Radiation’s Role in Metastatic Prostate Cancer Growing, Evolving

Radiation therapy, like other local therapies, has been an effective treatment option for patients diagnosed with local or locally advanced prostate cancer, or as a means of palliation of symptoms caused by the disease. More recently, though, research is shedding light on the possible role for radiation therapy in changing the course of metastatic disease.

“In general, local therapies like radiation are not used for systemic processes,” said Phuoc T. Tran, MD, PhD, a professor and vice-chair for research of radiation oncology at the University of Maryland School of Medicine. “Metastatic disease, by definition, has the potential to spread throughout the entire body, so why use a local therapy?”

However, in recent years, several studies have shown that local therapies—radiation being the most used—can change the natural history of a systemic process, Dr. Tran said.

“We used to think that the only thing that could extend survival or change the natural history was a systemic treatment like chemotherapy, or immunotherapy, but studies are suggesting that local therapies can also change the natural history of metastatic disease,” Dr. Tran said.

GU Oncology Now recently spoke with several physicians about what the newest data have shown about the use of radiation for metastatic disease, and how these data may change the current role of radiation in the treatment of prostate cancer.

De Novo Oligometastatic Disease

Advances in imaging technology have allowed for an increasing number of men with prostate cancer to be diagnosed with oligometastatic disease. Defined as a transitional state between localized disease and widespread metastatic disease, oligometastatic disease has a limited number of metastases, typically 3 or fewer lesions, although definitions may allow for up to 5 metastases in no more than 3 organ sites.

One of the first studies to support the idea of local therapy in de novo oligometastatic disease was the STAMPEDE trial. In Arm H of this trial, researchers tested if radiotherapy to the prostate would improve overall survival (OS) in men with newly diagnosed metastatic prostate cancer. Patients were randomly assigned to standard of care with or without radiotherapy.¹

“What they saw in STAMPEDE was that if you looked at all patients, there didn’t seem to be much of a benefit of irradiating the primary tumor in the prostate, but if you looked at patients with high- versus low-volume disease, there was a benefit in patients with low-volume disease,” said Matthew P. Deek, MD, an assistant professor of clinical radiation oncology at Rutgers University, the Cancer Institute of New Jersey.

Long-term data from the trial confirmed a significant improvement in OS in patients with low metastatic burden (hazard ratio [HR], 0.64; 95% CI, 0.52-0.79; P<.001) but not in those with high metastatic burden.²

“Now we will often offer patients with low-volume de novo disease radiation to their primary tumor based on STAMPEDE,” Dr. Deek said.

Use of radiotherapy in patients with de novo oligometastatic prostate cancer does have caveats, according to Chad Tang, MD, an associate professor of radiation oncology at The University of Texas MD Anderson Cancer Center.

“A subgroup analysis of the study showed that as the number of bone metastases goes up, the benefit of treating the primary goes down,” Dr. Tang said.

The subgroup analysis based on metastatic site showed that the benefit of treating the primary with radiation was most pronounced at up to 3 metastases. There was also no survival benefit seen in patients with visceral/other metastasis.³

“For a long time we really didn’t know if we should treat the primary tumor, but we did not prioritize treating the prostate if a patient presented with metastatic disease,” said Matthew Zibelman, MD, an associate professor in the department of hematology/oncology at Fox Chase Cancer Center. “Patients with lower burden of disease do seem to benefit. At Fox Chase, and a lot of other places, we have adapted that approach in patients with de novo, but low-volume, metastatic disease.”

Recurrent Oligometastatic Disease

In contrast to de novo oligometastatic disease, recurrent oligometastatic disease research has tested the benefit of metastasis-directed therapy to the metastases themselves. One of the first trials to test metastasis-directed therapy was the SABR-COMET trial, a phase 2 basket trial that randomly assigned patients with a controlled primary tumor and 1 to 5 metastatic lesions to receive either standard of care or standard of care plus stereotactic ablative body radiotherapy (SABR) to all metastatic lesions.⁴

“The metastases-directed therapy showed an overall survival advantage,” Dr. Tran said. “About a quarter of the included patients had prostate cancer.”

Specifically, of the 99 patients randomly assigned to therapies, 16 had prostate cancer; of these, 2 were assigned to the control arm and treated with standard of care and 14 were assigned to SABR. For the entire study population, there was a significant doubling of progression-free survival (PFS)⁴ and improved OS on long-term follow-up.⁵ The 8-year OS estimates were 27.2% (95% CI, 14.1%-42.1%) for SABR versus 13.6% (95% CI, 3.8%-29.7%) for standard of care, respectively (HR, 0.50; 95% CI, 0.30-0.84; stratified log-rank test: P=.008). Also, a minority of patients randomized to the SABR arm (21.3%) achieved >5 years of survival without recurrence.⁵

Dr. Tran acknowledged that this is very promising data, but that it is not level 1 evidence. The ongoing SABR-COMET-3 trial was designed to assess the effect of SABR on survival, as well as quality of life outcomes for patients with 1 to 3 oligometastatic lesions.⁶

In contrast to the SABR-COMET trial, where metastasis-directed therapy to the metastases was added to standard of care systemic treatment, the STOMP and ORIOLE trials in recurrent oligometastatic prostate cancer tested the benefit of radiation therapy in the absence of systemic treatment.

The phase 2 STOMP study included patients with asymptomatic prostate cancer with 3 or fewer extracranial metastatic lesions. Patients were randomly assigned to surveillance or metastasis-directed therapy in the form of surgery or SABR. At 3-year follow-up, androgen-deprivation therapy (ADT)-free survival was 7 months longer with radiation or surgery.⁷

Five-year results from the STOMP trial confirmed this benefit. The 5-year ADT-free survival was 34% for metastasis-directed therapy compared with 8% for surveillance.⁸

Drs. Deek and Tran were involved in the other phase 2 trial testing this approach. The ORIOLE trial enrolled 54 men with recurrent hormone-sensitive prostate cancer who had 1 to 3 metastases, and patients were randomly assigned 2:1 to SABR or observation.⁹

At 6 months, 3 times as many patients assigned to observation had progressed as compared with patients assigned to SABR (61% vs 19%; P=.005). There was a 70% reduction in the risk for progression or death (HR, 0.30; 95% CI, 0.11-0.81; P=.002) in patients assigned to SABR.

ORIOLE also analyzed the value of prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) radiotracer ¹⁸F-DCFPyL to try to identify which patients would benefit most from metastasis-directed therapy.⁸

“The emergence of PSMA PET/[computed tomography (CT)] has been a game changer,” explained Dr. Tang. “It has allowed us to put a whole population of patients who were once considered biochemically recurrent, nonmetastatic patients into the metastatic bucket but with a targetable lesion to treat.”

A post-hoc analysis of PFS that looked at the extent of disease seen on PSMA-targeted PET/CT showed significantly improved progression-free and distant metastasis-free survival in patients who had consolidation of all detectable disease.⁹

A pooled analysis of the 116 patients treated on STOMP and ORIOLE showed a median PFS of 11.9 months with metastasis-directed therapy compared with 5.9 months with observation. However, pooled HRs for time to radiographic PFS, castration-resistant prostate cancer, and OS were not different between the 2 groups.¹⁰

This analysis also stratified patients on the basis of high-risk mutational status and showed a potential larger benefit to metastasis-directed therapy in patients with a high-risk mutation—ATM, BRCA1/2, RB1, or TP53—with a median PFS of 13.4 months with SABR compared with 2.8 months with observation.

The use of metastasis-directed therapy in patients with recurrent disease is still a controversial topic, however, according to Dr. Zibelman.

“The data we have so far are interesting, but they are not definitive,” Dr. Zibelman said. “Different groups have used and interpreted the data in different ways.”

The goal is the same, though, he said. The goal is to delay systemic therapy.

“For patients with metastatic disease, the long-held dogma is that they should go on ADT, and then they are on it forever,” Dr. Zibelman said. “For patients who have oligometastatic disease, if we can safely radiate those sites, control disease, bring the [prostate specific antigen (PSA)] down, and delay having to start ADT, there is a good quality-of-life benefit at the very least.”

When discussing this approach with patients, Dr. Zibelman works to make sure they understand its goal.

“This is probably not going to cure them,” Dr. Zibelman said. “The goal is to delay treatment that they will definitely need.”

Dr. Tran compared this benefit with the idea of “kicking the can down the road.”

“Although it has never been definitively proven, some studies have shown a signal that when you start applying that selective pressure of hormone therapy to prostate cancer, it starts a countdown of sorts,” Dr. Tran said. “Eventually, disease will be resistant to it. With this approach, we may be able to reserve the hormone therapy for when the patient needs it.”

Patients also have to understand the potential risks of this approach, Dr. Zibelman said. If SABR is used and the PSA does not decrease, then it is possible that patients waited a bit longer than they otherwise would have to begin systemic therapy. However, there are no convincing data that this short or even a longer delay are detrimental.

Combination Approaches

Both STOMP and ORIOLE compared SABR and observation. Now the question is if there is a benefit to giving SABR and systemic therapy, Dr. Deek said. One trial investigating this question is the NRG-GU011 trial, which will randomly assign patients with recurrent oligometastatic disease to radiotherapy with or without ADT.¹¹

In contrast to delaying ADT, in 2022, Dr. Tang and colleagues presented results of the EXTEND trial, a phase 2 basket trial that tested if the addition of metastasis-directed therapy to intermittent ADT improved PFS in oligometastatic disease. Men with oligometastatic prostate cancer to 5 or fewer sites were randomly assigned after 2 or more months of ADT to continue ADT for an additional 6 months with or without metastasis-directed therapy.¹²

Patients assigned to both intermittent ADT and metastasis-directed therapy had significantly improved PFS. Importantly, as PFS translated directly to time on ADT, metastasis-directed therapy led to improvement of a key secondary end point, eugonadal PFS, defined as time from when a patient recovered normal testosterone until progression.

“This is something we do at MD Anderson for patients with low-volume disease,” Dr. Tang said. “The goal is to get a break 6 months after randomization—so after at least 8 months of hormones.”

Patients liked this extended break from ADT, Dr. Tang added.

“Having that testosterone back benefits patients both psychologically and physically,” Dr. Tang said. “At the time of the presentation, not even half of patients on the HT/radiation arm had gone back on hormones after almost 2 years.”

Widespread Metastases

PSMA-based radionuclide therapies are a more recent iteration of radiation therapy.

“Traditional radiation therapy, like external beam radiation, is a local therapy at a specific target,” Dr. Deek said. “Now we have these radioligands, which are like systemic agents that use radiation.”

One of the first trials to employ this approach was the ALSYMPCA trial, which used radium-223 dichloride, an alpha emitter, to selectively target bone metastases with alpha particles in men with castration-resistant prostate cancer (CRPC). Patients treated with radium-223 had a 30% improvement in the risk for death compared with placebo.¹³

“If you look at the periodic table, calcium and radium are in the same column, and radium has a property where it tricks the body into thinking it’s calcium and the bone takes it up,” Dr. Deek said. “However, radium can’t discriminate between prostate cancer in the bone and normal bone, which can lead to side effects.”

This concept was improved upon with 177 lutetium (¹⁷⁷Lu)-PSMA-617 (Pluvicto; Novartis), which targets PSMA expressed on prostate cancer cells with a beta-emitting isotope. The US Food and Drug Administration (FDA) approved ¹⁷⁷Lu-PSMA-617 for patients with PSMA-positive metastatic CRPC who have previously received ADT and taxane-based chemotherapy.¹⁴

The approval was based on results of the VISION trial. VISION was a phase 3 international trial that randomly assigned patients with PSMA-positive, metastatic CRPC 2:1 to either ¹⁷⁷Lu-PSMA-617 plus standard of care or standard of care alone. ¹⁷⁷Lu-PSMA-617 more than doubled median PFS compared with standard of care (8.7 vs 3.4 months; HR, 0.40; 99.2% CI, 0.29-0.57; P<.001) and significantly improved OS (median 15.3 vs 11.3 months; HR, 0.62; 95% CI, 0.52-0.74; P<.001).¹⁵

“I describe it to the patient like a Trojan horse that brings a radioactive element to the doorstep of the cancer,” Dr. Zibelman said. “It decreases pain, helps patients live longer, and is fairly well tolerated.”

One of the biggest limitations of ¹⁷⁷Lu-PSMA-617 has been availability, according to Dr. Zibelman. In February, news outlets reported that Novartis had temporarily stopped accepting new patients amid manufacturing difficulties.¹⁶

“They only have 1 plant in Italy, and there have been significant supply chain shortages. As a result, we are having difficulty getting the drug,” Dr. Zibelman said. “I hope it becomes more available soon.”

Future Uses

In addition to this more systemic approach for patients with widespread metastatic disease, studies are also testing the use of radiation therapy in the area of oligometastatic progression, Dr. Deek explained.

“Take a patient with 50 metastatic lesions who is receiving some kind of systemic therapy, and that systemic therapy is doing a great job, except for maybe 1 lesion that is growing or progressing,” Dr. Deek said. “What if we treated those 1 or 2 growing lesions with radiation?”

For example, a retrospective study looked at 86 patients with oligoprogressive CRPC who were treated with SABR with a median follow-up of 30.7 months. The median new metastasis-free survival after SABR was 12.3 months. Twenty-six of the 86 patients underwent a second course of radiation due to further oligoprogressive disease, resulting in a median systemic treatment-free survival of 21.8 months.¹⁷

The FORCE trial, which will randomly assign patients with oligoprogressive CRPC to systemic therapy with or without radiation, will hopefully provide more information about this approach.¹⁸

There are also several clinical trials in the works that are designed to further test or combine these treatment approaches.

According to Dr. Tran, another question that needs to be answered is how to best treat metastases in de novo metastatic disease.

“We know from STAMPEDE that primary radiation to the prostate increased overall survival in low-volume disease, but what about the metastases?” Dr. Tran said.

The TERPS trial will compare the effects of using standard of care treatment—systemic therapy plus primary prostate radiation—with standard of care plus SABR to metastatic lesions.¹⁹

The RAVENS trial is exploring the possible benefits of combining SABR with radium-223 in patients with hormone-sensitive, oligometastatic prostate cancer.²⁰

Additionally, there is hope that combining SABR with PSMA PET/CT will improve clinical staging of disease and allow patients to benefit from molecular, imaging-guided, metastasis-directed therapy, even as these approaches are refined.

“We are still learning how this can impact the treatment paradigm,” Dr. Deek said. “You can imagine there would be advantages to picking up disease earlier and targeting it with SABR. These advanced imaging techniques are going to revolutionize how we monitor and treat patients going forward.”

References

1. Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018;392(10162):2353-2366. doi:10.1016/S0140-6736(18)32486-3
2. Parker CC, James ND, Brawley CD, et al. Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: long-term results from the STAMPEDE randomised controlled trial. PLOS Medicine. 2022. doi:10.1371/journal.pmed.1003998
3. Ali A, Hoyle A, Haran AM, et al. Association of bone metastatic burden with survival benefit from prostate radiotherapy in patients with newly diagnosed metastatic prostate cancer: a secondary analysis of a randomized clinical trial. JAMA Oncol. 2021;7(4):555-563. doi:10.1001/jamaoncol.2020.7857
4. Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial. Lancet. 2019;393(10185):2051-2058. doi:10.1016/S0140-6736(18)32487-5
5. Harrow S, Palma DA, Olson R, et al. Stereotactic radiation for the comprehensive treatment of oligometastases (SABR-COMET): extended long-term outcomes. Int J Radiat Oncol Biol Phys. 2022;114(4):611-616. doi:10.1016/j.ijrobp.2022.05.004
6. Olson R, Mathews L, Liu M, et al. Stereotactic ablative radiotherapy for the comprehensive treatment of 1–3 oligometastatic tumors (SABR-COMET-3): study protocol for a randomized phase III trial. BMC Cancer. 2020. doi:10.1186/s12885-020-06876-4
7. Ost P, Reynders D, Decaestecker K, et al. Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: a prospective, randomized, multicenter phase II trial. J Clin Oncol. 2017. doi:10.1200/JCO.2017.75.4853
8. Ost P, Reynders D, Decaestecker K, et al. Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence (STOMP): five-year results of a randomized phase II trial. J Clin Oncol. 2020. doi:10.1200/JCO.2020.38.6_suppl.10
9. Phillips R, Shi WY, Deek M, et al. Outcomes of observation vs stereotactic ablative radiation for oligometastatic prostate cancer the ORIOLE phase 2 randomized clinical trial. JAMA Oncol. 2020;6(5):650-659. doi:10.1001/jamaoncol.2020.0147
10. Deek MP, Van der Eecken K, Sutera P, et al. Long-term outcomes and genetic predictors of response to metastasis-directed therapy versus observation in oligometastatic prostate cancer: analysis of STOMP and ORIOLE trials. J Clin Oncol. 2022. doi:10.1200/JCO.22.00644
11. Koontz B. NRG-GU011. A phase II double-blinded, placebo controlled trial of prostate oligometastatic radiotherapy with or without androgen deprivation therapy in oligometastatic prostate cancer (NRG Promethean). NRG Oncology. Accessed April 12, 2023. https://www.nrgoncology.org/Clinical-Trials/Protocol/nrg-gu011
12. Tang C, Sherry AD, Haymaker C, et al. Addition of metastasis-directed therapy to intermittent hormone therapy for oligometastatic prostate cancer (EXTEND): a multicenter, randomized phase II trial. Int J Radiat Oncol Biol Phys. 2022;114(5):1059-1060. doi:10.1016/j.ijrobp.2022.09.006
13. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369:213-223. doi:10.1056/NEJMoa1213755
14. FDA approves Pluvicto for metastatic castration-resistant prostate cancer. U.S. Food & Drug Administration. March 23, 2022. Accessed March 28, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pluvicto-metastatic-castration-resistant-prostate-cancer
15. Sartor O, de Bono J, Chi KN, et al. Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385:1091-1103. doi:10.1056/NEJMoa2107322
16. Liu A. Novartis halts Pluvicto new patient starts, struggles with radiotherapy’s supply amid manufacturing expansion. Fierce Pharma. February 28, 2023. Accessed March 27, 2023. https://www.fiercepharma.com/manufacturing/novartis-halts-pluvicto-new-patient-starts-struggles-radiotherapy-supply-amid
17. Triggiani L, Mazzola R, Magrini SM, et al. Metastasis-directed stereotactic radiotherapy for oligoprogressive castration-resistant prostate cancer: a multicenter study. World J Urol. 2019; 37(12):2631-2637. doi:10.1007/s00345-019-02717-7
18. FOcal Radiation for Oligometastatic Castration-rEsistant Prostate Cancer (FORCE). ClinicalTrials.gov Identifier: NCT03556904. ClinicalTrials.gov. Accessed April 12, 2023. https://clinicaltrials.gov/ct2/show/NCT03556904
19. TERPS Trial for de Novo Oligometastic Prostate Cancer. ClinicalTrials.gov Identifier: NCT05223803. ClinicalTrials.gov. Accessed April 12, 2023. https://clinicaltrials.gov/ct2/show/NCT05223803
20. Hasan H, Deek MP, Phillips R, et al. A phase II randomized trial of RAdium-223 dichloride and SABR Versus SABR for oligomEtastatic prostate caNcerS (RAVENS). BMC Cancer. 2020;20(1):492. doi:10.1186/s12885-020-07000-2