Baseline clinical characteristics predict overall survival in patients undergoing radioligand therapy with [177Lu]Lu-PSMA I&T during long-term follow-up

Background Radioligand therapy (RLT) with 177Lu-labeled prostate-specific membrane antigen (PSMA) ligands is associated with prolonged overall survival (OS) in patients with advanced, metastatic castration-resistant prostate cancer (mCRPC). A substantial number of patients, however, are prone to treatment failure. We aimed to determine clinical baseline characteristics to predict OS in patients receiving [177Lu]Lu-PSMA I&T RLT in a long-term follow-up. Materials and methods Ninety-two mCRPC patients treated with [177Lu]Lu-PSMA I&T with a follow-up of at least 18 months were retrospectively identified. Multivariable Cox regression analyses were performed for various baseline characteristics, including laboratory values, Gleason score, age, prior therapies, and time interval between initial diagnosis and first treatment cycle (intervalDiagnosis-RLT, per 12 months). Cutoff values for significant predictors were determined using receiver operating characteristic (ROC) analysis. ROC-derived thresholds were then applied to Kaplan–Meier analyses. Results Baseline C-reactive protein (CRP; hazard ratio [HR], 1.10, 95% CI 1.02–1.18; P = 0.01), lactate dehydrogenase (LDH; HR, 1.07, 95% CI 1.01–1.11; P = 0.01), aspartate aminotransferase (AST; HR, 1.16, 95% CI 1.06–1.26; P = 0.001), and intervalDiagnosis-RLT (HR, 0.95, 95% CI 0.91–0.99; P = 0.02) were identified as independent prognostic factors for OS. The following respective ROC-based thresholds were determined: CRP, 0.98 mg/dl (area under the curve [AUC], 0.80); LDH, 276.5 U/l (AUC, 0.83); AST, 26.95 U/l (AUC, 0.73); and intervalDiagnosis-RLT, 43.5 months (AUC, 0.68; P < 0.01, respectively). Respective Kaplan–Meier analyses demonstrated a significantly longer median OS of patients with lower CRP, lower LDH, and lower AST, as well as prolonged intervalDiagnosis-RLT (P ≤ 0.01, respectively). Conclusion In mCRPC patients treated with [177Lu]Lu-PSMA I&T, baseline CRP, LDH, AST, and time interval until RLT initiation (thereby reflecting a possible indicator for tumor aggressiveness) are independently associated with survival. Our findings are in line with previous findings on [177Lu]Lu-PSMA-617, and we believe that these clinical baseline characteristics may support the nuclear medicine specialist to identify long-term survivors.

The second most commonly administered radiotracer for PSMA RLT is [ 177 Lu]Lu-PSMA I&T [15], and results of a currently recruiting prospective trial (NCT04647526) will be reported in due course [16]. Despite sharing the same PSMA-binding site, both radiotherapeutics exhibit substantial differences, in particular in regard to the utilized chelator linked to the peptide [17,18]. Thus, outcome and prognostic parameters identified for [ 177 Lu]Lu-PSMA-617 may not be necessarily applicable to patients treated with [ 177 Lu]Lu-PSMA I&T. Using the latter compound, Heck et al. identified the presence of visceral metastasis and a rising LDH as independent predictors of OS [4], while Gafita et al. reported on the time since diagnosis of prostate cancer (PC) as a prognosticator for OS [19]. Supporting the notion that safety and efficacy profiles of both radioligands are less likely to be interchangeable, the current literature comprises only a limited number of approximately 100 subjects treated with [ 177 Lu] Lu-PSMA I&T, which is in contrast to more than 900 reported patients with PC treated with [ 177 Lu]Lu-PSMA-617 [15].
In this study that included 92 patients, we aimed to expand the current literature on [ 177 Lu]Lu-PSMA I&T and to identify predictive baseline characteristics, focusing on long-term follow-up.

Patient cohort
In this single-center study, we identified 118 men with mCRPC treated with [ 177 Lu]Lu-PSMA I&T. Only patients with a follow-up period of at least 18 months after commencing the first treatment cycle were included. Exclusion criteria was a follow-up of less than 18 months (Fig. 1). All patients signed written informed consent. The local Ethics Committee waived the need for further approval due to the retrospective character of this investigation (waiver no. 20210422 04). Parts of this cohort have been reported in [20]. However, that previous analysis did not focus on identifying prognostic parameters for longterm survival.

Treatment protocol
We conducted routine protocols for RLT. In this regard, [ 177 Lu]Lu-PSMA I&T was synthesized as described elsewhere [20]. A total of 6.0 GBq of [ 177 Lu]Lu-PSMA I&T was then administered every 42-56 days (maximum, 8 cycles per patient). If an individual exhibited markedly decreased

Statistical analysis
Statistical analyses were performed using GraphPad Prism version 9.3.0 running on Windows (GraphPad Software, San Diego, CA, USA). We presented median and range in parentheses. OS was defined as the time interval of the day of the first cycle until day of death (presented as median). Since nearly all parameters were not normally distributed, comparisons between cohorts were performed using the Mann-Whitney U test. For comparison of dichotomous variables, we applied Fisher's exact test. Uni-and multivariable Cox regressions were used to identify prognostic baseline parameters (including outlier correction). Cutoffs for survival prediction were determined by receiver operating characteristic (ROC) analysis and the Youden index for maximization of specificity and sensitivity. Kaplan-Meier curves and log-rank comparison were calculated to illustrate separation between responders and non-responders. We considered P < 0.05 statistically significant.

Patients' characteristics
A total of 92/118 (78.0%) patients were included in the final analysis (age, 71 years (52-90 years)). The median time interval between initial diagnosis and the 1st cycle of RLT (interval Diagnosis-RLT ) was 75.5 (range, 9-364) months. The median initial Gleason score of all patients was 8 (5-10). Patients were treated with a median of three cycles (cumulative activity, 14.9 GBq).

Discussion
In this study that included 92 mCRPC patients treated with [ 177 Lu]Lu-PSMA I&T, lower baseline CRP, LDH, and AST and longer interval Diagnosis-RLT independently predicted longer OS. Using predefined cutoffs provided by ROC analysis, Kaplan-Meier analyses differentiated between low vs. high risks, with the most prominent segregation for LDH and CRP. Of note, the herein observed follow-up period of 18 months is almost twice as reported previously for patients  [2,3,15]. In this regard, various clinical baseline characteristics have been reported to identify patients that will most likely fail under RLT with this agent, e.g., CRP, LDH, liver enzymes, or AP [5,9,10,14,21]. However, as stated by Herrmann and coworkers, findings from previous studies using [ 177 Lu]Lu-PSMA-617 have to be interpreted with caution in the context of RLT using [ 177 Lu]Lu-PSMA I&T [22], mainly due to relevant differences in the chemical structure, i.e., using the different chelators DOTA and DOTAGA [17,18]. Comparative studies on biodistribution and dosimetry showed longer half-lives in the tumor lesions for [ 177 Lu]Lu-PSMA-617, but higher initial tumor uptake for [ 177 Lu]Lu-PSMA I&T [23]. In addition, there is a significant imbalance in the current literature on the number of treated subjects with the latter agent (approximately n = 100) when compared to 617 (> 900) [15]. As such, further investigations focusing on outcome prediction with [ 177 Lu]Lu-PSMA I&T are needed.
We therefore evaluated 92 subjects with the longest follow-up period reported to date and were able to identify comparable baseline characteristics having predictive potential relative to [ 177 Lu]Lu-PSMA-617. In this regard, higher baseline CRP has already been described as a negative predictor of OS after RLT with [ 177 Lu]Lu-PSMA-617 [5,10,14]. Although CRP is readily available in the clinic, this parameter is rather non-specific and can be substantially elevated due to inflammatory disease [24]. The influence of LDH on OS after RLT, however, is discussed controversially. For [ 177 Lu]Lu-PSMA-617, elevated LDH has already been described as a negative predictor of OS [5], which was further corroborated by Ferdinandus et al. in an univariate analysis, identifying a comparable cutoff of 240.5 U/l when compared to our  [9]. Of note, other univariate analyses failed to confirm LDH as a prognostic factor for OS [8,10]. Also utilizing [ 177 Lu]Lu-PSMA I&T, Heck et al. demonstrated that elevated LDH was a significant predictor of worse outcome [4], whereas the second most relevant study on this compound yielded no predictive potential of this parameter [19]. Similar to LDH, the predictive performance of AST is also a matter of debate. Ahmadzadehfar et al. reported that elevated AST (≥ 24 U/l) is linked to less favorable outcome for RLT with Fig. 3 Kaplan-Meier curves for patients treated with radioligand therapy stratified into high-and low-risk patients using predefined cutoff values derived by receiver operating characteristics for C-reactive protein (CRP), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and time interval between initial diagnosis and 1st radioligand therapy (interval Diagnosis-RLT ). Lower baseline CRP, LDH, and AST predicted a significantly longer median OS. In addition, the median OS of patients with a longer interval Diagnosis-RLT was also prolonged  [5], which is comparable to our ROC-derived cutoff of 26.95 U/l. Previous studies utilizing [ 177 Lu]Lu-PSMA I&T did not investigate AST in the context of outcome prediction. Nonetheless, elevated baseline AST seems to be tightly linked to shorter survival regardless of which agent was applied.
Although reported for [ 177 Lu]Lu-PSMA-617 in several studies [5,8,9,11,21], we could not confirm a prognostic ability of elevated baseline AP for OS after RLT with [ 177 Lu] Lu-PSMA I&T, which is consistent with previous reports with this compound [4,19]. As such, for this radiotracer, AP may play a less important role for outcome prediction when compared to [ 177 Lu]Lu-PSMA-617.
Beyond laboratory values, longer interval Diagnosis-RLT also demonstrated independent predictive potential for prolonged OS in our cohort. As a possible explanation, this baseline characteristic may represent tumor aggressiveness, as one may speculate that a longer interval between initial diagnosis and RLT is also linked to a more treatment-sensitive tumor biology. For instance, Barber et al. found an association between interval Diagnosis-RLT and OS for taxanenaïve patients undergoing RLT with [ 177 Lu]Lu-PSMA-617 in an univariate analysis [25], while Gafita et al. also reported that a longer interval Diagnosis-RLT is associated with longer OS in men scheduled for [ 177 Lu]Lu-PSMA I&T [19]. As such, this time frame may support a decision-making process to consider RLT for both radiotherapeutics.
The present study may provide in-depth results of patients that have been referred to our center in a real-world scenario with a focus on long-term follow-up. However, given the exploratory design of the study we cannot rule out a possible lack of power for testing the described associations. Therefore, we want to emphasize that the correlations found in our analysis have to be interpreted with caution as they not necessarily mean causation. Moreover, 12/92 patients received reduced activity in at least one cycle, but failed to reach significance in a univariate analysis ( Table 2). Future studies may also control for this variable.
Further studies reported on the predictive value of image-based semi-quantification in the context of RLT [26,27]. In the present study, however, we focused on clinical parameters, which are easy to obtain relative to the time-consuming nature of manual segmentation procedures of PSMA PET/CTs. Given the rather low number of reported subjects treated with [ 177 Lu]Lu-PSMA I&T, we believe that the herein presented results are relevant for the practitioner [22]. Nonetheless, confirmatory clinical trials enrolling a substantially higher number of subjects are warranted, preferably also using PSMA-directed PET findings. In this regard, nomograms for patients treated with [ 177 Lu]Lu-PSMA (including both 617 and I&T) have been established and also consider such PSMA-avid disease sites on molecular imaging. Of note, those risk charts have been provided to the community as online tools and, thus, can be easily tested for patients which had exclusively received [ 177 Lu]Lu-PSMA I&T [6].

Conclusion
In this study that included 92 patients with mCRPC treated with [ 177 Lu]Lu-PSMA I&T, baseline laboratory values (CRP, LDH, and AST) and interval Diagnosis-RLT (reflecting a possible indicator for tumor aggressiveness) were independent predictors of survival during long-term follow-up. Our findings corroborate with previous findings on [ 177 Lu] Lu-PSMA-617 and we believe that these routinely available parameters may support the nuclear medicine physician to identify individuals that should be scheduled for RLT with Funding Open Access funding enabled and organized by Projekt DEAL. This work was supported by the IZKF Wuerzburg (grant Z-02/85 to P.H.). This publication was supported by the Open Access Publication Fund of the University of Wuerzburg.

Data availability
The main data presented in this study are available in the article. Detailed information about the image analysis or the overall survivals of the subjects presented in this study is available on request from the corresponding author.

Declarations
Institutional review board The study was conducted according to the guidelines of the Declaration of Helsinki. Ethical review and approval were waived for this study by the local Ethics Committee due to the retrospective character of the study (waiver no. 20210422 04).
Informed consent Informed consent was obtained from all subjects involved in the study.

Conflict of interest The authors declare no competing interests.
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