Radiopharmaceuticals and Radiation Therapy for Prostate Cancer Treatment

Savita Dandapani, MD, PhD

Combining radiopharmaceuticals and radiation therapy shows potential in the prostate cancer space. However, careful consideration of timing and sequencing is crucial to avoid increased toxicity.

A recent study from Savita Dandapani, MD, PhD, explored the combination of radium-223, hormone therapy, and stereotactic body radiation therapy (SBRT) in treating patients with metastatic castration-sensitive prostate cancer. This trial aimed to build on the success of previous trials like ALSYMPCA (NCT00699751).

The study aimed to treat micrometastatic bone disease early by using radium-223, typically administered later in treatment, alongside hormone therapy and SBRT to target visible lesions. The results showed promising outcomes, with some patients experiencing extended progression-free survival. Still, further research, including randomized trials, is necessary to confirm its effectiveness compared with standard treatments like 177Lu-PSMA-617 (Pluvicto).

In an interview with Targeted Oncology^TM, Dandapani, radiation oncologist at City of Hope, described the rationale behind her study and the promising but preliminary results observed.

Targeted Oncology: Can you discuss the rationale behind the study?

Dandapani: Originally, I thought of it in 2016 to 2017, so pretty early on, a few years after radium-223, the radiopharmaceutical that was FDA approved from the large ALSYMPCA trial. That was for metastatic castration-resistant prostate cancer. At the same time, there were a lot of trials being conducted for metastatic castration-sensitive prostate cancer or hormone-sensitive much earlier, when [patients] first get metastases. There are a lot of SBRT trials or [stereotactic ablative radiotherapy (SABR)] trials in that space.

3D rendered medically accurate illustration of prostate cancer: © SciePro - stock.adobe.com

Here at City of Hope, we have a unique radiation research platform where we do a lot of radiopharmaceutical research. Once this became approved, I thought, why not combine this as treating micrometastatic disease because the [patients] have had metastatic disease, they progressed from there aggressive prostate cancer that was localized to metastases, and primarily bone metastases, and radium-223 treats the bone metastases. I thought, let's combine a short course of hormones, which was the backbone of the medical oncologist's treatment for metastatic prostate cancer at the time, and also add in SBRT to all the lesions we see on the current imaging standards, and add in radium-223.

[Patients] appreciated this trial because it was a short course of hormones, and they do not like the [adverse] effects of hormones. The SBRT is well tolerated, as seen in multiple studies, and even in our study. Then, adding the radium-223 was the exploratory question. We were not sure how they were going to do that so early in their course, because in the ALSYMPCA trial, [patients] were getting it later in their course of treatment. Their ECOG status, things like that, were much different. These are very fit [patients] that I gave this course to. It was an aggressive treatment with the radiation combination of external radiation and radiopharmaceuticals. Then after that, stopping all treatment, and then just watching the [patients]. They liked that, because they wanted to see if we could treat all this, finish the treatment, and then just follow up with [prostate-specific antigen (PSA)] and imaging.

Can you discuss the role of each component utilized in the trial?

We finally decided to have an acronym ourselves called the SHARP trial. The SBRT part was to treat all the bone metastases because multiple trials had already shown that it provides good local control. We thought that would help disease burden locally with SBRT. The hormones were to help with the systemic treatment because it is released from the prostate to these different areas, and we do not know how it settles. There are many theories. That was the backbone of the systemic treatment we gave after 36 weeks. The radium-223 was because we already know it has been in the bone lesions from 1 to 5 lesions in our study. It was to treat micrometastatic disease we cannot see on the current imaging.

Could you explain the findings of this trial, particularly regarding its effectiveness?

Our main end point of the trial was to look for time to treatment failure. It was ambitious. Our secondary outcomes, I think, will be more interesting as well and look at bone-only metastases progression. But in terms of that, we did find similar studies to other comparable studies out there in the literature of radiation, with POPSTAR [NCT02933242], ORIOLE [NCT02680587], SABR-COMET [NCT01446744], etc. Those are big studies that have been published with SBRT alone. We found comparable studies that followed for almost 2 and a half years. At this initial result, we talked about 34 months, and the 1-year progression-free survival was over 80%. That was quite impressive. The 2-year overall survival and progression-free survival showed that there were some patients that were able to live for over 2 years and did not require any other systemic treatment. We thought in terms of the many other treatments that [patients] can get for metastatic castrate-sensitive prostate cancer, that there are many options, and this could be a feasible option. But it is a small study. We need to do a randomized study to really look at its effectiveness in a bigger picture with all the other treatments.

How do these initial results compare with what we typically see with current standard treatments for this type of prostate cancer?

I think it is not for every [patient]. We have to be very carefully selective. Almost at the end of our trial, [177Lu-PSMA-617], another radiopharmaceutical, got approved as well. We are aware of trying to compare our trial with [177Lu-PSMA-617] as well. Currently, we think, if patients have metastatic bone-only disease, and it is limited, that it could potentially be something that we can explore with them, especially if they have de novo metastatic-sensitive prostate cancer, because we have had [patients] past the 2-year mark not needing any extra systemic treatment. They are quite happy with their quality –of life. We are managing them now with the current imaging, such as the [prostate-specific membrane antigen (PSMA)] PET scans, and they are not progressing. We think there can be a role for it, but fitting it in with all the other treatments is going to be the hard part moving forward.

I think we are going to need more molecular analysis, more prediction, algorithms, and strategies to figure out which one would be the best. In terms of adding radiation and a radiopharmaceutical, we thought that was very novel in that we are not using systemic treatment. So, it is an option for [patients] who do not want as much systemic treatment and who want a break from the hormone therapy, or who do not want the extra abiraterone [Zytiga] or enzalutamide [Xtandi] or other treatments that have had large trials of hundreds of patients. Still, there are risks because it is a systemic treatment. We acknowledge that these are radiopharmaceuticals that are also systemic treatments. We give them [intravenously], we do not have to be cautious with blood counts, and we keep them safe for their future treatments. But I think it works for some [patients] who want to be off all treatment.

Were there any specific advantages or disadvantages with using this combination compared with SBRT alone?

The one advantage we were looking into that we have not reported on in this initial abstract was the development of other bone metastases and progression in that space. When we first gave the treatment, we had limited bone metastases; we gave SBRT and the radium. Initially, when time to treatment failure, our primary end point, patients failed, even with PSA, and they were anxious, even if we saw nothing on the scans, they would be given extra hormones. But we are looking at these [patients] long-term, and some of them are finding they are developing more bone metastases or macroscopic bone metastases. I think that has been the interesting take away from our dataset, looking at these [patients] long-term to see if they do develop bone metastases, the time to develop these metastases, and do they impact quality –of life? Do they cause any skeletal fractures, skeletal-related events, things like that?

What are the potential implications of this trial in the community oncology setting?

At City of Hope, we have a large community oncology practice, too, and so they have asked me a lot about when we could give the [177Lu-PSMA-617] or radium-223 for hormone-sensitive prostate cancer. Ours is a phase 2 trial, and we still should do the phase 3 trial. Johns Hopkins is doing the randomized phase 2 trial currently, so I think that will help also look to see if it was better than SBRT alone. They are doing a 2:1 trial of SBRT or SBRT and radium. But for now, we have not really told patients that they should get radium in the hormone-sensitive phase. We have been looking at it when they get to castrate-resistant, and considering that with [177Lu-PSMA-617], and depending on which one they could go for, so by looking at their PSA or PET scans, if they are PSA PET avid, they can do [177Lu-PSMA-617] or a PSA-directed therapy. But if they have bone metastases only, sometimes in the community, they have been considering the radium-223 more often as well, because it is well tolerated.

What are the next steps for this trial?

The next step would be to try to do a multi-institutional trial and also to compare the radium-223 with [177Lu-PSMA-617] or see if there is some way to combine the 2. I am involved in national meetings with other radiation oncologists who are trying to figure out, should we just give everyone [177Lu-PSMA-617] or radium-223, or should we combine it?For our trial, what was exciting is that we were able to complete it and show that there were some [patients] who can do well. Maybe that is the space for future trials that we do with radium-223 and do a randomized trial.

Radiopharmaceuticals have become very exciting recently in the radiation oncology space, and not only in prostate [cancer], but in other cancers as well. People are trying to combine radiopharmaceuticals and radiation. We have been doing this at our center for quite a number of years, not only for prostate cancer, but colon cancer, and I think it is going to be exciting to see how we combine them. I think we just have to be careful in how we combine them because the medical oncologists are doing a lot of systemic treatment in the background. One of the trials they tried to do with radium-223 actually found more toxicity. So, you cannot combine all these things together, and you cannot just put a whole bunch of different drugs and treatments together because they could have consequences. I think we have to be very careful with this timing and sequence. I think radiopharmaceuticals have made a paradigm shift and a treatment shift in how we can treat patients and offer radiation in different ways.

REFERENCE:

Dandapani S. Phase 2 trial of stereotactic body radiation therapy, hormone/androgen deprivation therapy and radium 223 dichloride for oligometastatic castrate sensitive prostate cancer (SHARP). Presented at: 2024 American Society for Therapeutic Radiology and Oncology Annual Meeting; September 29-October 2, 2024; Washington, DC. 1003.