RESIST-PC: U.S. Academic Foray into PSMA Theranostic Trials

Abstract

In this issue of The Journal of Nuclear Medicine, Calais et al. from UCLA present the results of their phase 2 RESIST-PC trial (1). This trial predated the VISION trial and enrolled patients prospectively in a 2-arm study intended to compare the efficacy and safety of Lu-PSMA-617 dosed at either 6.0 or 7.4 GBq (2). The study was performed collaboratively between UCLA and Excel Diagnostics, although only the 43 patients enrolled at UCLA are presented in the article. The UCLA team must be commended for the effort in initiating and performing this study without company support. The effort required to open the first Lu-PSMA trial in the United States cannot be understated. The absence of support for this study required that a cost recovery mechanism be used, something that is not commonly leveraged for therapeutic trials. Unlike in the Australian phase 2 study (3), in which the Lu was provided free of charge from the Australian Nuclear Science and Technology Organization, the study team had to procure Lu at cost. Prior diagnostic costrecovery trials led to the approval of both Ga-DOTATOC and Ga-PSMA-11 (4,5). It may seem odd that there was no corporate support for this study given the large interest in the field we see today, but at the time of trial design, there was limited corporate interest. Similar to cost recovery, many European studies have leveraged compassionate use in the absence of company support (6). Looking at the results presented for the RESIST-PC trial, the prostate-specific antigen (PSA) response ($50% PSA decline) was 37%, which is lower than reported in the LuPSMA (64%) and TheraP (66%) trials (1,3,7). Although the inclusion criterion for prostate-specific antigen (PSMA) expression was not predefined in the RESIST-PC trial, the difference in PSA response may be accounted for by a lower threshold of PSMA PET avidity. The LuPSMA trial required an SUVmax that was one and a half times that of the liver, whereas the TheraP trial required an SUVmax of 20 at one site and no measurable disease below an SUVmax of 10. In addition, the LuPSMA and TheraP trials used F-FDG PET/CT to exclude patients with disease heterogeneity and sites of disease demonstrating low PSMA expression. In the LuPSMA and TheraP trials, 25%–30% of patients were excluded, whereas in the RESIST-PC trial only 2 patients (,5%) were excluded on the basis of PSMA expression. PSMA expression is critical, as shown by Violet et al., who demonstrated a positive correlation between pretreatment PSMA uptake and posttreatment dosimetry on a whole-body scale, and as further supported by Seifert et al., who showed that low average PSMA expression is a negative prognostic factor (8,9). The VISION trial used a lower cutoff of a PSMA-positive lesion greater than liver uptake with no negative PSMA lesions, which resulted in 13% of patients being excluded, more than twice as many as in the RESIST-PC study (2). In the VISION trial, 46% of patients treated with Lu-PSMA-617 had a greater than 50% reduction, a PSA response rate between the RESIST-PC trial and the TheraP/LuPSMA studies, again supporting the idea that the higher the cutoff for PSMA positivity combined with F-FDG imaging, the better the response to treatment (2). Although it appears that the higher threshold for PSMA avidity would result in a higher response rate, the threshold of PSMA avidity below which the patients may not respond to treatment remains unclear. It is also possible that patients with a limited volume of the discordant F-FDG–avid disease may derive some benefit from Lu-PSMA, subject to sufficient PSMA expression at other sites and as long as a more intensive therapeutic strategy is adopted. This possibility may support the combination with other oncologic treatments to tackle sites that may have been suboptimally targeted by Lu-PSMA. Multiple phase I/II combination regimens are under way using immunotherapy (NCT03658447, NCT03805594), poly(adenosine diphosphateribose) polymerase inhibitor (NCT03874884), androgen receptor-targeted therapy (NCT04419402), and even tandem treatment with chemotherapy in the castration-sensitive state (NCT03828838). A separate issue with Lu-PSMA therapy is that the optimal treatment schedule is not well understood, including the administered activity per cycle, the interval between treatments, and the number of treatments/cumulative activity (10). The choice of a fixed administered activity of between 6 and 8 GBq and up to 6 cycles is based predominantly on the limits of normal-organ absorbed dose and thresholds extrapolated from external-beam radiotherapy, ignoring fundamental differences in the radiobiology of radiopharmaceutical therapies. One of the most interesting aspects of RESIST-PC was that it attempted to determine the difference in efficacy and toxicity between 2 different doses of Received June 3, 2021; revision accepted July 21, 2021. For correspondence or reprints, contact Thomas A. Hope (thomas.hope@ ucsf.edu). COPYRIGHT 2021 by the Society of Nuclear Medicine andMolecular Imaging.