Radiation Extends PFS in Recurrent Oligometastatic Prostate Cancer

Pam Harrison

September 17, 2019

CHICAGO ― High-dose, precise radiotherapy for treating one to three metastatic lesions significantly extends progression-free survival (PFS) compared with observation alone in men with recurrent prostate cancer that is oligometastatic, a prospective, phase 2 study indicates.

"There is a hypothesis that the first few sites of spread could pave the way for additional widespread metastases down the road, and if we could treat all detectable disease early enough, we may be able to achieve long-term control, or in the best case scenario, cure patients of early metastatic disease," Ryan Phillips, MD, PhD, chief resident in radiation oncology at the John Hopkins Sidney Kimmel Cancer Center in Baltimore, Maryland, told a press briefing here.

"We found that stereotactic ablative radiation — sometimes called SABR — for oligometastatic prostate cancer affords significant benefits in freedom from progression at 6 months, and in fact, the PFS for patients treated with SABR still has not been reached and is well over 1 year," he added.

The study was presented at the American Society for Radiation Oncology (ASTRO) 2019 Annual Meeting.

Study Design

The Observation Versus Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer (ORIOLE) study randomly assigned 54 men who had one to three metastatic lesions measuring ≤5 cm to either SABR or observation for 6 months. Thirty-six men were assigned to the SABR group, and the remaining 18 patients were assigned to the observational arm.

SABR is a form of high-precision cancer therapy that delivers substantially higher doses of radiation to the tumor site in just one or a few treatment sessions.

"Our primary endpoint was disease progression at 6 months," Phillips noted. Progression was defined as an increase in prostatic-specific antigen level of ≥2 ng/mL and a >25% increase from the lowest detectable value; evidence of new metastases by conventional imaging; worsening of symptoms related to metastatic prostate cancer; or initiation of hormone therapy for any reason.

At 6 months, 19% in patients in the SABR arm had not experienced disease progression, vs 61% in the observation arm (P = .005) — "so clinically, this is very promising," Phillips observed.

Indeed, median PFS was not reached for men treated with SABR; it was 5.8 months for men who underwent observation (hazard ratio, 0.30; P = .002), he added.

In addition, 35 of the 36 men treated with SABR underwent an experimental imaging test called PSMA PET (prostate-specific membrane antigen positron-emission tomography) at baseline and again at 6 months. Phillips explained that PSMA is highly expressed in prostate cancer cells; by using a radiotracer, physicians can identify lesions that might be missed or underappreciated on conventional imaging.

If all lesions detected by PSMA PET were treated with radiation up front, patients were classified as having achieved "total consolidation," whereas if PSMA PET scans showed at least one additional lesion at baseline, patients were classified as having experienced "subtotal consolidation."

Results in this subgroup analysis showed that men who received radiation treatment to all of their lesions up front had significantly fewer metastatic lesions 6 months later compared to men in the subtotal consolidation group — "so not only are we treating the disease we are detecting, but it seems as if SABR is preventing the development of new metastases outside the areas that we treated," Phillips observed.

PFS was almost five times greater for patients who achieved total consolidation of lesions compared with patients whose PSMA PET scans showed additional lesions, he added.

Researchers also observed significantly more activity and changes in the immune system in the SABR arm 3 months after treatment relative to baseline, whereas there was no change in the immune system among men in the observation arm.

"This suggests that SABR seems to be inducing some sort of system-wide immune response similar in scope to what we see after vaccination," Phillips observed. He later explained to Medscape Medical News that radiation damages DNA in cancer cells, and as it kills these cells, material, including mutations, is released into the system, priming the immune system against the tumor.

"There are also situations where radiation may be encouraging signaling from cancer cells that haven't died yet to recruit immune cells to them and do a better job of teasing out the difference between normal healthy cells and cancer cells," he added.

The group also assessed high-risk mutations associated with poor prognosis in prostate cancer.

In this analysis, men who harbored at least one high-risk mutation before SABR had outcomes that were equivalent to men in the observational arm, whereas men who did not have any high-risk mutations did significantly better with SABR than men in the observation arm.

"This is hypothesizing-generating, but it is promising that there may be measurable baseline factors that will help us decide which patients are likely to benefit from this approach and which would be better served with alternative treatment strategies," Phillips concluded.

Relatively New Approach

Asked by Medscape Medical News for comment, Bridget Koontz, MD, Duke Cancer Institute, Durham, North Carolina, noted that the use of SABR in this particular patient population is still a relatively new approach and that the additional use of PET imaging allowed researchers to get a better understanding of the biology of metastatic prostate cancer.

"What I think you are seeing is that by treating all of the metastases, there was no more viable tumor left in patients who had truly only a few metastases, so if you treat everything and there is nothing left to spread or grow, then you are going to see an extended PFS," Koontz noted.

This is also why in those patients who did have residual disease, disease continued to grow and create more metastases, she added.

"So that was also very interesting ― it was not just the metastases that they knew about, it was additional metastases, so by treating one, the one metastasis doesn't turn into multiple more metastases," Koontz emphasized.

"And this is the first study that has been able to hint at the biologic rational for treating these metastases — so there is at least some evidence to support what has been a hypothesis up to now," she said.

Phillips has served as a consultant for RefleXion Medical. Koontz has disclosed no relevant financial relationships.

American Society for Radiation Oncology (ASTRO) 2019 Annual Meeting: Abstract LBA3, presented September 15, 2019.

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