PSMA PET Imaging in the Management of Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Radioligand Therapy

Abstract

Despite an evolving treatment landscape for people with metastatic castration-resistant prostate cancer, prognosis for this patient population remains poor. Prostate-specific membrane antigen positron emission tomography (PSMA PET) imaging may be used to identify patients with PSMA-positive (and no significant PSMA-negative) metastatic castration-resistant prostate cancer who could benefit from PSMA-targeted radioligand therapy. As the PSMA PET imaging and treatment landscape expands, there is a growing need for guidance and greater utilization of PSMA-targeted tracers and radioligand therapies to improve outcomes for patients with metastatic castration-resistant prostate cancer. This review discusses the current clinical considerations of PSMA PET, including the various imaging agents available and how best to identify patients eligible for PSMA PET imaging and subsequent PSMA-targeted radioligand therapy. This review also examines opportunities to mitigate discordant findings, as well as considerations around the standardization of reporting of PSMA PET imaging, key gaps in the evidence base, and guidance around the use of PSMA PET in clinical and research settings.

Supplementary Information

The online version contains supplementary material available at 10.1007/s11523-025-01151-7.

Key Points

Prostate-specific membrane antigen positron emission tomography (PSMA PET) imaging may help to identify patients who will benefit from PSMA-targeted radioligand therapy.

Whilst the increased use of PSMA PET imaging and PSMA-targeted radioligand therapy has improved patient outcomes, there is a growing need for guidance that can further optimize its use. This review provides an overview of the clinical considerations for the use of PSMA PET, such as identifying patients eligible for radioligand therapy and guidance for using PSMA PET in the clinic.

Introduction

Despite the continuously evolving treatment landscape for metastatic castration-resistant prostate cancer (mCRPC), prognosis for patients remains poor [1]. Based on prior treatments received, disease pathology, and patient eligibility, treatment options for mCRPC vary. They currently include taxane-based chemotherapy (docetaxel and cabazitaxel), androgen receptor pathway inhibitors (ARPIs; enzalutamide and abiraterone), radioisotope therapy (²²³Ra), prostate-specific membrane antigen (PSMA)-directed radioisotope therapy ([¹⁷⁷Lu]Lu-PSMA-617), poly-ADP ribose polymerase inhibitors (olaparib, rucaparib, talazoparib, and niraparib), and sipuleucel-T [2]. The accurate localization of lesion sites is important for disease staging and optimal treatment selection [3], though current conventional imaging techniques (such as computed tomography [CT] and bone scintigraphy) have poor sensitivity and specificity, particularly when prostate-specific antigen (PSA) levels are low [3, 4]. How best to utilize imaging for treatment management, including selection and monitoring of response, remains unclear.

Prostate-specific membrane antigen is a transmembrane glycoprotein frequently upregulated in mCRPC cells [5–8] (Fig. 1). Overexpression of PSMA is present in approximately 90% of prostate cancer (PC) cells and is associated with poor prognostic outcomes [9, 10]; because of this, PSMA serves as an established target for radiopharmaceutical imaging and therapy in patients with PC [11]. Radioligand imaging using PSMA-targeted gallium-68 ([⁶⁸Ga]Ga)-based and fluorine-18 [¹⁸F]F-based tracers, in combination with positron emission tomography (PET), can offer non-invasive semi-quantitative imaging of tumor cells that express PSMA [12]. When combined with CT or magnetic resonance imaging (MRI), PSMA PET can be further integrated with anatomic imaging for a more comprehensive evaluation of primary and secondary tumor lesions [13, 14]. The rationale for requesting a PSMA PET scan is to assess the extent of PSMA-positive and PSMA-negative disease, and to decide whether or not radioligand therapy (RLT) is indicated [7, 15]. Optimal treatment of PSMA-positive mCRPC with PSMA-directed radioligands requires effective and specific methods of assessing PSMA-positive and PSMA-negative tumors in patients (Fig. 1) [11], particularly as patients with PSMA-negative disease may be ineligible for PSMA-directed RLT and have poor prognoses and survival outcomes [16].

Fig. 1.

Mechanism of action of prostate-specific membrane antigen (PSMA)-targeted radioligands. High PSMA expression at the surface of prostate cancer (PC) cells (A) makes it an effective imaging and therapeutic target for PSMA-targeted radioligands (B). After binding PSMA at the cell surface, a targeted radioligand, such as [¹⁷⁷Lu]Lu-PSMA-617 (C), enters the PC cell via endocytosis and initiates cell death by means of radiation-induced DNA damage. mAb monoclonal antibody

While it is not within the scope of this article to go into detail regarding PSMA PET image acquisition and post-scan processing methodologies, the interested reader can refer to articles describing these elsewhere [9, 12]. In this review, we focus on the use of PSMA PET imaging for the identification of patients with PSMA-positive mCRPC who would most benefit from PSMA-targeted RLT, including [¹⁷⁷Lu]Lu-PSMA-617, the only RLT so far approved by the US Food and Drug Administration (FDA) as a treatment for adult patients with PSMA-positive mCRPC (who had previously been treated with an ARPI, and were considered appropriate to delay taxane-based chemotherapy or had received prior taxane-based chemotherapy) [17]. We also explore the current clinical considerations of PSMA PET, including the various imaging agents available and how patients are identified by PSMA PET, as eligible for subsequent PSMA-targeted RLT. Finally, we will evaluate the reliability and standardization of reporting of PSMA PET imaging, assess opportunities to mitigate positive and negative discordant findings, and identify any gaps that remain to be addressed.

Current Status of PSMA-Targeted Imaging Agents

The current FDA-approved commercially available PSMA PET tracers are [⁶⁸Ga]Ga-PSMA-11, and the [¹⁸F]F-based radioligands [¹⁸F]F-DCFPyL (¹⁸F-piflufolastat) and [¹⁸F]F-rhPSMA-7.3 (¹⁸F-flotufolastat); [¹⁸F]F-PSMA-1007 is also available commercially in France [12, 18–26]. There is no definitive evidence to differentiate these radiotracers based on their clinical impact [27], although small-scale head-to-head comparisons have been conducted, the findings of these are summarized in Table 1 of the Electronic Supplementary Material (ESM) [28]. It has been suggested that [¹⁸F]F radioligands may potentially offer superior spatial resolution to [⁶⁸Ga]Ga radioligands, owing to the lower positron range of [¹⁸F]F compared with [⁶⁸Ga]Ga [29, 30]; however, [¹⁸F]F-PSMA-1007 has been observed to have a higher benign bone uptake than [⁶⁸Ga]Ga-PSMA-11 [27, 31]. These differences highlight the importance of a thorough understanding of the individual strengths and weaknesses of each radioligand imaging agent in order to achieve optimal results.

Table 1.

Emerging PSMA-targeted PET imaging agents and radioligand therapies

Trial number	Molecule(s)	Clinical trial summary	Phase	Patient population
NCT04868604 [115]	Combination of: [64Cu]Cu-SAR-bisPSMA and [67Cu]Cu-SAR-bisPSMA	[64Cu]Cu-SAR-bisPSMA and [67Cu]Cu-SAR-bisPSMA for identification and treatment of PSMA-expressing metastatic castrate resistant prostate cancer (SECuRE) Objective: To determine the safety and efficacy of [67Cu]Cu-SAR-bisPSMA in participants with PSMA-expressing mCRPC	I/IIa	mCRPC
NCT04838626 [116]	[18F]F-CTT1057	Study of diagnostic performance of [18F]F-CTT1057 for PSMA-positive tumors detection (GuideView) Objective: To evaluate the diagnostic performance of [18F]F-CTT1057 as a PET imaging agent for the detection and localization of PSMA-positive tumors using histopathology as the standard of truth	II/III	High-risk PC
NCT05653856 [117]	[64Cu]Cu-PSMA-I&T	[64Cu]Cu-PSMA-I&T positron emission tomography (PET) imaging of metastatic PSMA positive lesions in men with prostate cancer Objective: To evaluate [64Cu]Cu-PSMA-I&T injection for PET/CT imaging in patients with recurrent metastatic prostate cancer after radical prostatectomy or radiation therapy	II	Recurrent mCRPC
NCT04102553 [118]	[18F]F-PSMA-1007	F-18-PSMA-1007 versus F-18-fluorocholine PET in patients with biochemical recurrence Objective: To evaluate the diagnostic performance and safety of F-18-PSMA-1007 and F-18-fluorocholine PET/CT imaging in patients with suspected recurrence of prostate cancer after previous definitive treatment	III	Recurrent mCRPC

CT computed tomography, Cu copper, F fluorine, I&T 4,7,10-tetraazacyclododecane-1-(glutamic acid)-4,7,10-triacetic acid (DOTAGA; DOTA-GA), mCRPC metastatic castration-resistant prostate cancer, PC prostate cancer, PET positron emission tomography, PSMA prostate-specific membrane antigen, SAR sarcophagine

Although [⁶⁸Ga]Ga-PSMA-11 is the only approved tracer for use with [¹⁷⁷Lu]Lu-PSMA-617, the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) and American Society of Clinical Oncology guidelines recommend that [¹⁸F]F-DCFPyL and [¹⁸F]F-rhPSMA-7.3 can also be used in this setting, based on multiple reports describing the sufficient equivalence of these imaging agents [2, 27, 32–36]. However, it should be noted that the level of evidence for [¹⁸F]F-DCFPyL and [¹⁸F]F-rhPSMA-7.3 use in this setting is weak.

Emerging PSMA PET Imaging Agents and RLTs

As discussed above, radioligand tracers each have individual strengths and weaknesses and, as a consequence of this, the PSMA PET imaging landscape continues to evolve rapidly as better imaging agents are sought. Several PSMA imaging agents are currently being assessed in clinical trials, including [⁶⁴Cu]Cu-PSMA-I&T, [⁶⁴Cu]Cu-SAR-bisPSMA, [¹⁸F]F-CTT0157, and [¹⁸F]F-PSMA-1007 (Table 1). Further evidence and evaluation will be required to determine the utility and applicability of these agents in clinical practice, as well as any variance between molecules.

Clinical Applications and Guidelines for PSMA PET

PSMA PET imaging is now well established for evaluating biochemical recurrence (BCR) of PC, even at low PSA levels (i.e., PSA <1 ng/mL), and has also shown applications for tumor detection, primary staging, assessment of therapeutic responses, and treatment planning [2, 37, 38]. Although there are currently no universally accepted criteria for PSMA PET [39], a multidisciplinary panel of healthcare providers and PC imaging experts has recently developed a set of appropriate-use criteria for PSMA imaging [40, 41]. Utilization of PSMA PET has seen a rapid expansion in recent years, and its current clinical applications in the context of mCRPC are discussed below.

Mapping Metastatic Castration-Resistant PC

PSMA PET can be highly effective in mapping the extent of disease in the mCRPC setting. In a retrospective, investigator-initiated, multicenter trial (n = 200), PSMA PET detected metastatic lesions in 56% of PSMA-positive patients (109 of 196) who were classified as non-metastatic by conventional imaging, resulting in a new treatment being initiated after PSMA PET in 62% of PSMA-positive patients (122 of 196) [42]. These patients were then followed for a median of 43 months after PSMA PET, and the associations between patient characteristics, PSMA PET findings, treatment management, and outcomes were retrospectively assessed [43]. Polymetastatic disease (defined as five or more distant lesions on PET) was independently associated with reduced overall survival (OS; hazard ratio [HR]: 1.81, 95% confidence interval [CI] 1.00–3.27; p = 0.050). Shorter time to new metastases and initial pN1 (pathological lymph node involvement) status were also associated with reduced OS, demonstrating that PSMA PET-derived disease extent allows for a more in-depth level of risk stratification in this patient population than conventional imaging [43]. The investigators concluded that the novel risk stratification approach adopted in this trial should be replicated in other studies to confirm whether these, and other risk factors for poor outcomes, could be incorporated into future treatment algorithms [43].

A multicenter retrospective study compared the prognostic value of PSMA PET staging, categorized by Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE), with established clinical nomograms in a large PC dataset [44]. Using a development cohort, two nomograms were created based on Cox regression models, assessing potential predictors for OS: a quantitative nomogram (predictors: locoregional lymph node metastases, distant metastases, tumor volume [L], and tumor mean standardized uptake value); and a visual nomogram (predictors: distant metastases and total tumor lesion count) [44]. Both were found to accurately stratify high- and low-risk groups for OS in early and late stages of PC [44]. The performance of each was then compared with established clinical risk scores, with prediction accuracy for the quantitative and visual nomograms found to be equal or superior to existing clinical risk tools [44]. An international PROMISE-PET registry study for multicenter validation of nomograms and analysis of specific patient subgroups is ongoing (NCT06320223).

PSMA PET for the Selection of Patients for PSMA-Targeted RLT

PSMA PET/CT has also been carried out in people with mCRPC to confirm eligibility for RLT in clinical trials, for example, to confirm PSMA expression in metastatic sites prior to initiation of RLT in phase II/III clinical trials assessing the PSMA-directed RLT [¹⁷⁷Lu]Lu-PSMA-617 [45–47] and [¹⁷⁷Lu]Lu-PNT2002 [48].

In the open-label, randomized, phase III VISION trial (NCT03511664), the eligibility criteria included at least one PSMA-positive (tracer uptake visually greater than the liver) metastatic lesion visualized on [⁶⁸Ga]Ga-PSMA-11 PET/CT. Patients with PSMA-negative (tracer uptake visually equal to or less than the liver) lesions meeting specific size criteria on diagnostic CT/MRI were excluded [46]. Patients deemed eligible by the trial-specific criteria had improved median progression-free survival (PFS; 8.7 vs 3.4 months, HR: 0.40, 99.2% CI 0.29–0.57; p < 0.001) and median OS (15.3 vs 11.3 months, HR: 0.62, 95% CI 0.52–0.74; p < 0.001) with [¹⁷⁷Lu]Lu-PSMA-617 plus best standard of care versus best standard of care alone [46].

In the open-label, randomized, phase III PSMAfore trial (NCT04689828), the treatment eligibility of taxane-naïve patients was also determined by the presence of one or more PSMA-positive (and the absence of PSMA-exclusionary) lesions using [⁶⁸Ga]Ga-PSMA-11 PET/CT [47]. The primary endpoint of median radiographic PFS (rPFS) was significantly longer in patients treated with [¹⁷⁷Lu]Lu-PSMA-617 compared with patients treated with a change in ARPI, at 9.3 months versus 5.6 months, respectively (HR: 0.41, 95% CI 0.29–0.56; p < 0.0001) [47]. Similar to the other studies, a proportion of patients did not respond to [¹⁷⁷Lu]Lu-PSMA-617 treatment [47].

In the TheraP open-label, randomized, phase II trial (NCT03392428), patient selection was determined by the radiotracers [⁶⁸Ga]Ga-PSMA-11 and [¹⁸F]F-FDG PET/CT [45]. Significantly prolonged PSA and rPFS were observed in patients treated with [¹⁷⁷Lu]Lu-PSMA-617 compared with cabazitaxel [45]. Of note, despite the fact that the selection used a combination of PSMA PET and [¹⁸F]F-FDG PET, a proportion of patients in the VISION and TheraP clinical trials did not respond to treatment with [¹⁷⁷Lu]Lu-PSMA-617 [45, 46], highlighting the need to optimize methods for identifying patients who may benefit. Many oncologists may be unaware of the potential utility of FDG PET, or that it can be utilized in tandem with [⁶⁸Ga]Ga-PSMA-11 to aid patient selection for treatment with [¹⁷⁷Lu]Lu-PSMA-617, particularly in complex disease. Recent NCCN Guidelines^® suggest that a combination of PSMA PET and FDG PET may be of value in mCRPC, as this combination can better detect heterogeneous PSMA expression [2]. This is particularly important, as patients with mCRPC that have metastases with PSMA-negative/FDG-positive mismatch may have poorer survival outcomes than those without PSMA-negative/FDG-positive mismatch when treated with [¹⁷⁷Lu]Lu-PSMA-617 RLT [2, 49]. The secondary outcome study of the TheraP trial reported that the survival time of patients excluded on the basis of low PSMA expression (per PSMA PET) or discordant PET/FDG was lower than eligible participants (difference 7.8 months [95% CI 4.1–10.6; p < 0.0001]) [50]. In light of the limitations of PSMA PET in PSMA-negative mCRPC, use of additional contrast-enhanced CT or MRI is recommended for patients with PSMA-negative disease [2]. Although there is little consensus in the literature on the benefit of using FDG PET in addition to PSMA PET, in a recently conducted comparison of the trial inclusion criteria for VISION and TheraP, the investigators concluded that performing PSMA PET/CT with a contrast-enhanced CT (as performed in the VISION trial) might be sufficient for determining treatment eligibility in patients with end-stage PC [51]. Furthermore, selecting patients for treatment with [¹⁷⁷Lu]Lu-PSMA-617 using just FDG PET alone has not been evaluated in clinical trials, as such there is a limited rationale for using FDG PET in this setting [2].

The open-label, randomized, phase III SPLASH trial (NCT04647526) is investigating the efficacy and safety of [¹⁷⁷Lu]Lu-PNT2002 RLT versus abiraterone/enzalutamide in patients with PSMA-positive mCRPC [48, 52]. Patients eligible for a single-arm lead-in cohort study had PSMA-positive disease identified by a central reader, had one or more prior ARPI treatments, were chemotherapy naïve for mCRPC, and had adequate bone marrow and end-organ reserve [48]. A total of 27 participants met all eligibility criteria and 19/27 (70.4%) completed all four planned cycles of [¹⁷⁷Lu]Lu-PNT2002 at 6.8 GBq (± 10%) intravenously per cycle every 8 weeks [48]. So far, preliminary data from the lead-in cohort suggest that [¹⁷⁷Lu]Lu-PNT2002 is associated with promising dosimetry, safety, and efficacy outcomes, with a median rPFS of 11.5 months (95% CI 9.2–19.1).

As different patient selection criteria were used across these pivotal clinical trials, there is still a need for further optimization of the selection criteria for routine clinical practice, in order to ensure the maximum number of patients can derive the optimum benefit from this treatment modality. In an effort to address this issue, the Society of Nuclear Medicine and Molecular Imaging (SNMMI) released a consensus statement in 2023 recommending that treating physicians should use the phase III VISION trial criteria (Fig. 2) for selecting patients for treatment with [¹⁷⁷Lu]Lu-PSMA-617, viewing them to be more likely to provide an OS and PFS benefit to a greater number of patients when compared with the phase II TheraP criteria [51, 53, 54]. The SNMMI group also recommended that, in addition to imaging with PSMA PET, patients should be imaged with conventional imaging (either contrast-enhanced CT or MRI) to help determine the presence of PSMA-negative disease, a particularly important consideration for patients who have known or suspected liver disease [53].

Fig. 2.

VISION trial patient selection criteria for [¹⁷⁷Lu]Lu-PSMA-617 therapy for patients with metastatic castration-resistant prostate cancer. This figure was originally published in the Journal of Nuclear Medicine. Kuo PH, Benson T, Messmann R, et al. Why We Did What We Did: PSMA PET/CT Selection Criteria for the VISION Trial. J Nucl Med. 2022;63(6):816–18.

© SNMMI. ¹⁷⁷Lu lutetium-177, CT computed tomography, MIP maximum-intensity projection, MRI magnetic resonance imaging, PSMA prostate-specific membrane antigen

PSMA PET Interpretation and Reporting

Prostate-specific membrane antigen PET scan images should be reviewed and evaluated by a nuclear medicine specialist or radiologist with specific expertise [28, 55], and PSMA ligand uptake should be assessed in the prostate gland/bed, regional and distant lymph nodes, bones, lungs, liver, and other organs [12]. Clinical interpretation is typically based on a visual analysis, with the addition of quantification based on relative PSMA-ligand concentrations using standardized uptake values as an optional adjunct [12]. Furthermore, PSMA PET scan reports should provide useful findings and impressions to answer clinically relevant questions, such as patient eligibility for PSMA-directed RLT (e.g., a patient may be suitable for [¹⁷⁷Lu]Lu-PSMA-617 treatment if their report showed alignment with the VISION trial eligibility criteria). This is an important consideration for physicians in countries where the majority of imaging is done with a combination of FDG PET and diagnostic CT, as patients in the VISION trial were deemed eligible for treatment based on PSMA PET and diagnostic CT [46, 54]. Significant differences regarding the use of [¹⁷⁷Lu]Lu-PSMA-617 RLT in clinical practice, including assessing eligibility and treatment response, have been reported in an international study, highlighting the need for dedicated training and evidence-based recommendations as theranostics is more widely adopted [56]. The study was distributed to theranostic centers involved in patient recruitment for the TheraP and VISION trials, the corresponding authors on clinical [¹⁷⁷Lu]Lu-PSMA-617 publications, and international contacts of the investigators; the study received responses from 95 theranostic centers (48 in Europe, 21 in the Americas, 21 in Asia, three in Oceania, and two in Africa) [56]. While there is no widely agreed consensus on the standardized reporting of PSMA PET results as of yet, a number of proposed frameworks for reporting and interpretation are available [9, 57–59]; these are discussed in the following paragraphs.

Interpreting physicians need to be appropriately trained to read PSMA PET imaging because differences in tracer urinary excretion, presence of non-specific uptake in bone tissue, and the potential expression of PSMA in non-prostate tumor neo-vasculature, benign lesions, and inflammatory conditions may impact the interpretation of PSMA PET imaging outputs [14, 31, 60–65]. Furthermore, training is also required to correctly interpret unexpected imaging findings, such as deviations from the typical metastatic spread of PC metastases, to avoid unnecessary biopsies of non-PC lesions [14, 66, 67].

Various different frameworks have been proposed which aim to assist interpreting different PSMA PET/CT parameters [9, 57–59]. The PSMA-Reporting and Data System (RADS) Standardized Reporting System version 1.0 framework is a framework that can be used for the categorization of lesions outside the prostate [58]. PROMISE has been developed as a standardized framework for the evaluation of PSMA PET using a tumor, node and metastasis frame and a molecular imaging expression score (Table 2). As PROMISE scoring is relative to the reference uptake by the liver, PSMA ligands with predominantly hepatic excretion (such as [¹⁸F]F-PSMA-1007) should be scored against uptake by the spleen instead of uptake by the liver [59, 68]. E-PSMA, the EANM’s standardized reporting guidelines version 1.0 for PSMA PET, provides consensus statements for standardized reporting of PSMA PET [9] and also includes a highly detailed template for reporting PSMA PET results [9, 58, 59].

Table 2.

miPSMA expression scores from Eiber et al. [59].

This research was originally published in the Journal of Nuclear Medicine. Eiber M, Herrmann K, Calais J, et al. Prostate cancer molecular imaging standardized evaluation (PROMISE): proposed molecular imaging tumor, node and metastasis classification for the interpretation of PSMA-ligand PET/CT. J Nucl Med. 2018;59(3):469–78© SNMMI

miPSMA score	Reported PSMA expression	PSMA radioligand uptake
0	No	Below the blood pool
1	Low	Equal to or above the blood pool and lower than the livera
2	Intermediate	Equal to or above the livera and lower than the parotid gland
3	High	Equal to or above the parotid gland

miPSMA molecular imaging prostate-specific membrane antigen, PSMA prostate-specific membrane antigen

^aFor PSMA ligands with liver-dominant secretion (e.g., [¹⁸F]F-PSMA1007), the spleen rather than the liver is recommended as the reference organ

As PSMA technology becomes more integrated into clinical practice, there is an increased need for easy-to-use, standardized PSMA PET/CT reporting templates or guidelines, to ensure the accurate exchange of information between healthcare professionals [69]. Key information should include a summary of any prior treatments, the location and extent of radiopharmaceutical uptake in the primary tumor, and any metastatic tumor(s) that may exist, whether there are any lesions without uptake, and any additional lesions found with positive uptake on PET/CT [69].

Assessment of Responses to Treatment

There is a need for well-defined progression criteria that can provide clear diagnostic information for patients and clinicians in everyday clinical practice and clinical trials [70, 71]. To date, two frameworks have been developed for the assessment of response to treatment. The Response Evaluation Criteria In PSMA-imaging version 1.0 (RECIP), which was proposed to evaluate [¹⁷⁷Lu]Lu-PSMA-617 treatment efficacy using [⁶⁸Ga]Ga-PSMA-11 PET for monitoring in mCRPC, employs the appearances of new PSMA-positive lesions and changes in total PSMA-positive tumor volume to evaluate the response to treatment [71]. These changes in total tumor volume were measured using a segmentation software for whole-body tumor quantification (quantitative RECIP) [72], yet adoption of tumor segmentation software into clinical practice is unlikely to be imminent.

A retrospective analysis found good correlation between quantitative RECIP and visual RECIP (i.e., RECIP that is determined visually by nuclear medicine physicians) for response evaluation, offering a more immediate alternative for implementation [72]. In addition, a retrospective multicenter analysis demonstrated that interim PSMA PET/CT performed after two cycles of [¹⁷⁷Lu]Lu-PSMA-617 and evaluated by RECIP was prognostic for PSA-PFS, helping to identify those patients who are likely to exhibit disease progression [73]. Thus, PSMA PET/CT by RECIP may offer a useful approach to evaluate treatment response in earlier stages of PC [73]. Furthermore, in a small retrospective single-center study of 20 patients with mCRPC patients treated with [¹⁷⁷Lu]Lu-PSMA-617, progression at the end of treatment assessed by RECIP 1.0 was found to be prognostic for OS [74]. However, large multicenter clinical trials are necessary to confirm these findings [74].

The second framework, the PSMA PET progression criteria, includes assessments of laboratory and clinical findings, along with recommendations for biopsy or correlative imaging [70]. In addition to this, a preliminary proposal on assessing PSMA PET response/progression from the Prostate Cancer Working Group 4 was published in September 2024 [75]. An expert committee of five experienced nuclear medicine specialists conducted an independent review of all available PSMA PET/CT scans from the open-label, single group assignment, phase I/II PRINCE trial (NCT03658447) [75], which examined the safety, tolerability, and efficacy of [¹⁷⁷Lu]Lu-PSMA-617 in combination with pembrolizumab for the treatment of mCRPC [76]. All PSMA PET/CT scans were conducted every 12 weeks, and were blinded to conventional response prior to measuring reporter agreement [75]. The investigators found that reporter agreement on PSMA PET/CT response was “substantial” and “almost perfect” for level of response and progression, respectively; investigators also found that the Prostate Cancer Working Group 4 criteria used in this analysis could detect disease progression earlier than the Prostate Cancer Working Group 3 criteria [75]. However, as only 36 patients with serial PSMA PET/CT and CT/bone scans could be analyzed, it is difficult to draw any firm conclusions and further validation work in a larger cohort is being undertaken [75].

The SNMMI group recommends that patient response to PSMA-targeted therapy should be monitored with a contrast-enhanced CT to owing to its value in identifying soft-tissue disease (especially if uptake is low on PSMA PET) [53]. The SNMMI also highlight the value of post-treatment imaging with gamma-cameras (either planar imaging or single-photon emission CT; SPECT) [53], as [¹⁷⁷Lu]Lu simultaneously emits two imageable gamma photons [77]. They recommend that planar imaging/SPECT should be used to visualize disease changes particularly with doses one and two of [¹⁷⁷Lu]Lu-PSMA-617 treatment, given that changes on post-treatment gamma-imaging have been shown to correlate with patient outcomes and may therefore inform the need for additional treatment [53]. Evidence for the use of ¹⁷⁷Lu SPECT/CT to evaluate treatment response alongside PSA for patients with mCRPC is growing [78, 79]. A recent retrospective clinical trial registry study and prospective study have found SPECT-derived total tumor volume to be predictive of PFS as early as 6 weeks after commencing ¹⁷⁷Lu-based RLT in patients with mCRPC, helping to identify when to cease or intensify treatment [79–81]. Furthermore, a recent study reported that the incorporation of a “treatment holiday” into the therapy regimen based on PSA response and ¹⁷⁷Lu SPECT/CT imaging led to an improvement in survival times compared with a fixed regimen of six cycles every 6 weeks [82]. New-generation whole-body SPECT/CT performed 1–2 hours after [¹⁷⁷Lu]Lu-PSMA-617 treatment has also shown potential as a promising method for assessing treatment response in patients with mCRPC; however, this approach is currently hindered by its suboptimal detection of small tumor lesions and the necessity of incorporating a third-cycle SPECT/CT [83]. Early treatment response assessment using ¹⁷⁷Lu SPECT/CT in combination with PSA has the potential to allow for personalization of therapy regimens; however, further studies with larger patient numbers are required to establish criteria that can be used to identify disease progression [84, 85].

Predicting and Monitoring Treatment Responses

Prostate-specific membrane antigen PET may also be utilized as a method for predicting treatment response in PSMA-targeted RLT and other treatment regimens for mCRPC. For instance, PSMA PET/CT has been shown to be predictive of treatment response 3 months after ARPI treatment initiation [86]. Several studies of PSMA RLT suggesting that low PSMA expression or the presence of liver metastases on PSMA-ligand PET/CT imaging are associated with poor survival [87–89].

Re-imaging after RLT may reveal distinct patterns of progression, such as those occurring in previously identified sites of PSMA expression, new [¹⁸F]F-FDG–positive/low PSMA expression sites, or new sites of high PSMA expression [90]; PSMA PET standardized uptake parameters at screening have been shown to predict a ≥30% PSA reduction with [¹⁷⁷Lu]Lu-PSMA-617 treatment [90]. The findings of other clinical trials support the utility of PSMA for predicting and monitoring treatment response [91, 92]. For instance, in one subgroup analysis of the VISION trial, investigators showed that prolonged rPFS and better OS outcomes were associated with a greater decline in PSA from baseline in patients with mCRPC treated with [¹⁷⁷Lu]Lu-PSMA-617 plus standard of care. This suggests that PSA levels could act as a marker of responses to treatment with [¹⁷⁷Lu]Lu-PSMA-617 [91]. Another substudy analysis of the VISION trial evaluating the association between quantitative PSMA imaging parameters and treatment outcomes found that a higher whole body mean standardized uptake value was significantly associated with improved rPFS and OS outcomes in [¹⁷⁷Lu]Lu-PSMA-617-treated patients, suggesting that PSMA PET could help physicians identify which patients are most likely to benefit from PSMA-directed RLT [92, 93].

Currently, clinical guidelines exist for disease staging but there is no specific guidance on how to use PSMA PET to assess response to treatment. In order to enable clearer guidance to be offered, more data may be needed on the predictive value of PSMA PET. It is worth noting that PSMA-positive tumor volume has been shown to be superior to the maximum standard uptake value for assessing response in patients with mCRPC receiving taxane-based chemotherapy [86, 94]. Moreover, assessments that combine serum PSA and PSMA PET responses may improve treatment response evaluations in patients with mCRPC treated with novel hormonal agents [95]. It is important to consider that combining PSMA PET with conventional imaging is still necessary to detect the potential emergence of PSMA-negative disease.

Practical Considerations for the Implementation of PSMA PET

As with the introduction of any new treatment modality, effective implementation of PSMA PET into clinical practice requires careful deliberation around practical considerations concerning equipment, staffing requirements, training, administration, and radiation safety. Furthermore, it is imperative that nuclear medicine examinations are conducted by appropriately qualified physicians certified in nuclear medicine, in accordance with local regulations [55].

Whenever possible, requests for PSMA PET scans should be accompanied by a detailed summary of the patient’s history, including diagnosis, risk group, and oncological history (particularly of prior therapies) [12]; regions that may relate to any symptoms or pathology should also be noted on the referral form. PSMA PET/CT scans should use uptake times as close to 60 min as possible (Table 3). Furthermore, they should be carried out before the initiation of new androgen deprivation therapy, as newly administered androgen deprivation therapy is associated with a decreased PSMA-ligand uptake, possibly because of tumor reduction [12]. Finally, it is important to note that some institutional protocols may differ from the prescribing information, for example, by allowing longer uptake times of using different techniques to reduce urinary bladder activity.

Table 3.

Protocol factors for approved PSMA positron emission tomography tracers [12]

Item	[68Ga]Ga-PSMA-11	[18F]F-DCFPyL	[18F]F-rhPSMA-7.3	[18F]F-PSMA-1007a
Administered activity	111–259 MBq (3–7 mCi)	296–370 MBq (8–10 mCi)	210–280 MBq (3–4 MBq/kg body mass)	296 MBq (8 mCi)
Uptake time	60 min (acceptable range: 50–100 min)	60 min	90–120 min	60 min

MBq megabecquerel, mCi millicurie, PSMA prostate-specific membrane antigen

^aApproved for commercial use in France only

Patient Considerations

Prostate-specific membrane antigen PET with [⁶⁸Ga]Ga- and [¹⁸F]F-labeled radiotracers have been shown to be very well tolerated and have a generally favorable safety profile [96, 97]. Patients are advised to stay well hydrated and urinate frequently in order to clear the radiation from the body, despite the relatively short half-lives of the radiotracers not necessitating major radiation safety precautions [12]. Before requesting a PSMA PET scan, the rationale for the procedure, risk–benefit profiles, and any potential adverse events need to be discussed with the patient, their family, and their caregivers. Adaptations may also be required to facilitate adherence to radiation safety practices, particularly if patients are experiencing PC-associated comorbidities such as urinary incontinence [98].

Financial Impact

In countries where medical costs are covered by an individual or insurance companies, the financial implications of additional PSMA PET testing should be discussed with the patient and their family. This is primarily because the detrimental effects of financial strain caused by unexpected healthcare costs can negatively affect the patient’s well-being [99]. Variability in insurance coverage is primarily driven by inconsistencies between private insurance coverage plans, despite the US Medicare and Medicaid services approving reimbursement of [⁶⁸Ga]Ga-PSMA-11 in July 2021 [100].

Accessibility of Treatment

Racial disparities in PC outcomes become notably reduced when all individuals have equal access to healthcare [2]. However, disparities in access to PSMA PET versus [¹⁸F]F-fluciclovine PET have been reported from a retrospective analysis of patients with biochemically recurrent PC enrolled in clinical studies at a single tertiary center in the USA [101]. Compared with non-Hispanic White patients, Black/African American, or Asian American patients had lower access to both [¹⁸F]F and [⁶⁸Ga]Ga PSMA PET imaging (by a factor of 3.88) and a lower rate of PSMA PET (by 33%), respectively [101, 102]. The investigators commented that the exact causes of this disparity were unclear [101]; factors contributing to such disparities are multifactorial and may include financial burdens because of the costs of radiotracers or technical fees, and complex tertiary- or quaternary-care pathways for imaging referrals [103]. These financial factors may disproportionately impact Black/African American patients; when assessing neighborhood socioeconomic status, Black/African American patients comprised the highest percentage of patients in the lowest tertile and the lowest percentage of patients in the highest tertile [101].

There are also potential concerns that financial reimbursement for PSMA PET imaging is significantly less than the costs incurred, which may serve as a disincentive for many hospitals and imaging facilities to utilize PSMA PET imaging [104]. These concerns would particularly affect hospital-based outpatients. Though some larger hospitals may be able to absorb these associated costs without passing them on to patients/insurers, many smaller community hospitals do not have such budgets and so may be unable to offer PSMA PET imaging, resulting in inequity. Resolving this payment imbalance would ensure that patients can access PSMA PET imaging regardless of where they live in the USA. In May 2024, the Facilitating Innovative Nuclear Diagnostics (FIND) Act (H.R 1199/S.1544) was passed by the US House of Representatives Committee on Energy and Commerce [105, 106]. The FIND Act aimed to address the imbalance in PSMA PET reimbursement by establishing updated payment requirements for diagnostic radiopharmaceuticals [105, 106], thus helping to ensure that all patients receive access to medically appropriate imaging tests, ultimately improving their clinical outcomes. In November 2024, the Centers for Medicare & Medicaid Services updated the Nuclear Medicine Reimbursement Policy to extend access to diagnostic radiopharmaceuticals (effective from 1 January, 2025) [107]. As a result of this new policy, the Centers for Medicare & Medicaid Services will now unbundle and pay separately for diagnostic radiopharmaceuticals with daily costs exceeding $630, thus removing a financial obstacle that may have hindered patient access to nuclear medicine diagnostic procedures in the past [107].

Perspectives on PSMA PET: Expert Insights

Best Practice Recommendations from the Radiographic Assessments for Detection of Advanced Recurrence (RADAR) Group

Prostate-specific membrane antigen PET has been shown to offer superior sensitivity and specificity relative to conventional imaging (CT and bone scans) at an early disease stage (primary staging and BCR); however, no randomized controlled trial data exist on PSMA PET for patients with advanced castration-resistant prostate cancer. The rapid pace of advancement in PET imaging has outpaced clinical trials, resulting in a dearth of trial-derived data that can assist in treatment decision making [108]. As such, for restaging of advanced PC, the role of PSMA PET is not fully defined, and it remains uncertain how data from clinical trials based on conventional imaging staging can be used [85]. Because of this paucity of data, there is a demand for consensus-driven recommendations that can assist clinicians with selecting treatment options for patients. Since 2014, the RADAR group has met regularly to provide consensus recommendations on key questions on imaging in PC, for example, how best to facilitate the early detection and management of metastases [108, 109]. The group convened in 2021 to formulate a set of practical suggestions (RADAR VI) for healthcare professionals treating PC, based on the key question “What is the goal of imaging in each different group of patients”? Their recommendations, summarized below (Table 4), provide practical guidance regarding the timing and frequency of radioligand imaging along various points of the PC patient journey, and largely mirrored those of the NCCN Guidelines^® and SNMMI guidelines [108].

Table 4.

RADAR VI recommendations and observations to facilitate appropriate use of radioligand imaging in patients with mCRPC [108]

Patient population	RADAR group recommendations and observations
Newly diagnosed PC	Unfavorable intermediate-risk, high-risk, or very high-risk patients with PC ± conventional imaging (for all patients, negative conventional imaging should not be considered a prerequisite for radioligand imaging) Inconclusive prior conventional imaging in which there is a high clinical suspicion of metastatic or locoregional disease or risk of nodal metastasis (validated by a nomogram) Patients who have an elevated molecular marker (Decipher/Oncotype DX/Prolaris) score Patient populations with genomically/diverse high risk
Imaging-discordance (conventional imaging–/radioligand imaging+) newly diagnosed mCRPC	Radioligand imaging is redefining advanced/metastatic prostate cancer People with positive radioligand imaging results represent a wide spectrum of disease and heterogeneity Clinicians have a number of therapeutic agents/interventions available; most approvals are based on conventional imaging Earlier therapeutic approaches tend to improve survival and outcomes. Radioligand imaging offers an opportunity to implement MDT
BCR	For patients whom metastasis-directed therapy may be considered, radioligand imaging is preferred over conventional imaging Early and accurate identification of sites of disease can lead to more anatomically directed therapy Optimizing outcomes can be facilitated by early detection of the site(s) of recurrent disease
M0 CRPC	Radioligand imaging is recommended for people with PSA progression while on ADT for BCR if MDT is a potential option. Otherwise, conventional imaging can be performed to verify M0 status Patients whose disease is detectable only by radioligand imaging and not by conventional imaging should generally be treated as M0 CRPC because this approach is the most consistent with available level 1 evidence Role of radioligand imaging while on therapy for M0 CRPC For patients on systemic therapy for M0 CRPC who had radioligand imaging as baseline imaging for their M0 CRPC:  Imaging should be repeated at least annually and at the time of PSA recurrence. No PSA cutoff for repeat imaging, as yet, because radioligand imaging can be positive even at low PSA levels For patients treated with local therapy for M0 CRPC who had radioligand imaging as baseline imaging for their M0 CRPC:  TPI may be repeated within 4–6 months to document the response to therapy and assess for new metastases and then repeated annually as above
M1 CRPC	For disease detection For initial staging, radioligand imaging is recommended for staging of M1 CRPC if it is likely to affect clinical decisions For treatment eligibility Based on the phase III VISION and TheraP trials:  PSMA PET imaging can be used for treatment selection for PSMA-targeted therapies [18F]F-FDG/[18F]F-fluciclovine imaging can be obtained in patients with treatment-refractory M1 CRPC to inform subsequent treatment strategies For treatment monitoring At present, response criteria are lacking for TPI. TPI should not be used alone to make decisions regarding treatment discontinuation in the context of M1 CRPC

ADT androgen deprivation therapy, BCR biochemical recurrence, CRPC castration-resistant prostate cancer, mCRPC metastatic CRPC, MDT metastasis-directed therapy, PC prostate cancer, PSA prostate-specific antigen, PET positron emission tomography, PSMA prostate-specific membrane antigen, TPI targeted precision imaging

The RADAR group then convened again in 2022 (RADAR VII) to develop recommendations for the application of radioligand imaging results in patients with localized PC, BCR, and non-metastatic castration-resistant PC. Here, their focus was on the clinical question “How should molecular targeted imaging (i.e., PSMA PET) results influence management decisions?” [109] If the PSMA PET and conventional imaging results were discordant in this setting, they recommend treating according to biopsy results [109]. If a biopsy is not possible (e.g., because of risks associated with the biopsy location), they recommend obtaining additional imaging results (for patients with equivocal or unifocal disease) or proceeding with mCRPC (if they have oligometastatic or disseminated disease) treatment algorithms [109]. Their recommendations were similar for patients with BCR or non-metastatic castration-resistant prostate cancer; where conventional imaging and PSMA PET results were concordant, they recommended treating the patient as having BCR or non-metastatic castration-resistant prostate cancer (as appropriate) [109]. In the case of discordant PSMA PET and conventional imaging results, they recommend treatment based on results from an additional biopsy; in the case of patients with equivocal disease, additional imaging should be sought if a biopsy is unavailable, and in unifocal, oligometastatic, and disseminated disease, they recommend that patients are treated as if they have metastatic disease if a biopsy is unavailable [109].

Selecting Patients for [¹⁷⁷Lu]Lu-PSMA-617 Therapy

To date, there have been three significant, randomized, prospective clinical trials that have evaluated [¹⁷⁷Lu]Lu-PSMA-617 treatment in patients with mCRPC: VISION, TheraP, and PSMAfore [45, 46, 110]. As discussed earlier, the results from these trials have been used to develop patient selection criteria for treatment with [¹⁷⁷Lu]Lu-PSMA-617 (Fig. 2) [54]. However, there has been some discussion around which trial criteria should be used as a benchmark for selecting patient eligibility for this treatment. To try to address this issue, the SNMMI released a consensus statement in 2023 recommending that treating physicians should use the phase III VISION trial criteria for selecting patients for treatment with [¹⁷⁷Lu]Lu-PSMA-617, viewing them to be more likely to provide an OS and PFS benefit to a greater number of patients when compared with the phase II TheraP criteria [51, 53, 54]. The SNMMI group also recommended that, in addition to imaging with PSMA PET, patients should be imaged with conventional imaging (either contrast-enhanced CT or MRI) to help determine the presence of PSMA-negative disease, a particularly important consideration for patients who have known or suspected liver disease [53].

Predicting/Prognosticating Treatment Response

Prostate-specific membrane antigen-targeted therapies such as [¹⁷⁷Lu]Lu-PSMA-617 are a relatively new addition to the available treatments for healthcare physicians caring for patients with mCRPC. However, there is a dearth of clinically validated biomarkers for the prediction of treatment response to [¹⁷⁷Lu]Lu-PSMA-617 [111], and while the prognosis of patients with mCRPC is poor, there is still a need for prognostic biomarkers that can accurately inform on disease outcomes for patients with this heterogeneous disease. Biomarkers may be based on information gleaned from a variety of big-data sources, including genomics, proteomics, and radiomics. Artificial intelligence algorithms can then rapidly process these numerous inputs to provide an output that leads to actionable opportunities regarding disease behavior [78]. Several clinical (e.g., visceral metastases, lactate dehydrogenase levels, neutrophil-to-lymphocyte ratio), molecular (e.g., androgen receptor copy number, circulating tumor DNA levels), and PET imaging factors (e.g., mean standardized uptake value, PSMA-positive tumor volume) have been identified as promising candidates for prognostic and predictive biomarkers in this setting [111], and there is a considerable amount of ongoing research that aims to elucidate their prognostic and predictive value.

While it is not within the scope of this article to describe this ever-evolving field in detail, we encourage the reader to read the recently published review on prognostic and predictive biomarkers for the treatment of mCRPC using [¹⁷⁷Lu]Lu-PSMA-617 by Giunta et al. [111], and to regularly review congress abstracts that report data on this exciting field. In one recent trial of particular interest, investigators assessed the prognostic value of locoregional lymph node metastases, distant metastases, tumor volume, and mean standardized uptake values in 1612 patients with PC across all disease stages, and compared them against head-to-head clinical risk scores [112]. They found their nomograms were accurate for early and late stages of PC, and that their prediction of OS was superior to currently used clinical risk tools [112]. In another recent trial examining 115 patients with mCRPC treated with [¹⁷⁷Lu]Lu-PSMA-617, CDK12, MYC, and FGFR gene alterations were associated with a lower incidence of PSA reduction >50% from baseline levels [113]. Another noteworthy trial proposed using a quantitative and visual PSMA PET tumor-to-salivary gland uptake ratio (PSG score) as a biomarker to predict patient response to [¹⁷⁷Lu]Lu-PSMA-617 [114]. Across a population of 237 patients with mCRPC, a high PSG score was associated with a significantly better PSA response and OS following [¹⁷⁷Lu]Lu-PSMA-617 therapy [114].These three studies are examples of the plethora of research currently investigating predictive and prognostic biomarkers in mCRPC, and serve to show us that important breakthroughs are continually being made (and are yet to be made) in this setting. Research is also ongoing in the context of [¹⁷⁷Lu]Lu-PSMA-617 interventions in earlier disease settings [111]. This continued research is vitally important, given that accurate prediction and prognoses will help to further improve patient outcomes.

Conclusions

Prostate-specific membrane antigen PET has rapidly become the preferred imaging modality for PC staging and disease monitoring. Data continue to support its use at different stages of PC, including mCRPC, while evolving clinical knowledge and the availability of new tracers and RLTs drive the need for improved understanding and utilization of this tool. Radioligand agents, including [¹⁸F]F-DCFPyL, [¹⁸F]F-rhPSMA-7.3, and [⁶⁸Ga]Ga-PSMA-11, can currently be used for PET imaging of PSMA-positive lesions in PC. In this review, we focused on PSMA PET to determine eligibility for PSMA-targeted RLTs such as [¹⁷⁷Lu]Lu-PSMA-617, which is indicated for patients with PSMA-positive mCRPC that have been previously treated with ARPIs, and are considered appropriate to delay taxane-based chemotherapy or have received prior taxane-based chemotherapy. We have identified key gaps in the evidence base and guidance around the use of PSMA PET, including expanding the available evidence to support its impact on management and patient outcome, and a lack of standardization in imaging criteria and read paradigms between clinical trials and real-world clinical practice. Overall, PSMA PET is a promising and evolving tool for diagnosis in earlier stages of PC, and for selecting eligible patients for PSMA-directed RLT. However, more prospective data with long-term follow-up are required to clearly delineate its role in the management of patients with metastatic disease.

Supplementary Information

Below is the link to the electronic supplementary material.

Declarations

Funding

Open access funding provided by SCELC, Statewide California Electronic Library Consortium.This article was funded by Novartis Pharmaceuticals Corporation. Medical writing and editorial support was provided by Greg Rowe, MSc, and Laura McArdle, BA, of Spark (a division of Prime, New York, NY, USA) and was funded by Novartis Pharmaceuticals Corporation.

Conflicts of Interest/Competing Interests

Phillip H. Kuo received honoraria from Attralus, Blue Earth Diagnostics, dGenThera, Eli Lilly, General Electric Healthcare, Invicro, Novartis, and Telix Pharmaceuticals, research grants for his institution from Blue Earth Diagnostics and General Electric Healthcare, consulting fees from Attralus, Blue Earth Diagnostics, Chimerix, dGenThera, Eli Lilly, Fusion Pharma, General Electric Healthcare, Invicro, Life Molecular Imaging, Navidea, Novartis, Radionetics, Telix Pharmaceuticals, and United Imaging, support for attending meetings/travel from Blue Earth Diagnostics, Eli Lilly, General Electric Healthcare, Invicro, Novartis, and Telix Pharmaceuticals, served on an advisory board for dGenThera, has a patent planned/issued/pending (Patent No. US 10,013,743 B2), received equipment/materials/drugs/medical writing services/gifts/other services from Blue Earth Diagnostics, General Electric Healthcare, and Novartis, and holds a leadership/fiduciary role at the Society of Nuclear Medicine and Molecular Imaging and the International Accreditation Council. Jeremie Calais received honoraria from Amgen, Astellas, Bayer, Blue Earth Diagnostics, Curium Pharma, DS Pharma, Fibrogen, GE Healthcare, Isoray, IBA RadioPharma, Janssen Pharmaceuticals, Lightpoint Medical, Lantheus/Progenics/EXINI, Monrol, Novartis/Advanced Accelerator Applications, Pfizer, POINT Biopharma, Radiomedix, Sanofi, Siemens/Varian, SOFIE, and Telix Pharmaceuticals and research grants for his institution from Lantheus/Progenics/EXINI, Novartis/Advanced Accelerator Applications, and POINT Biopharma. Mike Crosby received honoraria from Pfizer and Johnson & Johnson and served on an advisory board/steering committee for Telix Pharmaceuticals, Novartis, and Johnson & Johnson.

Ethics Approval

Not applicable.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Availability of Data and Material

The data supporting the conclusion of this study have been included within the article.

Code Availability

Not applicable.

Authors’ Contributions

All authors discussed and conceived the idea for this article together. Literature searches and data analyses were performed by Spark, under the direction of Novartis Pharmaceuticals and the authors. All authors contributed to the drafting and critical review of this manuscript, and all authors read and approved the final manuscript.