Dr. Spratt on the evolving paradigm of radiation therapy in prostate cancer

In an interview at the 2023 LUGPA Annual Meeting, Daniel Spratt, MD, discussed the latest development with radiation therapy for the treatment of patients with prostate cancer.¹ Spratt is the chairman and professor of Radiation Oncology at University Hospitals Seidman Cancer Center and Case Western Reserve University in Cleveland, Ohio.

Could you provide an overview of the goal of your presentation at the 2023 LUGPA meeting on what's new in radiation oncology?

Spratt: In the 1980s, we saw fairly high toxicity, high inconvenience, and low tumor control [with radiation therapy]. Now, we’re talking about less than 1% of men with prostate cancer getting modern radiation therapy with image guidance and SBRT to give treatment in just 5 treatments. We are experiencing unprecedented, limited toxicity, as well as other advances with different types of technology, [such as] rectal spacing devices and other types of improved imaging. Ongoing trials are even further aiming to reduce AEs, whether they are gastrointestinal AEs, GU AEs, and even sexual AEs—trials are ongoing with a novel technique called vessel sparing radiation. [These advances] have been exciting for patients with prostate cancer.

“With radioligand therapy—some people call it radiopharmaceutical therapy—there are many different agents that are in development right now. The exciting aspect of it and why I think radioligands have shown [promise] in prostate cancer over another efficacious treatment such as antibody-drug conjugates [ADCs] is that radiation sometimes is cancer agnostic,” said Daniel Spratt, MD.

There's a wide array of other advances with radiation therapy in terms of the indications. We're seeing [the use of radiation] not just in patients with localized or recurrent prostate cancer after surgery; we now have randomized data to show benefit in patients with metastatic disease or oligometastatic disease, and there have even been recent data in advanced metastatic castration-resistant prostate cancer. Never before has radiation played such an integral role in the [treatment] of men with prostate cancer.

Advances in systemic therapies have emerged across the cancer treatment paradigm. How have new systemic regimens affected the role of radiation in the treatment of patients with prostate cancer?

It's been fantastic to see the evolution in systemic therapies, such as targeted therapies and immunotherapies. [However], these haven’t decreased the role of radiation therapy other than in some hematologic malignancies. In solid tumors, if anything, the role of radiation has expanded.

One reason [the role of radiation has expanded] is the accuracy and precision of treatment, irrespective of a patient’s mutational profile. Radiation, irrespective of that heterogeneity and those mutations, has a high probability of killing those cancer cells.

Another reason for the expanded use of radiation is that with these targeted therapies or immunotherapy, sometimes patients experience oligo-progression. There's some site that is progressing, but the therapy is keeping the rest of the metastatic disease under control. Therefore, radiation is a nice, non-invasive, and now very convenient and accurate way to get rid of those resistant clones.

I would view [radiation and systemic therapy] as complementary. Together, we're seeing unprecedented long-term survival rates in men with metastatic [prostate cancer] with more effective systemic therapy and local therapy.

For patient with prostate cancer, how do radiotherapy and androgen receptor (AR) inhibitors play a role together in treatment? What is the optimal sequencing approach for using these treatments?

For a long time, dating back to the 1970s, there was some signal that there was a synergistic action between radiation and hormone therapy, androgen deprivation therapy [ADT], or AR signaling inhibition. That has been borne out now over numerous trials over the past decades.

We've done work to try to understand how to optimally give [hormone therapy and radiation] together. Historically, people thought giving hormone therapy before radiation somehow might reduce hypoxia or reduce other things that were thought to be driving radiotherapy resistance. What modern work has shown is that [this is probably not the case], and it probably is not having an oncologic benefit. [Hormone therapy] is going to put the cancer to sleep, but it's probably not optimally helping the radiation. We've now learned that by giving hormone therapy right after radiation, it inhibits the repair of DNA damage. Giving the radiation together with hormone therapy and continuing it seems to elicit the greatest synergistic benefit.

Radioligands have continued to be developed for the treatment of patients with prostate cancer. What about these agents make them a viable option for this patient population, and what are the next steps for continuing to integrate these types of agents into the treatment paradigm?

With radioligand therapy—some people call it radiopharmaceutical therapy—there are many different agents that are in development right now. The exciting aspect of it and why I think radioligands have shown [promise] in prostate cancer over another efficacious treatment such as antibody-drug conjugates [ADCs] is that radiation sometimes is cancer agnostic. Both [ADCs and radioligands] are trying to deliver a drug or deliver radiation systemically, based on its homing or targeting approach. [Radiation delivered via radioligands] can be highly effective, and they have what we call a pathlength. Depending on the type of radiation used, such as a beta emitter or an alpha emitter, it can potentially hit multiple cancer cells. It doesn't have to immediately be targeted to 1 cell.

Given the current role of radiotherapy in the treatment of patients with prostate cancer, what are some of the unmet needs that still need to be addressed? Is there any ongoing research with radiotherapy that could address these needs?

All treatments have potential AEs, and it’s important that patients know that. However, things are being actively worked on right now for patients with localized prostate cancer. High-grade AEs are now pretty uncommon, but how do we eliminate the moderate or mild AEs that still can affect quality of life?

Strategies being evaluated include a concept called dose painting, where we can effectively give higher doses to the part of the prostate to where the dominant nodule is, and potentially give lower doses than we normally would to the remainder of the prostate. [This strategy] is actively undergoing trials right now to see if we can limit urination AEs and any of the lower-grade bowel AEs, and we are anticipating those results in the upcoming years.

The latest trial [on SBRT] called the phase 3 PACE-B study [NCT01584258] from the United Kingdom had [5-year] results presented at the 2023 ASTRO Meeting, [where study authors concluded that SBRT should be considered a new standard of care for patients with low- and favorable intermediate–risk prostate cancer].²

With radiation therapy, approximately 12% of men will report new erectile dysfunction 2 years after radiation. That's far better than most other treatments, such as surgery, which cause higher rates of erectile dysfunction. However, 12% [is still significant]. We are working on techniques and testing them to see if we can improve erectile function preservation in these patients, given its impact on quality of life.

Within your presentation, was there anything else regarding the use of radiation for patients with other GU cancers that you highlighted?

There are some great advances in kidney cancer. Historically, radiation actually played almost no role [in kidney cancer], and the mantra was that it was believed to be radio-resistant. As we have learned over the last 20 years, using ablative radiation with SBRT and higher doses per treatment is very efficacious.

Trials have been reported this past year of treating patients with metastatic kidney cancer to delay or avoid them going on to systemic therapy, and this has been a very effective approach. Ongoing trials are looking at giving radiation to the kidney itself, where the primary tumor is metastatic; this is similar to a cytoreductive nephrectomy approach, but with SBRT. That is a trial called the phase 2 SAMURAI study [NCT05327686].

Even in patients with newly diagnosed, localized kidney cancer, a lot of work has been done in trials that have been reported. Now with longer-term outcomes, we're talking about approximate 95% to 98%, local control with SBRT, where you don't have to take the kidney out and [patients] don't need surgery. Therefore, [the use of radiation in patients with kidney cancer] is definitely growing in acceptance as more of these data come out.

What have the advances in radiation meant for patients with prostate cancer and other GU malignancies?

We are able to personalize treatment for patients and maximize quality of life. The way that's being done with radiation therapy is convenient. For example, treatments have gone from 8 [treatments] down to 5 treatments, and some ongoing trials are going down to 2 treatments. These treatments are outpatient and non-invasive. These improvements do affect people, especially if they have loved ones, their caregivers, or they're working.

Additionally, the accuracy of that radiation [is beneficial] not only in planning, but in its delivery to make sure we're putting the radiation dose where it matters most.

Finally, we often give hormone therapy with radiation for various indications [in prostate cancer], and we have new tests, whether it's prognostic tests like Decipher or predictive tests like ArteraAI that can better personalize the use of hormone therapy with radiation to maximize tumor control and minimize AEs to improve quality of life.

References

1. Spratt D. What’s new in radiation oncology. Presented at: 2023 LUGPA Annual Meeting; November 2-4, 2023; Orlando, FL.

2. van AS N, Tree A, Patel J, et al. 5-year outcomes from PACE-B: An international phase III randomized controlled trial comparing stereotactic body radiotherapy (SBRT) vs conventionally fractionated or moderately hypofractionated external beam radiotherapy for localised prostate cancer. Presented at: 2023 ASTRO Annual Meeting; October 1-4, 2023; San Diego, CA. Abstract LBA 03.