pathologic fracture were 18%, 8%, and 10%, respectively, and the rates of spinal cord compression were 10%, 4%, and 5%, respectively.

Median age was 73 years in the entire population, 69 years in those receiving concurrent therapy, and 75 in patients undergoing layered treatment. The median prostate-specific antigen level in these groups was 38 µg/L, 29 µg/L, and 26 µg/L, respectively.

Approximately one-third of patients who received combination therapy in any fashion had prior enzalutamide treatment compared with 54% of the entire cohort. One-fourth (25%) of patients who received layered treatment, 31% of patients who received concomitant treatment, and 26% of the entire cohort had received prior docetaxel. Three percent of patients treated with either combination approach had previously received cabazitaxel versus 6% of the entire 625 patients. About two-thirds overall treated with the combination approach had received prior bone-directed therapy in the form of either denosumab (Xgeva) or zoledronic acid.

Some 62% of those receiving concurrent combination therapy, 61% receiving layered therapy, and 65% of the entire cohort received concomitant bone-directed therapy, defined as any use of a bone health agent between the start or end of either radium-223 or abiraterone/prednisone therapy.

George DJ, Sternberg CN, Sartor AO, et al. Clinical outcome with concurrent or layered treatment with radium-223 and abiraterone: A retrospective study of real-world experience with patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2019;37 (suppl; abstr 253).

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