Introduction:

PSMA-targeted radionuclide therapy (TRT) has demonstrated benefit. Most studies have selected patients with PSMA imaging and administered moderate radionuclide doses over cycles 6-10 weeks apart. Dose-escalation has been shown to be feasible and dose-intensity may be able to overcome repopulation as a mechanism of resistance. Higher or more potent radioactivity and dose-intense administration may compare favorably to the traditional approach. We present a combined analysis of two parallel prospective dose-escalation/expansion trials of high-potency, dose-intense PSMA-TRT (defined by a single cycle of dose-intense beta-emitting 177Lu-PSMA-617 or alpha emitting 225Ac-J591) with the primary intent to see if pre-selection by PSMA imaging is necessary when employing a dose-intense or high-potency approach.

Methods:

Patients with progressive mCRPC following at least 1 AR-pathway inhibitor (ARPI) and taxane chemo (or ineligible/refuse), intact organ function, and ECOG PS 0-2 were enrolled and received a single cycle of either fractionated (dose-intense) 177Lu-PSMA-617 or (high potency alpha) 225Ac-J591.  No limit on number of lines of therapy, but prior Sm-153 or Sr-89 were not allowed. Radium-223 was allowed provided at least 1 mo had passed since last dose. Patients receiving 225Ac-J591 could have received prior 177Lu-PSMA. Following dose-escalation, both studies treated additional men at the recommended phase 2 dose. PSMA expression not a prerequisite for treatment, but PSMA imaging was performed during screening or treatment and imaging scores with PSMA uptake compared to liver were calculated. PSA response, PFS, and OS were analyzed with baseline PSMA imaging. Ttreatment associated adverse events (TEAE’s) were also examined, as a heavier “antigen sink” may be associated with lower toxicity.

Results:

82 patients with heavily pre-treated mCRPC were enrolled. In the entire (PSMA unselected) population, 47.6% had >50% PSA decline. Stronger baseline PSMA imaging was associated with >50% PSA decline (p=0.02 for SUVmax of hottest lesions) controlling for administered dose and CALGB (Halabi) prognostic nomogram score.  Baseline imaging was also associated with PFS (p=0.04 for SUVmax of hottest lesions) on multivariable analysis. PSMA imaging was not associated with OS on multivariable analysis, but CALGB prognostic score was (p=0.03). Nearly all patients had at least minimal evidence of PSMA expression by imaging, with only 8 (10%) meeting criteria for weak PSMA uptake. Of those with weak PSMA imaging, 3/8 had some PSA decline and 2/8 had >50% PSA decline. There were no significant associations with baseline imaging and TEAE’s, though receipt of 177Lu-PSMA-617 was more associated with low grade xerostomia (p=0.02) and low grade fatigue with 225Ac-J591 (p< 0.001).

Conclusion:

In a PSMA-unselected population treated with an intense PSMA-targeted radionuclide regimen, PSA response rate is comparable to a PSMA-selected population treated with a less intense regimen (VISION study, Sartor el al NEJM 2021). Stronger baseline PSMA imaging is associated with PSA response and biochemical progression-free, but not overall survival when treated with an intense PSMA-targeted radionuclide regimen. However, a subset of patients with weak baseline PSMA imaging can also respond to treatment. In our analysis, intensity of baseline PSMA imaging was not associated with adverse events, but receipt of small molecule was associated with more xerostomia and alpha emitter with more fatigue. Additional studies are analyzing patient selection for PSMA-TRT as well as dose-intense and combination regimens.

Funding: Weill Cornell Medicine, Prostate Cancer Foundation, Department of Defense, National Institutes of Health