Targeting PSMA in Prostate Cancer Treatment - Episode 6

Radium-223 and the ALSYMPCA Trial

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A review of data from the ALSYMPCA clinical trial on the use of radium-223 for prostate cancer treatment.

Alicia Morgans, MD, MPH: Tanya, quick question on this particular patient: if this patient had bone-only metastatic disease, technically, he would also meet the criteria for radium, which is a separate radiopharmaceutical that we've had for some time. What are your thoughts there? How might radium come into play?

Tanya Dorff, MD: That's a great question, and very challenging because we don't have head-to-head data comparing radium 223 with the lutetium-PSMA [prostate-specific membrane antigen]. Sometimes I think about it from the perspective that eventually a patient may develop soft tissue involvement, which would then exclude them from being eligible for radium 223, and particularly patients who have very symptomatic bone involvement. I might really look at the radium 223 first. There is some work that we have to do to understand whether there is an impact of sequencing. For instance, whether cytopenias from 1 would limit future eligibility for the other, so to speak. In the absence of those, I think it's really just a discussion and a clinical intuition at this point. I don't know if Ulka has any other big ideas for how to choose this.

Ulka Vaishampayan, MD: There is some limited experience from the VISION trial. The VISION trial eligibility allowed prior radium 223 as long as it had been 6 months from their last dose of radium 223. I think we do know that the patients post-radium 223 did not have significantly different toxicity, but the numbers are fairly small, I imagine. There aren't a whole lot of patients, but there were some who were included in the VISION trial. There is some clinical experience. I agree with you that it depends on access to the patient and whether you use 1 vs the other, but radium 223 is also an available option for patients with symptomatic bone-only metastases.

Alicia Morgans, MD, MPH: Thank you both for your comments there.

Radium 223 was approved through the ALSYMPCA trial. Phil, can you walk us through that trial?

Phillip J. Koo, MD: It would be my pleasure. The ALSYMPCA trial was the registrational trial that was published in 2013 in the New England Journal of Medicine. Patients were patients with confirmed symptomatic metastatic castration of resistant prostate cancer greater than equal to 2 bone metastases and they had no known visceral metastases. This was all based on conventional imaging. These patients were either post-docetaxel, ineligible, or refused docetaxel. Then the patients were stratified based on their total bisphosphonate use and also their prior docetaxel use. Then they were randomized in a 2 to 1 ratio to either radium 223 plus best standard of care vs placebo plus best standard of care. If you look at this trial design, it looks very similar to VISION. I think in a lot of ways we have these investigators to thank for the great work that they were able to build upon for the VISION trial.

Tanya Dorff, MD: The ALSYMPCA trial did find that median overall survival was prolonged with radium 223 compared with the best standard care, which was essentially things like earlier generation androgen receptor antagonists and external beam radiation therapy for palliation, but it was a significant prolongation from 11.3 months on the standard-care-alone arm with 14.9 months for radium 223 and a strongly significant hazard ratio. There was also interest in symptomatic skeletal-related adverse events. This was a new definition for FDA but really looking not just at radiographic findings in the bone, but clinically meaningful skeletal events such as fractures or having more pain such that you need radiation to treat it. That was significantly prolonged as well, 15.6 months in the radium 223 arm compared with 9.8 months on the placebo. Definite clinical benefits were seen. In terms of adverse events, there are cytopenias, so you have to monitor a CBC [complete blood count] before each infusion. Anemia was the most common, with about 13% exceeding grade 2 levels. Thrombocytopenia was about 12% overall, but about 6% had grades 3 and 4. And then neutropenia was about 3% with grades 3 and 4. Of course, very little was seen on the placebo arm. Other events that can happen do include things like diarrhea, fatigue, and some nausea, but overall, when you look across the adverse events for radium compared with placebo, it's somewhat similar for some of these categories because these are symptomatic patients, so some of the adverse events are related to disease progression.

Alicia Morgans, MD, MPH: Wonderful. Thank you for taking us through that. Ulka, I'd love to hear your thoughts on some of the other options that may be available to this patient. We did hear Tanya allude to some of these earlier.

Ulka Vaishampayan, MD: I think it somewhat depends on where the disease is, how the patient is doing, their performance status, their comorbid conditions, etc. When you're looking at what other options there are aside from radiopharmaceuticals, I think germline testing and genomic testing become an important part of it. If it's not done already, then definitely germline and genomic testing for DNA repair mutations would be an important part, because there is a targeted PARP inhibitor therapy that is available and FDA [United States Food and Drug Administration]-approved for this. The other options are second-line chemotherapy such as cabazitaxel that needs to be considered, and then docetaxel rechallenged depending on how long ago the patient had docetaxel, as well as other hormonal agents. If the patient has had only one and has had chemotherapy in between, you could consider doing another androgen receptor inhibitor.

Alicia Morgans, MD, MPH: Wonderful, thank you. I think that should wrap up case 1.

Transcript edited for clarity.