Metastasis-Directed Radiotherapy Represents Significant Advancement in Prostate Cancer

Daniel Spratt, MD

As radiation therapy techniques in prostate cancer continue to evolve with advancements such as rectal spacer gels to spare adverse effects (AEs) and hypofractionation in place to reduce treatment burden, level 1 evidence continues to expand the role of radiotherapy in this patient population, according to Daniel Spratt, MD.¹

“In high-risk prostate cancer, [radiation has] category 1 evidence [for treatment]. That’s the only local therapy that has randomized evidence showing it improves survival over hormone therapy alone. [Therefore], we often use radiation combined with long-term hormone therapy,” Spratt said in an interview with OncLive®. “Now there’s data from the [phase 2/3] STAMPEDE trial [NCT00268476] regarding adding abiraterone acetate [Zytiga] to treatment for the highest of high-risk patients.”

In a presentation delivered at the 17th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies, Spratt noted that as radiation therapy’s role grows in this patient population, the phase 2 METANOVA trial (NCT06150417), which will evaluate metastasis-directed radiotherapy in patients with de-novo oligometastatic prostate cancer treated with long-term androgen deprivation therapy in the STAMPEDE trial, will soon be enrolling patients. He added that when it comes to oligometastatic disease, stereotactic body radiation therapy (SBRT) improves progression-free survival (PFS) for patients with metastatic hormone-sensitive prostate cancer (HSPC) as well as castration-resistant prostate cancer (CRPC).²

In the interview, Spratt, chairman and professor of radiation oncology at University Hospitals Seidman Cancer Center and Case Western Reserve University, in Cleveland, Ohio, further detailed key takeaways from his presentation, including advances that have made radiotherapy safer and where the field is headed next to further reduce the burden of treatment for patients.

OncLive: How has the NCCN Radiation Therapy Compendium positioned the use of radiation in prostate cancer?

Spratt: Radiation therapy has had dramatic increases in indications in the NCCN guidelines; it’s probably had the largest increase of any panel specifically for prostate cancer. Historically, it was only recommended as one of the treatment options for localized prostate cancer. Now with randomized evidence, it has indications for post-operative early salvage radiation therapy, for oligometastasis for metastasis-directed therapy, in metastatic prostate cancer with the treatment of low-volume prostate cancer, and we’re seeing even in more advanced disease states recognition that radiation plays a role.

We often think of radiation therapy as external beam radiation or brachytherapy, but radiation is also radionuclides.Radium-223 and Lutetium-177 (177Lu)–PSMA-617 are both forms of radiation therapy. Those now have level 1 evidence in advanced prostate cancer that they improve survival.

What data supports the use of radiation in the early-stage setting?

When we look at localized prostate cancer, we usually divide it up into NCCN risk groups from low risk to high risk. There’s a well-known study with very long-term follow-up, the Protect trial [NCT02044172], that compared active monitoring vs surgery vs radiation therapy. It enrolled mostly patients with low-risk risk disease, but approximately a third or a quarter of patients were intermediate risk, and given the era this trial was done, many of those patients with low-risk disease probably would be classified as intermediate risk by today’s standards.

Based on that evidence for low-risk prostate cancer, active surveillance is preferred over any radical therapy, but for patients with intermediate-risk disease now we have good data that tumor control outcomes are very similar between surgery and radiation therapy. However, even more modern studies such as [the phase 3] randomized PACE-A trial [NCT01584258] of surgery vs SBRT—a type of radiation of just 5 treatments—showed consistent results in that there’s significantly more urinary incontinence with the use of surgery as well as erectile dysfunction compared with radiation.

But, given the advances in radiation therapy with image guidance and even other trials using rectal spacer gels, there was no significant difference in the PACE-A trial in moderate or bothersome rectal toxicity between surgery and radiation, which is different than the older techniques with radiation therapy. Now in intermediate-risk disease, the use of more hypofractionated radiation— which is fewer treatments such as SBRT—plays a primary role.

In terms of adding agents such as abiraterone to treatments for high-risk populations, do you find that a medical oncologist’s opinion coincides with a radiation oncologist’s opinion?

Right now, there’s a lot of confusion as well as opacity. We don’t know who exactly with high-risk localized prostate cancer needs further treatment intensification and the reason is the only trial we have showing benefit is the STAMPEDE trial which, if you look at the patients who do not have metastatic disease, these are not the type of patients with high-risk disease we see today. These patients’ prostate-specific antigen [PSA] levels were very high, some of them were in the thousands, which by today’s standards especially with PSMA PET imaging [means that] probably most of those patients would have nodal if not distant metastasis.

There is some gray area that [asks] should we simply say a patient by STAMPEDE needs 2 of 3 criteria: Gleason 8 to 10, T3 disease, or PSA over 40. You need 2 or 3 of those—if patients had an MRI showing a little bit of T3 or extracapsular extension and 1 [biopsy] core of Gleason 8, they meet the criteria, but that’s not really who was on the trial.

Right now, different institutions are probably going to interpret the data differently and I generally caution people overall about overusing abiraterone in this setting because we’re using other biomarkers [such as]PSMA PET. Also, other trials have been conducted such as the [phase 3] ATLAS study [NCT02531516] which adds apalutamide [Erleada] or the [phase 2] ENZART study [NCT03196388] which adds enzalutamide [Xtandi, and those still haven’t been reported yet; we don’t know if this is going to be a slam dunk where we see a clear benefit or not.

What data has shed light on treatments in the metastatic setting?

Historically in metastatic disease, you never would think about using radiation therapy or any local therapy because the cat is out of the bag. When this concept [of radiation therapy] was tested initially, it was tested in an old trial in high-risk localized prostate cancer of androgen deprivation therapy with or without radiation. But if you go back these patients, this is in the pre-PSA era, had digital rectal T3 disease, PSAs were very high, and many of them were not even required to have CT or bone scans to rule out metastatic disease. [Therefore], many probably had metastatic [disease] and we didn’t know, and that trial showed a survival benefit of adding radiation.

Many years later now doing dedicated trials in patients with metastatic prostate cancer, treatment at the primary [site] consistently shows benefit, especially in lower volume of disease. In STAMPEDE, there’s a survival benefit, and in newer trials such as [the phase 3] PEACE-1 [NCT01957436], which uses androgen deprivation therapy plus abiraterone [there was benefit seen] and many patients [in PEACE-1 received] docetaxel which we would consider over treatment for low volume disease. But even in that setting, adding radiation improved radiographic PFS, time to castration resistance, and decreased serious genitourinary AEs. It’s now recommended in conjunction with standard systemic therapy.

What is the next frontier and what remains to be done in this space?

One of the biggest changes to come is going to be the integration of radiation therapy to metastatic sites themselves. In radiation oncology, there’s been this evolution or dynamic of what a technical limitation vs an oncologic limitation is. When the technology was [older], we couldn’t technically treat multiple areas. A great example is in cancers, not prostate, [but for] brain metastases, we could only treat 1, 2, or 3 brain metastases; now with all the technological advancement, we can treat 20 or 30 in a very short treatment course.

I think that’s going to happen similarly in the body—there are trials ongoing of treating not just 1 or 2 metastatic sites, but up to 10. That will continue to evolve because there are systemic therapies, especially if you think of chemotherapy, trying to cytoreduce or attack the cancer cycle after cycle. You could also do that with how precise radiation is and how convenient doing it is in just 1, 2, or 3 fractions, now you could target multiple lesions in cycles. This has to be tested in trials, but we’re going to continue to see an evolution of metastasis-directed therapy as well as more of those radionuclides that are going to be tested.

How is hypofractionation changing treatments in the prostate cancer field?

[A] shift that we’ll continue to see is the hypofractionation in treatments. Already there’s a surge of using just 5 treatments in localized prostate cancer and trials that are completed or near completed are going to be reducing that further to 2 treatments.

Trials in the post-operative setting where typically we still do 6 weeks or 7 weeks of radiation are ongoing [but] are now doing just 5 treatments as well. This reduces barriers to getting treatment [because] if you live a great distance, it’s far more convenient. [Additionally], it improves the acceptance from other referring providers because they are now seeing this newer type of radiation and letting go of some of the historical bias of when they saw a lot of AEs. They see this newer treatment that seems to have fewer AEs.

Many people will wonder who cares [because] you went from 40 treatments to 20 to 5, it’s already so short. It’s a fair point, what’s the big deal about going from 5 treatments to 2 treatments? When it comes down to the patients we’re now treating. When I was trained we were giving 48 treatments and the AE profile was significantly higher than it is today.

We’re now at a point where there are so few AEs, we’re talking less than 1% grade 3 AEs and close to 0% grade 2 rectal AEs, that these small little differences now become an inconvenience to the patient because we’ve reduced [other barriers]—there are no catheters needed, staying overnight in a hospital, or using urinary pads. A lot of my patients come from a distance, out of state, or even internationally, and so [if you can do] those 5 treatments which are given every other day [over] approximately a week and a half in 2 treatments, that is much more feasible.

Ideally, one day we could get it to a single treatment, and they have done trials with that, [but] there might be some radiobiology that may not be as effective. People are cautious to go to a single treatment, but they have it in other cancers—in kidney cancer they’ve now shown the safety of a single treatment of SBRT and in lung cancer as well.

References

1. Spratt DE. Advances in radiation therapy for prostate cancer. Presented at: 17th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies; March 8-9, 2024. New York, NY.
2. MDRT in prostate cancer treated with long-term androgen deprivation therapy in the STAMPEDE Trial (METANOVA). ClinicalTrials.gov. Updated November 29, 2023. Accessed April 1, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06150417