SUV_mean on baseline [¹⁸F]PSMA-1007 PET and clinical parameters are associated with survival in prostate cancer patients scheduled for [¹⁷⁷Lu]Lu-PSMA I&T

Prostate-specific membrane antigen (PSMA)-targeted radioligand therapies (RLT) using [¹⁷⁷Lu]Lu-PSMA-617 have been shown to improve overall survival (OS) and/or biochemical response (as measured by prostate specific antigen (PSA) levels) compared to standard of care and cabazitaxel [1, 2]. This led to approval by the U.S. Food and Drug Administration [3] and the European Medicines Agency [4]. However, not all patients respond to RLT, highlighting the need for reliable prognosticators of treatment outcomes, preferably by combining available clinical and imaging parameters at baseline.

Several studies have identified clinical prognostic factors for patients receiving [¹⁷⁷Lu]Lu-PSMA-617, including the presence of visceral metastases [5-8], elevated alkaline phosphatase (AP) [9, 10], C-reactive protein (CRP) levels [11], prior chemotherapy [8, 12, 14], elevated lactate dehydrogenase (LDH) [9-11, 14], elevated aspartate aminotransferase (AST) [6, 14], and lower hemoglobin [6, 11]. For survival prediction in patients treated with [¹⁷⁷Lu]Lu-PSMA I&T, Heck et al. also identified the presence of visceral metastases and a rising LDH as being associated with OS [5], while a recent analysis from our group showed that baseline CRP, LDH, AST, and time interval until RLT initiation were associated with survival in patients receiving the identical compound [14].

Beyond those clinical parameters, recent efforts also turned towards investigating baseline PSMA PET uptake in men treated with PSMA-directed RLT. For instance, Seifert et al. reported on PSMA-positive tumor volume (PSMA-TV) [14] and PSMA total lesion quotient derived from [⁶⁸ Ga]Ga-PSMA-11 as being associated with OS [14], while a low average SUV_max of all PSMA-positive lesions was a negative prognosticator for survival [14]. Widjaja and coworkers also reported that quantification of [⁶⁸ Ga]Ga-PSMA-11 was prognostic for PSA response in subjects being treated with [¹⁷⁷Lu]Lu-PSMA-617 [22]. In addition, the TheraP trial also used [⁶⁸ Ga]Ga-PSMA-11 and sites of disease with a SUV_mean ≥ 10 had a higher likelihood of favorable response to [¹⁷⁷Lu]Lu-PSMA-617 [14]. All of those previous studies, however, focused on the prognostic value of [⁶⁸ Ga]-labeled PSMA PET in the context of [¹⁷⁷Lu]Lu-PSMA-617, while the prognostic capability of [¹⁸F]-labeled PSMA PET agents in men treated with other PSMA-targeted β-emitters has not been elucidated yet in a larger cohort. Such information, however, may be of importance, as recent years have witnessed an expanded use and clinical adoption of [¹⁸F]-labeled PSMA agents, in particular in the theranostic context [22].

As such, in this study, we aimed to identify prognostic baseline imaging parameters using [¹⁸F]PSMA-1007 in patients who were treated with [¹⁷⁷Lu]Lu-PSMA I&T. Additionally, we aimed to provide a risk factor (RF) model that includes not only imaging but also clinical parameters available at the time of treatment planning. Such an approach may help to better identify patients at high risk for treatment failure of PSMA RLT.

In 103 patients with mCRPC who were treated with [¹⁷⁷Lu]Lu-PSMA I&T, lower baseline SUV_mean derived from [¹⁸F]PSMA-1007 PET and lower age at the 1st cycle of RLT were associated with early PSA failure after 8 weeks. Furthermore, lower baseline SUV_mean, higher CRP, decreased hemoglobin levels, and hepatic metastases were independently associated with reduced OS. Last, when computing an RF model, the presence of more than two of those factors also identified patients with shortest survival, thereby demonstrating that all available clinical and imaging parameters should be taken into account to identify men at highest risk for RLT failure.

Regarding clinical parameters available at baseline, the vast majority of studies published to date have focused on the use of [¹⁷⁷Lu]Lu-PSMA-617, showing that CRP, LDH, liver enzymes, or AP can identify men prone to treatment failure [6, 10, 11, 14, 29]. In the present analysis, however, only patients treated with another commonly used β-emitting PSMA radiotherapeutic (i.e., [¹⁷⁷Lu]Lu-PSMA I&T) were included. In this regard, we have already reported that baseline CRP is a significant predictor in PCa patients treated with this compound [14], which has also been described for [¹⁷⁷Lu]Lu-PSMA-617 [6, 11, 14]. As a major drawback, however, CRP is nonspecific and can be significantly elevated in inflammatory disease [22].

Comparable to our previous and other reports, we could not confirm a prognostic ability of elevated baseline AP for OS after RLT with [¹⁷⁷Lu]Lu-PSMA I&T [5, 14, 35], although this was reported for [¹⁷⁷Lu]Lu-PSMA-617 [6, 9, 10, 12, 29]. Interestingly, in our study, age at initiation of RLT was significantly associated with early PSA response but not OS. This has also been previously reported by Widjaja et al. using [¹⁷⁷Lu]Lu-PSMA-617 [22]. This phenomenon may be partially explained by the assumption that older patients may have less aggressive variants of underlying tumor biology [14] and, thus, are more likely to respond to PSMA-targeted RLT, irrespective of the agent.

Taken together, although survival has been demonstrated to be comparable for both compounds [22], outcome prediction based on clinical parameters may be complex for both PSMA-targeted compounds. As such, extrapolation from [¹⁷⁷Lu]Lu-PSMA I&T to those subjects scheduled for therapy with -617 should be made with caution. Thus, we also investigated the prognostic value of an [¹⁸F]-labeled PSMA PET compound for identifying patients with high risk of treatment failure, while previous studies mainly focused on [⁶⁸ Ga]-labeled PET compounds. Those considerations are further fueled by the fact that there is an increasing shift towards radiofluorine in the context of PSMA-targeted molecular imaging and risk stratification in a theranostic approach [22], thereby making our findings relevant for the broader nuclear medicine community.

We observed that the presence of PSMA-avid hepatic liver lesions has a negative impact on survival, a finding that has also been extensively described for [¹⁷⁷Lu]Lu-PSMA-617-treated patients imaged with [⁶⁸ Ga]-labeled radiotracers [5-8]. On a quantitative assessment, an increasing SUV_mean was associated with a higher probability of early PSA response and longer OS. Those results are in line with TheraP, which showed that men with a PSMA SUV_mean ≥ 10 in their metastatic lesions had a higher likelihood of favorable PSA response to [¹⁷⁷Lu]Lu-PSMA-617 when compared to chemotherapy [14]. The analysis of the pre-therapeutic [⁶⁸ Ga]-labeled PSMA PET/CT scans from the VISION trial also showed that a higher SUV_mean was associated with an improved survival [39]. Of note, our analysis showed an impact on survival, and patients with SUV_mean > 9.4 (which is virtually identical to the cut-off used in TheraP) showed a median OS twice as long as patients with SUV_mean below this cut-off. The SUV_mean might thus be seen as a marker for heterogeneity of PSMA expression, as a low value could indicate a partially decreased/absent PSMA expression of the tumor cells. In preclinical work, it has been shown that the fraction of PSMA-positive cells correlates with PSMA RLT efficacy and that an overall decreased PSMA expression is associated with a weaker effect of RLT [29].

The present study also provides results on PET quantification using [¹⁸F]PSMA-1007 in a large and homogenously treated cohort of 103 patients with mCRPC. A recent study including 20 subjects investigated the use of this radiotracer for identifying high-risk patients along with DNA damage response markers, and the authors reported that SUV_max failed to predict progression-free survival. Those differences relative to the present study may be explained by the larger number of individuals investigated in our analysis and by varying endpoints (progression-free vs. OS) [22]. Moreover, the presented AIC and Harrell’s C indices used in our report provide an assessment of the different fitted survival models, thereby allowing a determination as to which parameter has the most prominent role in outcome. In this regard, CRP and hemoglobin yielded improved statistics (reflected by lower AIC and higher C-index) when compared to SUV_mean, suggesting a greater importance of clinical parameters when compared to PET-based quantification. Nonetheless, the herein provided RF model still showed that a combination of all available (clinical and PET) parameters should be taken into account to identify those patients with shortest survival. In this regard, the herein used RF model is easy to implement in clinical practice, with more than two RFs tightly linked to decreasing survival. This is also in line with a recent study providing nomograms, which also incorporated varying clinical predictors (including hemoglobin) and tumor burden derived from [⁶⁸ Ga]Ga-PSMA-11 PET [7]. Taken together, those previous findings on [⁶⁸ Ga]-,and our results on [¹⁸F]-labeled, PSMA PET further emphasize the importance of considering both clinical and imaging parameters prior to treatment with RLT.

Lower SUV_mean derived from [¹⁸F]PSMA-1007 PET is associated with less favorable PSA response rates and overall survival in patients treated with [¹⁷⁷Lu]Lu-PSMA I&T. Furthermore, higher CRP, lower hemoglobin levels, and the presence of hepatic metastases were independently associated with reduced OS. Finally, a RF model including all of those parameters also demonstrated that an increasing number of those factors is linked to worse outcome, in particular in patients with more than two RFs. As such, our results may also emphasize the importance of a holistic approach to treatment planning, which should include clinical and imaging parameters for adequate risk stratification.