CHICAGO, IL USA (UroToday.com) - Radium-223 was generally well tolerated and no new safety concerns emerged from a recently reported phase 3b international, prospective, interventional, open-label, multicenter early access program (EAP) of metastatic castrate-resistant prostate cancer (mCRPC) patients from Europe, Canada, and Israel.
In a post-hoc analysis of the study, overall survival (OS) was longer for patients who were asymptomatic or had ECOG performance status of 0-1, or total alkaline phosphatase (ALP) levels less than220 U/L. A preliminary post hoc analysis also found improved survivals among patients receiving Ra-223 and concomitant denosumab or abiraterone—results the investigators say call for further analysis of these combinations in controlled clinical study settings.
These data follow those from the pivotal ALSYMPCA trial. In ALSYMPCA, mCRPC patients with symptomatic bone metastases were treated with Ra-223 and best standard of care, versus best standard of care and placebo. Treatment with the combination resulted in significantly improved overall survival, at a median of 14.9 vs 11.3 months (HR=0.70, p < 0.001), a delayed time to first symptomatic skeletal event, and was generally well tolerated, with minimal hematological toxicity.
Study objectives of this EAP study by lead author Fred Saad, from Montreal, Canada, and multi-national co-investigators were safety and OS. Pre-planned exploratory analyses included time to first skeletal-related event (SRE), changes in ALP activity and prostate specific antigen (PSA) levels from baseline, and time to ALP/PSA progression.
Post hoc analyses included OS in subgroup populations based on concomitant medications at baseline (i.e., abiraterone, enzalutamide, docetaxel, denosumab, and bisphosphonates), baseline total ALP values, baseline ECOG PS, and baseline pain.
A total of 839 patients from 113 sites and 14 countries were enrolled in the study. Of these, 696 patients were treated with one or more doses of Ra-223. (Baseline characteristics of study subjects were similar to the ALSYMPCA trial, with the exception of the pain at baseline and prior and concomitant treatment.) At 16 months, median OS was comparable with ALSYMPCA OS results.
In comparison with the U.S.-based, randomized investigation of radium-223 in pretreated CRPC patients, these data are stronger, said co-investigator Joe O’Sullivan, MD, from Queens University, Belfast, “Survival and toxicity data are more robust by virtue of the numbers of patients. This study also shows that the good safety profile of the drug was maintained, thereby supporting the good safety profile that was shown in the randomized trial.”
However, overall survival was slightly longer than in the ALSYMCA trial, possibly because patients were treated at a slightly earlier stage, Dr. O’Sullivan, suggested. Still, a median survival of 16 months, compared very favorably to the 14-month survival data in the ALSYMCA trial.
This international trial also produced some “hypothesis-generating” analyses, he said. For example, the investigators tried to look at overall survival according to baseline total alkaline phosphatase (ALP) levels, by whether patients had received prior bisphosphonate therapy (concomitant medications at baseline), by baseline ECOG status or whether enrolled patients were receiving abiraterone or enzalutamide.
“It would appear—and again this is hypothesis-generating because patients were not randomized,” Dr. O’Sullivan said, “that patients receiving abiraterone or enzalutamide, along with radium, had better survivals. Whether that’s a synergistic effect or not is very hard to tell. But there is something – a separation of the survival curves which certainly merits further study.”
Some ongoing large, randomized trials are testing the hypothesis of combining abiraterone or enzalutamide with radium-223. Based on these—(albeit unrandomized) data, Dr. O’Sullivan suggested, “…there would appear that there would be some effect.”
“To me the most reassuring thing, as a clinician treating patients, is that the toxicity profile remains good, and acceptable. And in real-world patients, it looks like the survival is in the range of – or slightly better than – what was seen in the ALSYMCA trial, at a median of 16 months.”
Of course, he added that additional benefit could arise from the new hormonal agents (abiraterone or enzalutamide) which didn’t exist or weren’t widely available at the time of the ALSYMCA trial.
“It’s interesting how the goal posts are shifting in the castrate-resistant prostate cancer patient. We’re seeing better survivals, and I guess we’re trying to figure out where all the new therapies fit in a sequence. These data, although they don’t answer the question, at least help us think about this and helps us to understand—that it’s reasonably safe to combine these agents, without encountering any significant additional toxicity.”
Click HERE to view the poster from this session
Saad F, Carles J, Gillessan S, et al. Radium-223 in an international early access program (EAP): Effects of concomitant medication on overall survival in metastatic castrate-resistant prostate cancer (mCRPC) patients.
Presented by Fred Saad, MD, FRCS at the American Society of Clinical Oncology (ASCO) Annual Meeting - Illumination & Innovation: Transforming Data into Learning - May 29 - June 2, 2015 - Chicago, Illinois USA
University of Montreal Hospital Centre
Montreal, QC Canada