The randomized, phase II ORIOLE trial studying the efficacy of targeted high-dose radiation for men with oligometastatic prostate cancer has shown that stereotactic ablative radiation (SABR) is an effective and safe option for patients who wish to delay hormone-suppression therapy. Data from the trial also showed radiation therapy can generate an immune system response not previously seen in oligometastatic prostate cancer. These findings were presented by Phillips et al at the 61st Annual Meeting of the American Society for Radiation Oncology (ASTRO) (Abstract LBA3).

“Single-institution studies and limited prospective data have recently suggested that high-dose, targeted radiation may be effective for men whose prostate cancer had spread, and now these ORIOLE randomized data confirm those observations,” explained lead study author Ryan Phillips, MD, PhD, of the Johns Hopkins School of Medicine in Baltimore, in a press release.

ORIOLE Methods

Fifty-four men with recurrent, hormone-sensitive oligometastatic prostate cancer were stratified by primary disease management, prostate-specific antigen (PSA) doubling time, and prior androgen-deprivation therapy. They were randomly assigned 2:1 to observation and no further treatment for 6 months or to receive SABR (also known as stereotactic body radiation therapy [SBRT]) to the metastatic sites outside of the prostate.

The primary endpoint was progression at 6 months by PSA, conventional imaging, or symptomatic decline.

Results

Six months after randomization, progression was observed in 19% of patients treated with SABR vs 61% of those in the observation arm (P = .005). The median progression-free survival (PFS) for those in the observation arm was 5.8 months (hazard ratio = 0.30, P = .002) vs not reached for those treated with SABR.

Patients assigned to the SABR arm (n = 36) received radiation to all lesions detected by conventional imaging. However, they also underwent prostate-specific membrane antigen (PSMA) positron emission tomography (PET) scans prior to and 180 days after treatment. The results of those scans were not made available to the physicians developing their treatment plans; they were used only for further analysis and comparison of cancer growth. PSMA PET scans showed that patients with no additional untreated lesions detected by the PSMA PET scan at baseline were significantly less likely to develop new metastatic lesions at 6 months (16% vs 63%, P = .006) than those whose PSMA PET scan showed at least one additional lesion at baseline. Patients with total consolidation of lesions also had a longer median PFS (unreached vs 11.8 months, P = .003) and distant metastasis-free survival (29 vs 6 months, P = .0008).

Phuoc Tran, MD, PhD

What this suggests, said principal trial investigator Phuoc Tran, MD, PhD, of the Johns Hopkins Kimmel Cancer Center, is that the high-dose radiation treatments are not just destroying the tumors targeted by SABR—they are changing the course of metastatic disease.

“Importantly, patients with subtotal consolidation had more new lesions,” he said. “It isn’t just that the untreated lesions are continuing to grow. This phenomenon suggests that treating macroscopic metastatic disease alters the natural history of the disease; that existing macroscopic metastases can influence the nonvisible or microscopic disease development into new visible metastases.”

Researchers also looked at T-cell receptor DNA sampled before radiation therapy and 90 days after treatment; they found “significant, measurable changes” in the T cells of patients on the SABR arm, but no change in the T cells of those in the observation arm. T-cell receptor DNA identified more clonotypic expansions between baseline and day 90 in patients treated with SABR; greater peripheral baseline clonality was correlated with disease progression at 180 days in patients in the SABR arm only; and clusters of similar expanded T-cell receptors were identified in three patients in the SABR arm after treatment.

“The magnitude of change in the immune system response was similar to what you see after a vaccination,” said Dr. Phillips, suggesting that radiation may spark the immune system to more aggressively fight the cancer.

“This is the first bit of evidence that I’m aware of showing that SABR can induce a systemic immune response in patients with prostate cancer,” said Dr. Tran. “Other studies have made similar observations, but these are probably the most robust, sensitive, and controlled observations that SABR can excite a systemic immune response.”

The trial also analyzed circulating tumor DNA using an ultra-sensitive liquid biopsy test and identified a specific mutational signature that predicted which men most benefited from SABR.

The authors concluded, “SABR for oligometastatic prostate cancer affords significant benefits in freedom from progression at 6 months and PFS. In fact, the PFS for patients treated with SABR still has not been reached and is well over 1 year…these results underline the importance of prospective randomized investigation of the oligometastatic state with concurrent collection of imaging and biological correlates.”

Disclosure: For full disclosures of the study authors, visit astro.org.