(UroToday.com) PSMA-targeted radionuclide therapy (TRT) is one of the most promising investigational therapies in prostate cancer currently. In the phase II TheraP trial and the phase III VISION trial, 177-lutetium-PSMA-617 has demonstrated better outcomes compared to the current standard of care treatment options for patients who have received many lines of therapy for metastatic castration resistant prostate cancer (mCRPC). Both TheraP (PSMA-PET and FDG-PET) and VISION (PSMA-PET) have been used for patient selection. Further, to date, most studies have administered moderate radionuclide doses over cycles 6-10 weeks apart. However, dose-escalation is feasible and may be able to overcome treatment resistance due to repopulation.
In a poster presentation at the Society of Urologic Oncology Annual Meeting, Dr. Tagawa and colleagues presented the combined results 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). The authors sought to assess, primarily, if pre-selection by PSMA imaging is necessary when employing a dose-intense or high-potency TRT approach.
To do so, the authors enrolled patients with progressive mCRPC following at least 1 AR-pathway inhibitor (ARPI) and taxane chemo (or ineligible/refuse). Eligible patients had to have intact organ function and ECOG performance status of 0-2. The authors did not impose a limit on the number of lines of therapy. While prior Sm-153 or Sr-89 were not allowed, radium-223 was allowed provided at least 1 month had passed since last dose. Patients receiving 225Ac-J591 could have received prior 177Lu-PSMA.
The authors did not use PSMA-PET imaging for study inclusion (ie. PSMA expression was not a prerequisite for treatment), though PSMA imaging was performed during screening or treatment.
Once enrolled, patients received a single cycle of either fractionated (dose-intense) 177Lu-PSMA-617 or (high potency alpha) 225Ac-J591. Following initial dose-escalation, both studies treated additional men at the recommended phase 2 dose.
The authors assessed PSA response, PFS, and OS, with analysis assessing the association with baseline PSMA imaging. Further, treatment-associated adverse events (TEAE’s) were also examined.
In total, the authors enrolled 82 patients with heavily pre-treated mCRPC. In the entire population, without stratification according to baseline PSMA expression, 47.6% had >50% PSA decline. However, 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. Additionally, while baseline imaging was also with PFS (p=0.04 for SUVmax of hottest lesions) on multivariable analysis, it was not associated with overall survival.
The vast majority (90%) of patients had at least minimal evidence of PSMA expression by imaging. Of those with weak PSMA imaging, 3/8 had some PSA decline and 2/8 had >50% PSA decline.
The authors concluded that using this PSMA-unselected approach with an intense PSMA-targeted radionuclide regimen can induce PSA response rates comparable to a PSMA-selected population treated with a less intense regimen in the VISION trial. However, the authors found that stronger baseline PSMA imaging was associated with PSA response and biochemical progression-free, but not overall survival when treated in this manner.
Presented by: Scott T. Tagawa, MD, MS, FACP, Professor of Medicine and Urology, Weill Cornell Medicine, New York City, New York