Clinical Study Shows Isotoxic Improvements in Patients With Prostate Cancer

A phase 2 trial (NCT03525288) demonstrated an isotoxic improvement in cancer control with prostate-specific membrane antigen (PSMA)-PET–guided intensification of salvage radiotherapy (SRT) after radical prostatectomy (RP).¹

The trial occurred from May 2018 to February 2021 and had a total of 128 patients assigned to a control group and a treatment arm group.² The PSMA-PET–guided intensification of SRT was found to be associated with significantly improved failure-free survival (FFS) compared with standard-of-care SRT. The 2 groups had comparable quality of life. The median age of patients was 71 years (range, 64-74). The median prostate-specific antigen (PSA) level at enrollment was 0.3 (range, 0.1-3.0) ng/mL. Over half of patients in the PSMAiSRT group (n = 33 of 64) received intensified SRT with the addition of pelvic RT (n = 16 [25%]), metastasis-directed RT (n = 2 [3%]), lymph node boost (n = 19 [30%]), or prostate bed boost (n = 15).¹

The median follow-up of 37 months showed that PSMAiSRT improved FFS and eugonadal FFS, with significant improvements in the subgroup with a PSA level of 0.3 ng/mL or more (HR, 0.17; 95% CI, 0.04-0.79; P =.01). Additionally, fewer next-line treatment events occurred in the PSMAiSRT arm, at 4 vs 12.¹

“To our knowledge, this is the first randomized clinical trial demonstrating an isotoxic improvement in prostate cancer control outcomes with intensification of SRT informed by PSMA-PET in men who present with [biochemical recurrence] after [radical prostatectomy], in a modern cohort with prevalent use of adjuvant [hormone therapy],” said the authors of the study.¹ “Although this imaging-guided technique has demonstrated advantages, it seems most effectively applied to patients undergoing SRT with a PSA level of 0.3 ng/mL or higher.”

Primary and Secondary End Points

The primary end point was FFS, which was defined by PSA progression, radiological progression, next-line therapy initiation, or death. Secondary end points included metastasis-free survival, overall survival, biochemical progression-free survival, next-line treatment-free survival, adverse events, and quality of life.¹

In comparing the 2 groups, investigators noted no statistical significance in biochemical relapse-free survival (18 [control] vs 9 [PSMAiSRT] 9 events; P =.06; HR, 0.47; 95% CI, 0.21–1.05).

Half of the patients who experienced recurrence after treatment were PSMA-PET positive and benefited from further RT. Recovery to eugonadal testosterone levels occurred in 86 male patients (67%). The median time from achieving eugonadal testosterone levels to failure was 22.3 (range, 0-90) months. For patients in the PSMAiSRT group, eugonadal FFS was significantly longer (HR, 0.45; 95% CI, 0.21-0.96; P =.03).¹

Safety Profile

Grade 2 or higher RT-related events totaled 60 in the control arm and 59 in the PSMAiSRT arm. Grade 3 or higher events were 3 in the control arm and 6 in the PSMAiSRT arm, including cardiac stent placement, lymphedema drainage, and a penile prosthesis for erectile dysfunction. There were no differences in event-free survival for grade 2 or grade 3 or higher seen at 6 months or their median follow-up periods.¹

“Among patients in the experimental cohort, analysis suggests that patients who received intensified radiotherapy due to PSMA-PET–avid lesions had similar outcomes to those with negative PSMA-PET results,” said the authors of the study.¹ “Specifically, 5 of 33 patients (15%) with intensified radiotherapy due to positive PSMA-PET results and 5 of 31 patients (16%) with negative PSMA-PET results before initiating SRT experienced subsequent recurrence. This suggests the hypothesis that intensified radiotherapy is effective in eradicating PSMA-PET–positive sites, resulting in outcomes similar to those of patients with negative imaging results.”

Due to the positive results that PSMA-PET exhibited, a phase 3 randomized clinical trial (NCT04557501)³ will be conducted to further examine the effects of the drug on patients.

REFERENCES

1. Belliveau C, Saad F, Duplan D, et al. Prostate-specific membrane antigen PET-guided intensification of salvage radiotherapy after radical prostatectomy: a phase 2 randomized clinical trial. JAMA Oncol. Published online October 2, 2025. doi:10.1001/jamaoncol.2025.3746

2. PSMA-PET guided radiotherapy (PSMA-PETgRT). ClinicalTrials.gov. Updated March 13, 2025. Accessed October 9, 2025. https://clinicaltrials.gov/study/NCT03525288

3. PSMA PET/CT guided intensification of therapy in patients at risk of advanced prostate cancer (PATRON). ClinicalTrials.gov. Updated March 13, 2025. Accessed October 9, 2025. https://www.clinicaltrials.gov/study/NCT04557501