Threshold for defining PSMA-positivity prior to ¹⁷⁷Lu-PSMA therapy: a comparison of [⁶⁸Ga]Ga-PSMA-11 and [¹⁸F]F-DCFPyL in metastatic prostate cancer

Prostate cancer is a major public health concern, as it is the second most common malignancy in adult males worldwide [1]. Despite multimodal treatments that delay disease progression, advanced metastatic prostate cancer remains fatal [2, 3].

Nuclear medicine is becoming increasingly important in the treatment of prostate cancer, using overexpression of the prostate-specific membrane antigen (PSMA) on the surface of prostate cancer cells to internalise intravenously administered, radiolabelled PSMA ligands for diagnostic and therapeutic purposes [4, 5, 6, 7, 8, 9]. Such PSMA ligands can be labelled with positron emitters (e.g. gallium-68, fluorine-18), allowing diagnostic imaging by positron emission tomography (PET), or with beta emitters (e.g. lutetium-177) to perform radioligand therapy [4, 5].

Radioligand therapy with ¹⁷⁷Lu-labelled PSMA ligands has been used successfully for several years as part of individualised treatment plans for patients with prostate cancer [10]. In 2022, based on the PSMA-VISION trial, [¹⁷⁷Lu]Lu-PSMA-617 (PLUVICTO™, Novartis AG, Basel, Switzerland) became the first PSMA-directed radiopharmaceutical to be formally approved by the American Food and Drug Administration and the European Medicines Agency for the treatment of patients with PSMA-positive metastatic castration-resistant prostate cancer who had previously been treated with androgen receptor pathway-inhibiting drugs and taxane-based chemotherapy [11, 12].

Although PSMA overexpression is a common finding in patients with prostate cancer, there is a considerable intra- and interpatient heterogeneity [13, 14]. Appropriate patients should therefore be identified by PSMA-PET prior to radioligand therapy according to the principles of theranostics [3, 4, 10]. In the PSMA-VISION trial, patients were required to have PSMA-positive tumour lesions, defined as PSMA expression above the liver background on PET using [⁶⁸Ga]Ga-PSMA-11 [3]. In order to be able to offer radioligand therapy based on PET diagnostics with an alternative ¹⁸F-labelled PSMA tracer, we aimed to address the question whether employing the ¹⁸F-labelled PSMA-specific radiopharmaceutical [¹⁸F]F-DCFPyL would result in comparable patient classification to established [⁶⁸Ga]Ga-PSMA-11-PET [15]. For this purpose, we compared PET scans of patients who had undergone both PET with [⁶⁸Ga]Ga-PSMA-11 and [¹⁸F]F-DCFPyL within a short time interval as part of their clinical workup. We measured uptake levels of metastases and background regions (liver, mediastinum) in order to calculate and compare tumour-to-background ratios. As tumour expression of PSMA above the hepatic background was the main criterion for PSMA-positivity in the PSMA-VISION trial, we paid particular attention to differences in the tumour-to-liver ratio between PET images using [⁶⁸Ga]Ga-PSMA-11 and [¹⁸F]F-DCFPyL [3].

The following findings emerge from our analysis:

Our first observation was that contrast-to-noise ratios were significantly higher on [¹⁸F]F-DCFPyL-PET than on [⁶⁸Ga]Ga-PSMA-11-PET, demonstrating the better image quality with superior lesion detectability obtainable with [¹⁸F]F-DCFPyL-PET. This is consistent with previous observations of an improved image quality with ¹⁸F-labelled PSMA tracers. For example, data from our previous investigations suggest that ¹⁸F-labelled PSMA ligands are at least non-inferior to ⁶⁸Ga-labelled PSMA ligands in detecting tumour lesions and offer some further advantages in detecting smaller tumour lesions at low PSA levels [20, 21, 22]. Higher contrast-to-noise ratios on [¹⁸F]F-DCFPyL-PET could be explained by the ability of ¹⁸F-labelled radiopharmaceuticals to be used for later imaging (due to a longer half-life and availability of higher activity provided by cyclotron production compared to ⁶⁸Ga-labelled radiopharmaceuticals) [4].

Our second observation was that comparable tumour-to-liver ratios and tumour-to-mediastinum ratios were obtained with [⁶⁸Ga]Ga-PSMA-11-PET and [¹⁸F]F-DCFPyL-PET. This is of particular interest, since PSMA-positive disease is a prerequisite prior to radioligand therapy with ¹⁷⁷Lu-labelled PSMA ligands for patients with metastatic castration-resistant prostate cancer [3, 4, 10]. So far, in the approach taken by the pivotal PSMA-VISION trial, PSMA-positivity has been defined as tumoural PSMA expression above the liver background level on PET with [⁶⁸Ga]Ga-PSMA-11 [3]. Despite their known advantages in image quality and logistics, ¹⁸F-labelled PSMA ligands were not considered in the PSMA-VISION trial [4, 23]. However, given their advantages, ¹⁸F-labelled PSMA ligands could become the future tracers of choice in PET diagnostics, as ¹⁸F-labelling make on-site radiolabelling unnecessary and would enable wider commercial distribution [4]. In this context, our present data suggest that PET with [¹⁸F]F-DCFPyL also offers the possibility of identifying PSMA-positive disease prior to radioligand therapy using the same qualitative liver-dependent approach as that proposed in the PSMA-VISION trial with [⁶⁸Ga]Ga-PSMA-11 [3]. Given the comparable liver-to-background ratios obtained for [⁶⁸Ga]Ga-PSMA-11 and [¹⁸F]F-DCFPyL, it is reasonable to consider tumour uptake above the liver background level as a definition of PSMA-positivity prior to radioligand therapy when using [¹⁸F]F-DCFPyL. This is consistent with the conclusions of Ferreira et al., who compared 34 patients who had received both [⁶⁸Ga]Ga-PSMA-11-PET and [¹⁸F]F-DCFPyL-PET [24]. They showed an acceptable intra-individual agreement in terms of uptake in the liver background and took this to indicate a comparability of the two tracers in defining PSMA-positive disease prior to radioligand therapy [24]. However, in this previous study, no direct comparison of individual tumour-to-background ratios for different tracers in the same patients was performed [24]. Furthermore, our results support the consensus statement on the role of PSMA-PET published by the European Association of Nuclear Medicine and the European Association of Urology [25]. The participating experts agreed that the tracers studied here are equivalent to select patients for radioligand therapy [25]. This consensus is now underlined by direct evidence from our data.

As various ¹⁸F-labelled PSMA tracers are used in clinical evaluation, it is reasonable to question whether these tracers provide the same results in terms of predicting the likely success of radioligand therapy. In our view, it is quite possible that PSMA tracers such as [¹⁸F]F-PSMA-1007, which are predominantly eliminated via the liver, produce different results to those of their predominantly renally excreted competitors [26]. Thus in our opinion, it cannot be easily assumed that the qualitative liver-dependent approach proposed by the PSMA-VISION trial for [⁶⁸Ga]Ga-PSMA-11 is equally suitable for tracers with distinctly different biodistribution [3]. However, it also remains unclear whether our results for [¹⁸F]F-DCFPyL can be extrapolated to other predominantly renally excreted tracers such as [¹⁸F]F-JK-PSMA-7 [26].

Our present study has some limitations. First, our comparison of [⁶⁸Ga]Ga-PSMA-11 and [¹⁸F]F-DCFPyL was not designed as a prospective clinical trial. Second, our observations were focused on a highly select group of 11 patients with biochemical recurrence of prostate cancer due to the rare occurrence of dual PET protocol in clinical practice. Therefore, it must be taken into account that the patients studied were in an early stage of disease and thus should not receive radionuclide therapy according to current guidelines. It remains unclear whether our results can be transferred to patients with advanced disease who are eligible for radionuclide therapy, as changes in tumour biology or therapy-related effects may alter the uptake ratios. In addition, our retrospective data do not provide sufficient information on histopathological confirmation of suspicious PET findings. In order to obtain more solid evidence, it is necessary to validate our findings in a prospective trial with an appropriate study protocol and a larger number of patients. However, the option for a direct comparison within the same patients may represent a strength of the current study despite the small sample size. It will be generally difficult to obtain dual PET data for direct comparison and most previous studies have used matched-pair analyses to compensate for this lack of data [27]. It appears reasonable to assume that a reliable impression on the general tracer distribution behaviour with regard to tumour-to-background ratios can be drawn from the current sample. Therefore, despite its small cohort size, this study does help to provide further evidence of the comparability of these tracers.

Our data showed that [¹⁸F]F-DCFPyl-PET and [⁶⁸Ga]Ga-PSMA-11-PET provide comparable tumour-to-liver and tumour-to-mediastinum ratios. Therefore, a tumour uptake of [¹⁸F]F-DCFPyL above the liver background, like using [⁶⁸Ga]Ga-PSMA-11, can be considered as equally suitable for defining PSMA-positivity by a semiquantitative assessment based on the liver background, e.g. prior to radioligand therapy with ¹⁷⁷Lu-labelled PSMA ligands. In addition, our data suggest a tending advantage of [¹⁸F]F-DCFPyL in terms of lesion detectability.