High PSMA Predictive of Good Response to Radioisotope Therapy in Prostate Cancer

Uptake of a transmembrane protein, which is expressed by virtually all prostate cancers, on imaging could be a viable predictive biomarker of patient response to isotope-based therapy, according to data from the phase II TheraP trial.

High baseline prostate-specific membrane antigen (PSMA) uptake on PET was predictive of a favorable response to treatment with lutetium-177 PSMA-617 versus cabazitaxel (Jevtana) in men with previously treated castration-resistant prostate cancer, reported Michael S. Hofman, MBBS, of MacCallum Cancer Centre in Melbourne, Australia, and colleagues.

Among patients with a baseline PSMA-PET mean standardized uptake value (SUVmean) ≥10, 91% (n=32/35) treated with lutetium-177 PSMA-617 had a PSA response (defined as a decline in PSA of ≥50%), compared with 47% (n-14/30) treated with cabazitaxel (odds ratio 12.19, 95% CI 3.42-58.76 vs 2.22, 95% CI 1.11-4.51, adjusted P=0.039), they stated in the Lancet Oncology.

Additionally, high FDG-PET molecular tumor volume (MTV) was associated with lower responses, regardless of the assigned treatment, the authors noted.

“[¹⁷⁷Lu]Lu-PSMA-617 should be prioritized in men with metastatic castration-resistant prostate cancer with high PSMA-PET SUVmean, while FDG-PET MTV can identify men with worse prognosis, warranting further research for treatment intensification,” they said.

However, in an accompanying comment, Oliver Sartor, MD, of Tulane University of Medicine in New Orleans, suggested the results may have been more valuable if the trial had focused on overall survival (OS). He pointed out that an analysis of OS in the ANZUP 1603 trial (also by Hofman’s group) after a median follow-up of 36 months showed that patients receiving the radionuclide treatment had similar OS to those who received cabazitaxel.

“Some might say that the randomized phase II study was underpowered to assess survival as an endpoint,” Sartor observed. “Conversely, others might say that given the HR [hazard ratio] for overall survival was 0.97 in a trial with 200 patients, trial outcomes were unlikely to be different even if the trial were larger.”

He acknowledged that “PSMA-PET and FDG are important parameters and clearly matter when it comes to the endpoints examined,” but noted that “the question most clinicians want to know remains unanswered: which patients will benefit from” the isotope-based therapy? “Such an analysis will require overall survival to be analyzed in a prospective study,” Sartor stated.

Hofman’s group acknowledged the fact that biomarkers were not evaluated with OS as a primary endpoint was a trial limitation. “We intend to update this analysis with data for overall survival, although radiographic progression-free survival [PFS] is likely to be more representative because it is not affected by crossover to other treatments following progression,” they wrote.

TheraP recruited 200 adult men from 11 hospitals in Australia from 2018-2019. Participants had adequate hematological, renal, and liver function, and an ECOG performance status of 0-2. They were randomly assigned 1:1 to receive IV cabazitaxel (20 mg/m2 every 3 weeks for up to 10 cycles) or the radionuclide via IV every 6 weeks for up to six cycles.

Previously reported results from the trial showed that, in terms of PSA response, the isotope improved responses compared with cabazitaxel, with PSA declines of 50% or more seen in 66% of patients in the lutetium-177 PSMA-617 group versus 37% of patients in the cabazitaxel group. Similar benefits were seen for radiographic progression and PSA PFS.

In the current analysis, Hofman’s group assessed PSMA-PET and FDG-PET as predictive and prognostic biomarkers for this patient population.

An SUVmean of 10 or higher on PSMA-PET was evaluated as a predictive biomarker for response to lutetium-177 PSMA-617 versus cabazitaxel. An MTV of 200 mL or higher on FDG-PET was tested as a prognostic biomarker.

At a median follow-up of 18.4 months, high uptake on PSMA-PET was reported in 35% (n=35/99) of men who were assigned to the radionuclide group and 30% (n=30/101) of men in the cabazitaxel group. High-volume disease on FDG-PET (MTV ≥200 mL) was reported in 30% (n=30/99) and 30% (n=30/101), respectively.

Hofman and colleagues found that even among men with a low uptake (PSMA-PET SUVmean of less than 10), PSA responses were more frequent in those who were assigned to lutetium-177 PSMA-6176 (52% vs 32% in the cabazitaxel group).

They also reported that lower PSA response rates were seen in men with FDG-PET MTV of 200 mL or higher (38%) than in men with FDG-PET MTV less than 200 mL (56%). After adjusting for randomized treatment, the odds of PSA responses were significantly lower in patients who had FDG-PET MTV of 200 mL or higher versus patients who had FDG-PET MTV of less than 200 mL (OR 0.44, 95% CI 0.23-0.84, adjusted P=0.035).

Hofman and colleagues pointed out that TheraP results were in line with those from the VISION trial (led by Sartor) in terms of providing “evidence to show the effectiveness of [¹⁷⁷Lu]Lu-PSMA-617 with different imaging-based patient selection.”