Prospective Analysis of The Effect of Germline Mutations on Outcomes for mCRPC Patients Treated With Radium-223 (PRORADIUM) – Elena Castro

November 9, 2021

Elena Castro joins Alicia Morgans to discuss the PRORADIUM study, examining the effect of germline mutations on outcomes for patients treated with radium-223. The hypothesis of this study was that patients with germline mutations in HR genes may have a potentiated response to radium-223. Regulatory approved based on data from the ALSYMPCA trial, radium-223 is an alpha-emitter that induces double-strand DNA breaks (DSBs) and selectively targets bone metastases. Such DSBs are accurately repaired by the homologous recombination (HR) pathway that is impaired in a significant proportion of mCRPC patients that harbor pathogenic mutations in HR genes (gHR+). The authors hypothesized that patients with germline mutations in HR genes may have a potentiated response to radium-223.


Elena Castro, MD, Prostate Cancer and Genitourinary Tumors Clinical Research Unit, Spanish National Cancer Research Center, Centro Integral Oncológico Clara Campal, Hospital Universitario Madrid Norte, Madrid, Spain

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts

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Alicia Morgans: Hi. My name is Alicia Morgans, and I am a GU Medical Oncologist at Dana-Farber Cancer Institute in Boston, in the US. I am so excited to have here with me today, a good friend and colleague, Dr. Elena Castro, who is a GU Medical Oncologist at the Institute of Biomedical Research of Malaga, Spain. I'm so excited to have you here today to talk with me, Dr. Castro.

Elena Castro: Hi, Alicia, it is my pleasure.

Alicia Morgans: Wonderful. So I wanted to talk with you a little bit about some information that you and your team have presented at ESMO 2021 on PRORADIUM, which is really trying to understand radium use, and radium responses, in patients with prostate cancer. Can you tell us a little bit about that?

Elena Castro: Yes. In the PRORADIUM study, what we did was to address the response of patients, with and without germline mutations in homologous recombination genes. It is a prospective study. We included 169 men that were treated with radium in the mCRPC scenario. Most of them after two lines of treatment had received two lines of therapy before, and the majority of them had already received docetaxel. And it was an observational study, so we didn't intervene, we just observed their outcomes.

Alicia Morgans: Perfect. So can you tell us a little bit about what you saw, the difference between these patients?

Elena Castro: Patients were treated, when they started treatment with radium, they didn't know. They didn't know, and their physicians didn't know whether they were mutation carriers or not. And what we found out, was that 15 of them carried a mutation. Five of them had a mutation in BRCA2, four of them had a mutation in ATM, and there was a long tail of mutations in, [inaudible 00:02:01].

What we observed was, that the alkaline phosphatase response at 12 weeks, was significantly greater in patients with germline mutations compared to patients without these alterations. We decided to look at alkaline phosphatase at 12 weeks because it was reported, in the ALSYMPCA trial as a marker of prognosis in patients treated with radium, and also because it is quite difficult to assess radiographic responses in patients treated with radium.

We also observed a trend to improve overall survival in patients with HR alterations, germline mutations, which probably the number of patients was not enough to get definitive and strong results.

Alicia Morgans: That is such an interesting hypothesis, of course, that patients who had these DNA repair defect alterations could have a stronger response to our radiopharmaceuticals. So very, very interesting. How would you apply this to your clinical practice, and what other assessments, of course, did you make within this trial, that might inform your clinical decision-making?

Elena Castro: We also looked at some bone biomarkers, but the results are not so strong as the data we got with germline mutations. For these patients, I think the results and the data we have at present, with PARP inhibitors are very strong, particularly for patients with alterations in BRCA1, and BRCA2. But unfortunately, these patients will eventually progress to treatment with PARP inhibitors, and we may have to consider other therapeutic options.

So according to our results, and where others have also observed, treatment with radium could be a good option for these patients. And I think it also serves as rational, and to support trials analyzing the combination of radium with PARP inhibitors, or maybe with other therapies, for patients with these alterations.

Alicia Morgans: I would completely agree. And I do think that there have been some approaches that have used this context to move that combination approach forward. I think it's only early stages, and early days, of course, so really Phase I type trials, but very, very interesting. So if you had to sort of sum up your message to clinicians, as they are trying to think through your data, and apply it to their clinical practice, what would that be?

Elena Castro: Well, if you have a patient that carries germline mutations, consider radium-223 as a treatment option, as what we have observed is that it could be a good choice for those patients.

Alicia Morgans: I think that makes a lot of sense. And thank you so much for sharing your expertise, and certainly, for sharing your time today. Thank you so much, Dr. Castro.

Elena Castro: Thank you.