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Clinical Outcomes With Early vs Late Ra-223 for Patients With Metastatic CRPC

April 23, 2021

Richard Lee‑Ying, MD, Tom Baker Cancer Center, University of Calgary, Canada, discusses results from a study evaluating clinical outcomes of patients with metastatic castrate‑resistant prostate cancer when Ra-223 is used early versus late in the treatment sequence.

These results were presented at the virtual 2021 ASCO Genitourinary Cancers Symposium.


My name is Richard Lee‑Ying. I'm a medical oncologist at the Tom Baker Cancer Center in Calgary and a clinical assistant professor at the University of Calgary. I'm here to talk to you today about the presentation at the GU 2021 ASCO meeting on clinical outcomes of patients with metastatic castrate‑resistant prostate cancer receiving radium‑223 early versus late in the treatment sequence.

Ultimately, this study was done with help from data sources from ICES in Ontario, where they use data analytics services to find our patient cohort, and it's sponsored by Bayer. It's part of a larger project called Reactivate.

Essentially, the whole purpose behind this study was to see, what are the real‑world outcomes of patients who received radium‑223, and does the sequencing that we choose impact the outcomes?

As many of you will know, there's about five life‑prolonging therapies approved in Canada for metastatic castrate‑resistant prostate cancer. There's radium‑223, there's cabazitaxel, docetaxel, abiraterone, and enzalutamide presently. There's other things in the pipeline, but these are things that have been most readily available to us in Canada.

Essentially, most of these drugs were studied in relation to docetaxel. It's actually a little bit unclear, even though we have all these different options, how best to sequence. That's how this study came about.

In Canada, we have universal health care system, so all of these treatments are Health Canada‑approved, but the way that we get access to them can vary from province to province. Each province has to make its own decisions about if and when treatments going to be funded or reimbursed or not. That can lead to some differential access in Canada.

In Alberta, the province that I'm in, we can't access radium‑223. In Ontario, where this study was performed, radium‑223 can be accessed quite readily. That's why we went there to see what the outcomes are depending on when the radium‑223 is used, if it's early or late.

Early, we defined as a second‑line treatment, and then late, we defined as a third‑line treatment or beyond. We took public data sources through the ICES program, which pools all the administrative data in the province of Ontario, and then categorized that to having received at least two lines of life‑prolonging therapy. Having received radium‑223 either in the second‑line setting or third or later.

Our primary outcome was looking at overall survival to see, are patients going to be living longer or have better outcomes depending on when they use radium‑223? Our secondary outcomes were things like event‑free survival, time to first hospitalization, and time to first emergency visit.

We used a Cox proportional‑hazard model, so both counting process methods, to control specifically for the risk of immortal time bias. Just because of how we organized our groups, second‑line treatment radium‑223 versus third‑line or later, everyone in the third‑line or later is probably going to be living longer or surviving longer in order to receive the treatment in a third or later line setting.

The counting process methods allows us to account for that and still compare these two groups essentially in a bit more of a fair fashion. Then we also also adjusted for relevant fixed and time‑varying covariance as well to try to control for these potential confounders, essentially. We looked at patients from 2012 to 2017.

All the men who had a diagnosis of metastatic castrate‑resistant prostate cancer, and then who've received at least two months of therapy. 253 of them were categorized into the early radium‑223 use group, and then 345 were categorized into the late group.

The baseline characteristics between the two groups were relatively similar. The main outlier was the fact that the median time from their first life‑prolonging therapy to their second life‑prolonging therapy was longer in the early group compared to late by just a little bit over two months.

In terms of the follow‑up time, the patients in the late group had a much longer follow‑up time. It was almost a little under two years compared to one year in the late versus the early group.

Despite the longer follow‑up at the late group, a similar number of patients died, so about 85% of them, I believe. The patients in the late group had more exposure to the different life‑prolonging therapies. They had high rates of being exposed to the different agents.

The most striking difference, ultimately, was that, in the late group, about 90% of patients were exposed to docetaxel, while only about 48% were exposed to docetaxel in the early group.

Overall, our findings from the study was that the hazard ratio for overall survival favored the early versus the late groups. The hazard ratio was 0.79 after adjustments and the 95% confidence intervals was about 0.66 to 0.95. The adjusted median overall survival time was 10.7 months compared to 8.3 months in the early versus late group.

Similarly, for event‑free survival, we found that the hazard ratio was 0.71, also favoring the early group, so that the adjusted median time was 9.3 compared to 6 months.

Then our other secondary outcomes in terms of time to first hospitalization and time to first emergency visit also favored the early group. The hazard ratios were 0.61 and 0.78 respectively. Overall, all these things seem to be signaling that the earlier use of radium‑223 seems to be associated with better outcomes.

Of course, this study does have some limitations, though. It's a retrospective type study, or observational study is probably a better way to put it. There are unmeasured confounders that we're not controlling for, and the risk of selection bias. People might be choosing to use radium‑223 earlier. For some people, for other reasons, that could impact their outcomes.

Then, ultimately, the study does focus on how best to position radium‑223. It doesn't take into account how best to position the other life‑prolonging therapies. It does limit how we should interpret these results.

Overall, despite these limitations, it's a real‑world, it's a population‑based assessment of what the outcomes are like when people get radium‑223, either early or late in their disease course. We're able to control for things like time‑varying covariance and that immortal time bias. Those are the things that make these results quite valuable.

Overall, my interpretation of this study is that patients who had radium‑223 earlier as opposed to later in their treatment course did seem to have better outcomes. That's in keeping with the general trend that we see in other life‑prolonging therapies in prostate cancer in general. The earlier we use agents, the more effective they seem to be.

If you have a patient who you think would benefit from radium‑223, using it sooner rather than later would make sense. Again, it doesn't quite take into account the fact that you have choices between the different life‑prolonging therapies. If someone is a candidate, don't wait to use it. Thank you very much for your attention.   

Mbuagbaw L, Lowther J, Lee-Ying RM. Clinical outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) receiving radium-223 (Ra-223) early versus late in the treatment sequence. Presented at: the virtual 2021 ASCO Genitourinary Cancers Symposium; February 11-13, 2021. Abstract 136.

Dr Lee-Ying reports consultation payment from Bayer, Janssen, Sanofi, and Amgen, and research funding from Sanofi.

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