Prostate-specific membrane antigen (PSMA)-PET appeared to cut the risk for treatment failure by half in patients receiving salvage radiotherapy (RT) after radical prostatectomy, without increasing toxicity, according to a new phase 2 randomized clinical trial.

“For prostate cancer specialists, the key takeaway is that integrating PSMA-PET into salvage radiotherapy planning can safely improve outcomes by allowing precise treatment intensification where disease is detected,” lead author Colin Belliveau, MD, of Centre Hospitalier de l’Université de Montréal in Montreal, Quebec, Canada, told Medscape Medical News by email.

PSMA-PET has better sensitivity and specificity than bone plus CT scans and is now the preferred imaging strategy after biochemical recurrence following definitive therapy. But how much patients benefit is still not clear. The new work, online this month in JAMA Oncology, starts to get at that question in the salvage setting.

The researchers analyzed data from a stratified cohort within the larger PSMAgRT trial, a phase 2, two-center, cohort multiple randomized clinical trial. A total of 130 men with biochemical recurrence following radical prostatectomy were randomly assigned to two groups: standard-of-care salvage RT to the prostate bed — with or without elective pelvic RT and with or without adjuvant hormonal therapy — or PSMA-PET/CT-guided salvage RT — intensified to detected sites of disease. Two patients did not proceed to RT, leaving 64 patients in each group.

Overall, 52% of the PSMA group received intensified salvage RT, with addition of pelvic RT (25%), metastasis-directed RT (3%), lymph node boost (30%), or prostate bed boost (23%). Adjuvant hormone therapy was equally prevalent in both arms (86% in control arm vs 84% in PSMA arm), as was the use of adjuvant hormone therapy in the two groups (86% vs 84%).

After a median follow-up of 37 months, the PSMA group had significantly improved failure-free survival (hazard ratio [HR], 0.50; P = .04) defined as prostate-specific antigen (PSA) progression (PSA nadir > 0.2 ng/mL), radiological progression, next-line therapy initiation, or death. Eugonadal failure-free survival was also better in the treatment arm (HR, 0.45; P = .03).

A subset analysis showed the greatest failure-free survival benefit was in the subgroup with higher-than-median PSAs of 0.3 ng/mL or more (HR, 0.17). When PSA was less than or equal to the median, however, there was no significant difference between treatment arms.

Patients in the PSMA arm had fewer next-line treatment events (4 vs 12; HR, 0.32 for treatment-free survival; 95% CI, 0.11-1.02; P = .04), suggesting more durable disease control, Belliveau noted. PSMA-guided therapy did not appear to affect toxicity or quality of life, and PSMA findings changed management in about half of patients.

Overall, “our study shows that the greater accuracy of PSMA-PET does translate into better patient outcomes when it guides targeted intensification of salvage radiotherapy,” said Belliveau. “We now await the confirmatory results from our phase 3 trial.”

David Einstein, MD, a prostate cancer medical oncologist at the Beth Israel Deaconess Medical Center in Boston, who was not involved in the work, called the article “very interesting and important.”

“The results seem to indicate that patients with higher-than-median PSAs may have the most to gain, which is consistent with our experience that PETs tend to be low yield when applied to the modern approach of treating patients with very early salvage RT at very low PSAs,” Einstein told Medscape Medical News by email.

But he cautioned that the trial excluded men with prior PSMA-PET scans, “so this may be less applicable to a modern population where many patients are getting upfront PET at initial diagnosis.”

Another caveat, Einstein noted, is that most of the improvement in the primary endpoint was driven by a reduction in biochemical recurrence, but this “is not a surrogate for overall survival, which would take a much bigger and longer study,” he said.

The authors of an accompanying editorial also highlighted several questions raised by the findings, such as what to do when patients have PSA levels < 0.3 ng/mL and what an optimal endpoint might look like.

“Given that the overall survival from prostate cancer can be prolonged despite biochemical disease progression, perhaps our field should consider a composite endpoint that incorporates time, competing comorbidities, and freedom from salvage treatment,” the editorialists wrote.

Belliveau and Einstein both reported having no relevant disclosures.