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Dr. Fred Saad: It gives me pleasure to summarize the lecture and the presentation that was given here at ESMO by Matthew Smith, my colleague and co-author on the Abiraterone Acetate and Prednisone in Combination with Radium-223 or Placebo in Patients with Castration-Resistant Prostate Cancer in Bone Metastases: The Results of the Phase Three Trial.

Just a historical note, we know that ALSYMPCA, the phase three study of radium-223 versus placebo in men with metastatic CRPC and bone mets showed clearly a significant improvement in overall survival and significant improvement in time to symptomatic skeletal events. 

This study, ERA 223, takes patients at an earlier state of the disease and takes into consideration the fact that now we have agents that weren't available at the time of ALSYMPCA. This was 800 patients, all with metastatic CRPC with at least two bone mets that were asymptomatic or mildly symptomatic, had good performance status of 0 or 1 ECOG, no prior chemotherapy for CRPC, no brain mets or visceral mets. They were randomized one to one between abiraterone acetate, at the normal dose, plus 10 mg of prednisone per day, plus radium, 55 kBq every four weeks for six cycles, versus abiraterone acetate and prednisone as the standard of care arm. The primary endpoint of the study was symptomatic skeletal event free survival with important secondary endpoints of overall survival, rPFS, time to chemotherapy, time to opiate use for cancer pain and safety. 

The way we defined symptomatic skeletal event-free survival was time from randomization to first SSE or death from any cause. SSEs itself was defined as use of external beam radiation therapy to relieve skeletal symptoms, new symptomatic pathological bone fractures, spinal cord compression or tumor-related orthopedic surgical intervention. 

Baseline characteristics were well balanced between both groups, with 401 patients receiving abiraterone/radium and 405 receiving abiraterone + placebo. Median age was 71 years old and the majority of patients had more than five bone metastases coming into the study. About 40% of patients had concurrent use of denosumab or of bisphosphonate, before entering the study. Of note, patients were not allowed to start a bone targeted therapy after joining the study, since this may impact the primary endpoint of the study. Approximately half the patients had no pain at all coming into the study. Baseline laboratory values were well balanced and within normal range. PSA values were a medium of 30 in both arms. 

In November of 2017, on the recommendation of the IDMC, the study was prematurely unblinded because there was a note of more fractures and deaths that were observed in the abiraterone acetate + radium arm. All patients had already completed pre-specified radium-223 prior to the unblinding. The last radium injection was given in February 2017.

In terms of the primary endpoint of symptomatic skeletal event free survival there was no statistically significant difference in both arms and the p-value was .2636. Unfortunately, we did not meet the primary endpoint of the study. 

In terms of skeletal events or deaths, also here, there was no significant difference between both arms. We noted a numerically less number of patients having the need for external beam radiation for pain. There were less spinal cord compressions in the patients receiving radium. There were the same number of deaths in both arms, 38% in both radium + abiraterone versus abiraterone + placebo. There was a slightly higher number of patients in the radium/abiraterone that had symptomatic pathological fractures.

Looking at overall survival, here again, there was no statistically significant difference between both arms. Numerically, there was slightly more patients that died in the abiraterone/radium arm. This was not statistically significant with a p-value of 0.128.

In terms of secondary and exploratory endpoints, rPFS, time to cytotoxic chemotherapy, and time to opiate use for bone progression pain was no different, even though it looked like there might be some trend towards delay in cytotoxic chemotherapy with the radium arm.

In terms of overall survival in the intent to treat population, again here, no significant difference between radium and the placebo arm.

In terms of emergent adverse events, here, this is what the IDMC had noticed, that there was an imbalance in terms of the number of fractures in the radium arm compared to the placebo arm, where 103 patients in the abiraterone and radium had a fracture versus 38 patients in the abiraterone + placebo arm.

Looking more closely in terms of fractures and the use of bone health agents, it was noted that the majority of patients were the ones that did not have a bone health agent accompanying the treatment arm they were assigned to. 

Fractures with or without a bone health agent, the difference became insignificant in patients who had a bone health agent, regardless of which arm they were in, between abiraterone/radium or abiraterone + placebo, but without a bone health agent, there was clearly a difference in favor of patients not receiving radium, those that had radium and abiraterone seemed to have a much higher incidence of fractures.

In terms of the independent review of the fracture events, we notice that the majority of fractures were non-pathological fractures, either post-traumatic or osteoporotic in the patients on the radium and abiraterone arm. 60 patients that had fractures had no bone metastases at the site of the fracture and only 20 patients had bone metastases at the sight of the fracture. 

In summary, concurrent treatment with abiraterone + radium-223 did not improve skeletal symptomatic event free survival or overall survival compared to patients with abiraterone acetate + prednisone + placebo in the patients with metastatic CRPC. There was an increased risk of clinical fractures in the abiraterone + radium group. The use of bone health agents was associated with a significantly lower fracture rate in both treatment groups. 

We do not recommend the use of radium-223 in combination of abiraterone acetate, at this time. Prescribing recommendations around the world have been revised accordingly.

The warnings for the US, Canada and Asia is that the recommendation is not to combine radium with abiraterone acetate and this does not change the indication for radium in the later stages of the disease.

Thank you very much for your attention.