An In-Depth Review of Flotufolastat F-18 (Posluma®): Pharmacology, Clinical Efficacy, and Positioning in PSMA-PET Imaging for Prostate Cancer

Compound Profile and Physicochemical Characteristics

Identification and Nomenclature

Flotufolastat F-18 is a small molecule radiopharmaceutical diagnostic agent that has been developed for advanced imaging of prostate cancer.[1] To provide a comprehensive reference, it is essential to collate its various identifiers used in clinical, regulatory, and research contexts. In the clinical setting, it is marketed under the brand name Posluma®.[1] Its non-proprietary or generic name is Flotufolastat F-18, where the "(18F)" or "F 18" suffix specifies the use of the radioactive isotope fluorine-18.[1]

During its development, the compound was widely known by the code 18F-rhPSMA-7.3, a designation that reflects its novel radiohybrid (rh) molecular structure and its position within a series of developmental compounds targeting the Prostate-Specific Membrane Antigen (PSMA).[2] Other synonyms and codes used in various databases and literature include flotufolastatum (18F), rhPSMA-7.3C, and the United States Adopted Name (USAN) designation flotufolastat F18.[3]

For unambiguous identification across global scientific and regulatory databases, the compound is assigned several unique codes. These are summarized in Table 1, providing a centralized reference for researchers and clinicians. The Anatomical Therapeutic Chemical (ATC) classification code, V09IX18, formally categorizes Flotufolastat F-18 within the class of "Other diagnostic radiopharmaceuticals for tumour detection," situating it within the broader pharmacopeia of oncologic imaging agents.[3]

Chemical Structure and Properties

Flotufolastat F-18 is a complex conjugate molecule with a multi-component structure meticulously designed to optimize its function as a targeted imaging agent.[1] It is classified as a (18)F radiopharmaceutical, a crown amine, an organosiloxane, a member of benzamides, and a secondary carboxamide.[5] The empirical molecular formula for the compound is $C_{63}H_{99}FN_{12}O_{25}Si$, and it has a molecular weight of approximately 1470.6 g/mol.[5]

The molecular architecture of Flotufolastat F-18 is the foundation of its "radiohybrid" designation and can be deconstructed into several key functional moieties. These include:

1. A high-affinity PSMA-binding motif, which is responsible for selectively targeting the molecule to prostate cancer cells.[11]
2. A sophisticated peptide spacer, which optimally positions the binding motif and the radiolabeling group for effective interaction with the target and subsequent imaging.[11]
3. A chelator complex, specifically 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), in this case as DOTAGA, which is complexed with non-radioactive gallium in the final formulation.[11]
4. A novel silicon-fluoride acceptor (SiFA) moiety, to which the radioactive fluorine-18 isotope is covalently bound, providing the positron-emitting signal for Positron Emission Tomography (PET) imaging.[11]

This intricate structure is not merely an assembly of parts but a highly engineered platform. The inclusion of both a DOTA-based chelator, typically used for binding metallic radioisotopes, and a SiFA group for fluorine-18 is a deliberate and strategic design choice.[13] While a standard PET agent is typically designed for a single type of radioisotope—for instance, PSMA-11 for Gallium-68 or DCFPyL for Fluorine-18—the radiohybrid technology of Flotufolastat F-18 endows it with dual-labeling potential. The DOTAGA chelator is capable of binding not only diagnostic metallic isotopes but also therapeutic alpha- and beta-emitting radionuclides, such as Lutetium-177 ($^{177}Lu$) or Actinium-225 ($^{225}Ac$).[13]

This dual-capability platform is the cornerstone of a theranostic paradigm, an approach in medicine that combines specific targeted therapy based on specific targeted diagnostic tests. The development of Flotufolastat F-18 represents the diagnostic arm of this broader strategic platform. The underlying rhPSMA ligand technology enables a "see what you treat, treat what you see" approach. Clinicians can first use Flotufolastat F-18 PET to visualize the extent and location of PSMA-positive disease, and subsequently, the same targeting molecule, labeled with a therapeutic isotope, could be used to deliver targeted radiation to those very same sites. This positions the rhPSMA family of compounds as a potential end-to-end solution for prostate cancer management, with profound implications for the future of personalized medicine, patient selection for radioligand therapy, and the design of next-generation clinical trials.

Table 1: Key Identifiers and Physicochemical Properties of Flotufolastat F-18

Identifier Type	Value(s)	Source(s)
Brand Name	Posluma®	1
Generic Name	Flotufolastat F-18	1
Developmental Code	18F-rhPSMA-7.3	2
DrugBank ID	DB17851	2
CAS Number	2639294-14-5	2
UNII	811W19E3OL	2
ATC Code	V09IX18	3
Molecular Formula	$C_{63}H_{99}FN_{12}O_{25}Si$	8
Molecular Weight	1470.6 g/mol	5
Monoisotopic Mass	1469.662296 Da	5

Mechanism of Action and Clinical Pharmacology

Molecular Target and Binding Affinity

The clinical utility of Flotufolastat F-18 is predicated on its highly specific interaction with its molecular target, the Prostate-Specific Membrane Antigen (PSMA).[16] PSMA, also known by its formal name Glutamate carboxypeptidase 2 (gene name: FOLH1), is a type II transmembrane glycoprotein that functions as a folate hydrolase and a neuropeptidase.[1] Its expression is relatively low in most normal tissues but is significantly upregulated, often by a factor of 100 to 1000, on the surface of prostate adenocarcinoma cells.[13] This dramatic overexpression makes PSMA an exceptional biomarker and an ideal target for both diagnostic imaging and targeted therapy in prostate cancer.[17]

Flotufolastat F-18 is designed to bind with high affinity and specificity to the extracellular domain of the PSMA protein.[13] Quantitative binding assays have determined its half-maximal inhibitory concentration ($IC_{50}$) to be 4.4 nM, a value that indicates very potent and tight binding to its target.[1] This high-affinity interaction is crucial for ensuring that the radiopharmaceutical accumulates preferentially in tumor tissue over background tissues, which is a prerequisite for generating high-contrast diagnostic images.

Following the initial binding event at the cell surface, the entire Flotufolastat F-18/PSMA complex is actively internalized into the prostate cancer cell.[13] This internalization process serves as a critical trapping mechanism. By sequestering the radiolabeled agent inside the cell, it prevents its rapid washout and leads to a sustained accumulation of the radioactive signal within the tumor. This retention is a key factor in enhancing the signal-to-noise ratio and enabling the clear visualization of PSMA-positive lesions, even small ones, during the PET scan.[16]

Radiopharmaceutical Action

Flotufolastat F-18 functions as a radioactive diagnostic agent by virtue of the fluorine-18 ($^{18}F$) radionuclide covalently attached to its structure.[5] Fluorine-18 is a positron-emitting isotope, meaning it undergoes radioactive decay by releasing a positron ($ß^{+}$), the antimatter counterpart of an electron.[19]

The fundamental principle of PET imaging relies on this decay process. Once administered to the patient, Flotufolastat F-18 circulates and accumulates in PSMA-expressing tissues. The emitted positrons travel a very short distance within the tissue (typically less than a millimeter) before they encounter and annihilate with an electron. This annihilation event converts the mass of both particles into energy in the form of two high-energy (511 keV) gamma photons, which are emitted in nearly opposite directions (180 degrees apart).[16] A ring of detectors in the PET scanner is designed to detect these pairs of coincident photons. By analyzing the timing and location of millions of these detection events, a computer algorithm can reconstruct a three-dimensional map of the radionuclide's distribution within the body.[16] The resulting PET image provides a quantitative and highly sensitive visualization of metabolic or molecular activity, in this case, highlighting regions of high PSMA expression that correspond to primary and metastatic prostate cancer lesions.[17]

Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of Flotufolastat F-18 is a critical determinant of its imaging performance and has been characterized in detail.

Absorption and Administration: The agent is administered exclusively via intravenous (IV) bolus injection, ensuring immediate and complete (100%) bioavailability into the systemic circulation.[2]

Distribution: Following IV administration, Flotufolastat F-18 is rapidly distributed throughout the body via the bloodstream. Biodistribution studies have quantified its uptake in major organs at early time points, showing accumulation in the liver (15.8% of the administered activity), the heart blood pool (7.4%), and the kidneys (3.2%).[1] The agent is progressively cleared from the blood, allowing for a decrease in background signal over time, which enhances the visibility of tumor-specific uptake.[1]

Metabolism: A key feature of Flotufolastat F-18 is its high metabolic stability. Pharmacokinetic studies have shown that the compound does not undergo any significant metabolism for up to 50 minutes following injection.[1] This stability is highly advantageous for a diagnostic agent, as it ensures that the signal detected by the PET scanner originates from the intact parent compound specifically bound to PSMA. This prevents the potential for radioactive metabolites to distribute non-specifically throughout the body, which could otherwise create confounding background signals and degrade image quality.

Excretion: The primary route of elimination for Flotufolastat F-18 is renal, with the agent being excreted in the urine.[1] Approximately 7% of the administered radioactive dose is excreted in the urine within the first 2 hours post-injection, increasing to approximately 15% by 4.5 hours.[1]

The favorable pharmacokinetic profile of Flotufolastat F-18 is not accidental but rather the result of a deliberate and sophisticated drug design strategy. Multiple sources emphasize that Flotufolastat F-18, which is a specific, single diastereoisomer of the parent compound 18F-rhPSMA-7, exhibits faster clearance from the blood pool, liver, and kidneys compared to its other diastereoisomers, while maintaining high tumor accumulation.[1] This demonstrates that subtle variations in the three-dimensional stereochemical structure of the molecule have a profound impact on its interaction with the body's clearance mechanisms, without compromising its high-affinity binding to the PSMA target.

This optimized pharmacokinetic behavior directly translates into superior imaging characteristics. Faster clearance from blood and background organs like the liver and kidneys leads to a lower background signal, thereby increasing the tumor-to-background ratio and making cancerous lesions more conspicuous. Furthermore, Flotufolastat F-18 is characterized by relatively low urinary excretion compared to other PSMA-PET agents.[20] This is a distinct clinical advantage, as high concentrations of radioactivity in the urinary bladder and ureters can create significant "shine-through" artifacts on PET images. Such artifacts can obscure the view of adjacent structures in the pelvis, particularly the prostate bed (the site of potential local recurrence after surgery) and pelvic lymph nodes. By generating a "quieter" bladder signal, Flotufolastat F-18 provides a clearer, less obstructed view of these critical regions. This selection of a single, pharmacokinetically superior diastereoisomer showcases a drug development process that has successfully fine-tuned the molecule to solve a known clinical imaging challenge, thereby enhancing its overall diagnostic utility.

Clinical Efficacy in Newly Diagnosed Prostate Cancer: The LIGHTHOUSE Trial

The pivotal evidence supporting the use of Flotufolastat F-18 for the initial staging of prostate cancer comes from the Phase 3 LIGHTHOUSE study. This trial was designed to rigorously evaluate the diagnostic performance of the agent in a clinically relevant patient population where accurate staging is critical for determining the appropriate course of treatment.

Study Design and Patient Population

The LIGHTHOUSE trial (NCT04186819) was a prospective, multicenter, single-arm, open-label imaging study conducted to assess the safety and efficacy of Flotufolastat F-18 PET/CT.[2] The study enrolled 356 men with newly diagnosed, biopsy-proven prostate cancer.[24] The inclusion criteria specifically targeted a high-risk population, enrolling patients with unfavorable intermediate-risk, high-risk, or very high-risk disease.[25]

A critical element of the trial's design was the requirement that all enrolled patients were candidates for, and were scheduled to undergo, a standard-of-care radical prostatectomy with pelvic lymph node dissection (PLND).[14] This design is particularly robust because it allows for a direct comparison of the findings from the PET imaging with the definitive "gold standard" of histopathology obtained from the surgical specimens. This enables a precise calculation of the agent's sensitivity and specificity for detecting metastatic disease.

The imaging protocol was standardized across all study sites. Patients received a single intravenous dose of 296 MBq (8 mCi) of Flotufolastat F-18, and PET/CT imaging was performed 50 to 70 minutes after the injection.[24] The resulting images were then evaluated by three independent, blinded central readers to minimize bias in interpretation.[24]

Efficacy Endpoints and Results: Pelvic Lymph Node (PLN) Detection

The primary objective of the LIGHTHOUSE trial was to assess the diagnostic performance of Flotufolastat F-18 PET in detecting prostate cancer metastases within the pelvic lymph nodes.[14] This was evaluated through the co-primary endpoints of sensitivity and specificity, with histopathology serving as the standard of truth.

Specificity: The study successfully achieved its co-primary endpoint for specificity. Across the three blinded readers, the specificity for detecting pelvic lymph node metastases ranged from 93% to 97%.[13] These results comfortably exceeded the pre-specified statistical success threshold of 82.5%, demonstrating a very high ability of the agent to correctly identify patients who do not have macroscopic nodal disease.[14]

Sensitivity: The trial did not meet its pre-specified statistical threshold for the co-primary endpoint of sensitivity, which was set at 22.5%.[14] The observed sensitivity across the three readers ranged from 23% to 30%.[25]

While the failure to meet the sensitivity endpoint might be perceived as a limitation, a nuanced clinical interpretation is required. The low sensitivity reflects a well-understood limitation inherent to all current medical imaging technologies, including state-of-the-art PSMA-PET. Histopathology is capable of detecting micrometastases, which can consist of single cancer cells or microscopic cell clusters far below the spatial resolution limit of a PET scanner (typically 4–5 mm).[26] Consequently, it is expected that any imaging modality will "miss" some pathologically positive lymph nodes that contain only microscopic disease.

Conversely, the high specificity of 93% to 97% is of immense clinical value. Specificity represents the true negative rate, meaning that if a Flotufolastat F-18 scan is negative for pelvic lymph node involvement, there is a very high probability (93% to 97%) that the patient is truly free of significant, macroscopic nodal metastases. This high negative predictive value provides strong reassurance to clinicians. For a surgeon planning a curative-intent radical prostatectomy, a negative scan supports the assessment that the disease is likely confined to the prostate, reinforcing the decision to proceed with surgery. On the other hand, a positive scan, given the high specificity, strongly suggests the presence of metastatic disease. Such a finding could fundamentally alter the treatment plan, potentially shifting the patient away from a non-curative surgery towards systemic therapies or extended-field radiation, thereby sparing them the morbidity of an ineffective operation. Therefore, the results of LIGHTHOUSE position Flotufolastat F-18 not as a replacement for surgical staging, but as a powerful, non-invasive tool to refine risk stratification and guide more personalized treatment decisions.

Table 2: Summary of Efficacy Results from the Phase 3 LIGHTHOUSE Trial (Pelvic Lymph Node Detection)

Endpoint (vs. Histopathology)	Reader 1	Reader 2	Reader 3	Majority Read
Specificity (%)	97%	93%	95%	96%
(95% CI)	(93.7, 98.8)	(88.8, 95.9)	(91.0, 97.5)	(92.3, 98.1)
Sensitivity (%)	23%	30%	28%	28%
(95% CI)	(14.2, 34.0)	(19.9, 42.6)	(17.9, 40.4)	(17.9, 40.4)
Positive Predictive Value (%)	70%	57%	62%	62%
Negative Predictive Value (%)	81%	81%	80%	80%
Data derived from analyses of 296 patients with sufficient histopathology data.13

Detection of Distant Metastases (M1 Disease)

Beyond pelvic staging, a crucial role for PSMA-PET is the detection of distant metastases (M1 disease) at the time of initial diagnosis. The presence of M1 disease upstages the cancer and typically precludes curative local therapy. In the LIGHTHOUSE trial, Flotufolastat F-18 PET identified suspected M1 lesions in 16% to 28% of patients, depending on the reader.[24] The verified detection rate for M1 disease, confirmed by a composite standard of truth, was between 8.1% and 13%.[27] Overall, approximately 1 in 10 patients in this high-risk cohort was found to have at least one verified distant metastatic lesion that was not detected by conventional imaging.[26] This finding is highly impactful, as it directly alters patient management by identifying individuals who require systemic therapy from the outset.

Inter- and Intra-Reader Reliability

For any diagnostic imaging biomarker to be clinically useful, its interpretation must be consistent and reproducible. The LIGHTHOUSE study demonstrated a high degree of reliability for Flotufolastat F-18 PET imaging. The analysis of reader agreement showed that pairwise inter-reader agreement was 95% or greater, and intra-reader agreement (the same reader evaluating the same scan at two different times) was 96% or greater.[14] This high level of reproducibility indicates that the interpretation of Posluma scans is robust and consistent across different physicians, which is a critical attribute for supporting its widespread adoption into clinical practice.

Clinical Efficacy in Recurrent Prostate Cancer: The SPOTLIGHT Trial

The management of patients with biochemical recurrence (BCR) of prostate cancer following initial definitive therapy represents a significant clinical challenge. The SPOTLIGHT trial was the pivotal study designed to evaluate the efficacy of Flotufolastat F-18 in this specific and critical setting.

Study Design and Patient Population

The SPOTLIGHT trial (NCT04186845) was a Phase 3, prospective, multicenter, single-arm, open-label imaging study.[2] The study enrolled a cohort of 389 men who had suspected recurrence of prostate cancer after undergoing prior definitive treatments such as radical prostatectomy or radiation therapy.[21] The key inclusion criterion was the presence of BCR, which is defined by a persistently rising serum prostate-specific antigen (PSA) level from a post-treatment nadir.[21]

The patient population in SPOTLIGHT was representative of a clinically challenging scenario, with a low median baseline PSA of 1.1 ng/mL.[21] At such low PSA levels, conventional imaging modalities like CT and bone scintigraphy are notoriously insensitive and often fail to localize the site of recurrence. The trial was therefore designed to assess whether Flotufolastat F-18 PET could accurately detect and localize disease in this "low-PSA" setting, where early and precise detection can have a major impact on subsequent treatment decisions.

Detection Rates and Diagnostic Performance

The SPOTLIGHT trial demonstrated the high diagnostic performance of Flotufolastat F-18 in detecting recurrent prostate cancer.

Detection Rate (DR): The overall patient-level detection rate, defined as the proportion of patients with at least one PET-positive lesion, was 83% according to the majority read of three blinded readers.[21]

Verified Detection Rate (VDR): The primary endpoint of the study was the VDR, which requires that PET-positive findings be confirmed by a standard of truth (either histopathology from biopsy/surgery or confirmatory follow-up imaging). The overall VDR for Flotufolastat F-18 was 57%.[21] It is noteworthy that in the subset of patients where the more rigorous standard of histopathology was available, the VDR was substantially higher at 81%.[21]

Performance at Low PSA Levels: A key strength of Flotufolastat F-18 highlighted by the SPOTLIGHT results is its robust performance even at very low PSA concentrations, an area of significant unmet clinical need. The detection rate was directly correlated with PSA levels but remained clinically meaningful even in the lowest strata, as shown in Table 3. In the cohort of patients with a PSA less than 1.0 ng/mL, 68% had a positive scan.[21] Even in the challenging group with PSA levels below 0.5 ng/mL, 64% of patients had a positive scan, and critically, 21% of these patients were found to have extrapelvic metastatic disease.[21] The detection rate rose steadily with PSA, reaching 100% in patients with a PSA level of 10 ng/mL or higher.[21]

Performance by Other Clinical Factors: The diagnostic performance of Flotufolastat F-18 was shown to be consistently high across other important prognostic indicators. Exploratory analyses demonstrated that detection rates were uniformly high regardless of the patient's pre-treatment Gleason Grade Group or the PSA doubling time (PSAdt), supporting the agent's broad clinical utility across a diverse spectrum of patients with recurrent disease.[21]

Table 3: Summary of Detection Rates from the Phase 3 SPOTLIGHT Trial, Stratified by Baseline PSA

Baseline PSA Level (ng/mL)	Patient-Level Detection Rate (DR) (%)	Patients with Extrapelvic Lesions (%)
< 0.2	33%	N/A
< 0.5	64%	21%
< 1.0	68%	27%
≥ 10.0	100%	66%
Data derived from analyses of 389 patients in the evaluable scan population.21

Impact on Patient Management

The ultimate value of a diagnostic test lies in its ability to influence clinical decision-making and improve patient care. A sub-study within the SPOTLIGHT trial involving 97 patients specifically evaluated the impact of the Flotufolastat F-18 PET scan on intended patient management plans. The results were striking: the scan findings led to a change in the planned clinical management for 89% of the patients.[29]

A "major change" in management was recorded for 80% of these patients. These changes were bidirectional and driven by the precise information provided by the scan. For instance, patients with a negative scan, providing reassurance of no detectable disease, had their management changed from active salvage therapy to a more conservative "watchful waiting" approach. Conversely, and perhaps more critically, patients who were planned for localized salvage therapy (e.g., radiation to the prostate bed) but were found to have previously undetected distant metastases on the PET scan had their management appropriately escalated to systemic therapy.[29]

These findings illustrate a paradigm shift in the management of biochemical recurrence. Historically, clinicians often had to resort to "blind" salvage radiation to the prostate bed in the absence of definitive localization by conventional imaging. The ability of Flotufolastat F-18 to accurately identify the location and extent of disease at low PSA levels transforms this approach from a probabilistic one to a precise, image-guided strategy. It enables clinicians to deliver the right treatment to the right targets at the right time. Patients with truly localized recurrence can receive targeted salvage therapies with curative intent, while those with occult metastatic disease can be spared the toxicity and cost of futile local treatments and be promptly started on more appropriate systemic therapies, potentially leading to improved long-term outcomes.

Performance in Specific Subpopulations

The SPOTLIGHT trial also provided valuable data on the performance of Flotufolastat F-18 in specific patient subgroups.

African American Men: Given the higher incidence, aggressiveness, and mortality of prostate cancer in African American men, ensuring the efficacy of new diagnostic tools in this population is crucial. A post-hoc analysis of the 61 African American participants in SPOTLIGHT revealed a high patient-level detection rate of 93%, which was numerically higher than the 87% rate observed in all other participants combined. The verified detection rate was also higher in this subgroup (64% vs. 55%).[33] These findings are significant as they support the broad applicability and robust performance of Flotufolastat F-18 in this high-risk population.

Bone Metastases: The detection of bone metastases is a critical component of staging. An analysis of bone lesion detection in the SPOTLIGHT trial showed an overall positive predictive value (PPV) of 73%.[34] While this demonstrates good performance, it also indicates that false-positive findings can occur, as benign bone conditions such as fibrous dysplasia can sometimes exhibit PSMA uptake. This result underscores the importance of careful, multidisciplinary image interpretation, where PET findings are always correlated with the anatomical information from the corresponding CT or MRI scan and considered within the patient's overall clinical context.[34]

Safety, Tolerability, and Radiation Dosimetry

The clinical development program for Flotufolastat F-18 has established a favorable safety profile, and its radiation dosimetry characteristics are well-defined, ensuring its safe use in the intended patient population.

Clinical Safety Profile

Across the pivotal clinical trials, which included data from over 747 patients receiving a single administration of the agent, Flotufolastat F-18 was demonstrated to be well-tolerated.[19] The incidence of treatment-emergent adverse events (AEs) considered potentially related to the drug was very low.

The most commonly reported adverse reactions were mild and transient in nature. These included:

• Diarrhea (reported in 0.7% of patients)
• An increase in blood pressure (0.5%)
• Injection site pain (0.4%).[2]

In the LIGHTHOUSE study, no serious adverse events were attributed to the administration of Flotufolastat F-18.[27] The overall safety data indicate that the agent poses a minimal risk of acute side effects to patients undergoing the diagnostic procedure.

Radiation Dosimetry and Patient Exposure

As with any radiopharmaceutical, the administration of Flotufolastat F-18 results in radiation exposure to the patient. The radiation dose has been carefully calculated to be as low as reasonably achievable while maintaining high image quality.

For a standard recommended administration of 296 MBq (8 mCi) of Flotufolastat F-18, the calculated effective radiation dose to the patient is 4.1 mSv.[12] This is a modest level of radiation exposure, comparable to that from other common nuclear medicine procedures and equivalent to approximately 1-2 years of natural background radiation in many parts of the world. While any radiation exposure carries a theoretical long-term risk of cancer, this level is considered acceptable and appropriate for the significant diagnostic benefit provided by the scan.[13]

The distribution of the radiopharmaceutical determines which organs receive the highest absorbed radiation doses. For Flotufolastat F-18, the critical organs (those receiving the highest dose) are the adrenal glands (54.3 mGy), the kidneys (51 mGy), and the submandibular glands (43.8 mGy).[12] This pattern of uptake is consistent with the known biodistribution of PSMA-targeting ligands. The detailed dosimetry data, as summarized in Table 4, provides essential information for medical physicists and nuclear medicine physicians to ensure radiation safety and for counseling patients about the risks and benefits of the procedure.

Table 4: Estimated Absorbed Radiation Doses in Adult Patients from Flotufolastat F-18

Organ	Mean Absorbed Dose (mGy/MBq)
Adrenal glands	0.183
Brain	0.007
Gallbladder wall	0.019
Lower large intestine wall	0.010
Small intestine	0.014
Stomach wall	0.010
Upper large intestine wall	0.012
Heart wall	0.011
Kidneys	0.172
Liver	0.047
Lungs	0.007
Pancreas	0.016
Red marrow	0.015
Salivary glands (Submandibular)	0.148
Spleen	0.038
Testes	0.008
Thymus	0.008
Thyroid	0.007
Urinary bladder wall	0.036
Total Body	0.011
Effective Dose (mSv/MBq)	0.014
Data adapted from the official prescribing information.12 The effective dose for a standard 296 MBq administration is 4.1 mSv.

Radiation Safety and Handling

The safe use of Flotufolastat F-18 requires adherence to standard radiation safety protocols for both the patient and healthcare personnel.

Patient Recommendations: To minimize the radiation dose, particularly to the urinary bladder, patients are instructed to be well-hydrated before the injection and to continue drinking fluids and voiding frequently for the first few hours after the scan.[13] Urinating immediately prior to image acquisition is also recommended to reduce signal from the bladder that could interfere with image interpretation.[12]

Handling Precautions: Flotufolastat F-18 is a radioactive drug and must be handled only by personnel qualified and licensed to handle radioactive materials. To minimize radiation exposure to healthcare workers during preparation and administration, appropriate safety measures are mandatory. These include the use of waterproof gloves and effective radiation shielding, such as lead-lined syringe shields.[18] The high-energy 511 keV gamma photons emitted as a result of fluorine-18 decay require substantial lead shielding for effective attenuation.[19]

Regulatory Status and Prescribing Information

U.S. Food and Drug Administration (FDA) Approval

Flotufolastat F-18, under the brand name Posluma, received marketing approval from the U.S. Food and Drug Administration (FDA) on May 25, 2023.[1] This approval marked the introduction of the first radiohybrid PSMA-targeted PET imaging agent to the U.S. market.[4]

The FDA-approved indications for Flotufolastat F-18 are for positron emission tomography (PET) of PSMA-positive lesions in men with prostate cancer in two distinct clinical scenarios:

1. Initial Staging: For patients with suspected metastasis who are candidates for initial definitive therapy.[1]
2. Biochemical Recurrence: For patients with suspected recurrence based on an elevated serum prostate-specific antigen (PSA) level following prior therapy.[1]

These indications are directly supported by the efficacy and safety data from the pivotal LIGHTHOUSE and SPOTLIGHT trials, respectively.

European Regulatory Landscape

It is critically important to clarify the regulatory status of Flotufolastat F-18 in Europe, as there is significant potential for confusion with another similar agent. As of the latest available information, Flotufolastat F-18 (Posluma) is not approved for marketing or clinical use in the European Union.[15]

The confusion arises because the European Medicines Agency (EMA) did grant marketing authorization in July 2023 to a different F-18 labeled PSMA-PET agent, which is marketed in the EU under the brand name Pylclari®.[43] The active substance in Pylclari is piflufolastat (18F).[44] Piflufolastat F-18 is the same active ingredient that is sold in the United States under the brand name Pylarify®.[46]

Therefore, clinicians, researchers, and patients must clearly distinguish between these two separate products. While both are F-18 labeled PSMA-PET agents, only Piflufolastat (18F) (Pylclari) is approved by the EMA. The clinical trial data and prescribing information for Flotufolastat F-18 (Posluma) are applicable only within jurisdictions where it has received regulatory approval, such as the United States.

Dosing and Administration

The recommended dosage and administration protocol for Flotufolastat F-18 is clearly defined in the prescribing information.

Recommended Dose: The recommended amount of radioactivity for an adult patient is 296 MBq (8 mCi), administered as a single, slow intravenous bolus injection.[12] The maximum recommended volume for an undiluted injection is 5 mL.[39]

Image Acquisition: For optimal imaging, the PET scan should be initiated approximately 60 minutes after the injection (the protocol for the pivotal trials was 50-70 minutes).[12] The patient should void immediately before being positioned on the scanner. The scan acquisition should cover the anatomical region from the mid-thigh to the base of the skull to ensure all common sites of prostate cancer metastasis are evaluated.[18]

Warnings and Precautions

The official prescribing information includes important warnings and precautions that clinicians must consider to ensure the safe and effective use of Flotufolastat F-18.

Image Interpretation Errors: The most significant warning relates to the risk of image misinterpretation. It is emphasized that PET imaging with Flotufolastat F-18 is not perfectly sensitive or specific. A negative scan does not definitively rule out the presence of prostate cancer, and a positive scan does not unequivocally confirm it.[1] Flotufolastat F-18 uptake is not specific to prostate cancer and can occur in other types of cancer as well as in various non-malignant inflammatory and benign processes.[36] Therefore, clinical correlation is essential, and multidisciplinary consultation and/or histopathological confirmation are strongly recommended when major clinical decisions hinge on borderline or equivocal PET findings.[13]

Drug Interactions: A key potential for drug interaction involves therapies that target the androgen pathway. Androgen deprivation therapy (ADT) and androgen receptor antagonists (e.g., enzalutamide, bicalutamide) are known to modulate the expression of PSMA on prostate cancer cells. This can result in changes in the uptake of Flotufolastat F-18, potentially affecting the intensity of the signal on the PET scan.[13] The precise effect of these therapies on the diagnostic performance of Flotufolastat F-18 PET has not been formally established, and this potential interaction should be considered when interpreting scan results.[18]

Comparative Analysis and Clinical Positioning

The approval of Flotufolastat F-18 introduced another option into the growing landscape of PSMA-targeted PET imaging agents. Its clinical positioning is best understood through a comparative analysis with the other established agents, primarily Gallium-68 ($^{68}Ga$)-labeled ligands and the other FDA-approved Fluorine-18 ($^{18}F$)-labeled agent, Piflufolastat F-18.

Comparison with $^{68}$Ga-labeled PSMA Ligands (e.g., Ga-68 PSMA-11)

Isotope Physics and Logistics: The fundamental difference lies in the radioisotope used. Fluorine-18 has a longer physical half-life of approximately 110 minutes, compared to about 68 minutes for Gallium-68.[5] This longer half-life has significant logistical advantages. It allows for centralized production in a cyclotron, manufacturing in larger batches, and subsequent distribution to imaging centers that may be hours away. This "hub-and-spoke" model can improve patient access and scheduling flexibility. In contrast, Ga-68 is typically produced on-site from a portable generator, which offers convenience for a single institution but is less scalable for widespread distribution.[22]

Image Quality: The physics of positron decay also favor F-18 for image quality. F-18 emits positrons with lower energy, resulting in a shorter travel distance (positron range) in tissue before annihilation. This shorter range translates directly to higher intrinsic spatial resolution and the potential for sharper, more clearly defined images compared to Ga-68.[14] Some studies have also suggested that F-18 labeled agents may produce higher Standardized Uptake Values (SUVs) in tumor lesions, which can aid in lesion conspicuity and interpretation.[22]

Comparison with Piflufolastat F-18 (Pylarify®)

As both Flotufolastat F-18 and Piflufolastat F-18 utilize the same F-18 isotope, they share the logistical and image resolution advantages over Ga-68 agents. They also have similar FDA-approved indications for initial staging and biochemical recurrence. However, a critical distinction emerges from their differing molecular structures and resulting pharmacokinetic profiles.

The Key Differentiator: Urinary Excretion: The most significant and clinically relevant distinguishing feature of Flotufolastat F-18 is its demonstrably lower rate of urinary excretion and consequently, reduced accumulation of radioactivity in the urinary bladder when compared to other renally-cleared PSMA-PET agents like Piflufolastat F-18.[20]

This difference in urinary clearance is not a minor technical point; it has direct implications for clinical practice. A major challenge in PET imaging of the male pelvis is the intense radioactive signal that accumulates in the urinary bladder. This high signal can create significant "halo" or "shine-through" artifacts that can obscure or mask the visualization of adjacent anatomical structures. The structures most affected are the prostate bed—the primary site of local recurrence after a radical prostatectomy—and the pelvic lymph nodes.

An agent like Flotufolastat F-18, which results in a "quieter" or less intense bladder signal, provides a clearer, unobstructed view of these critical regions. This can be the deciding factor in detecting a small, early, and potentially curable local recurrence that might otherwise be missed. This unique pharmacokinetic profile carves out a specific clinical niche where Flotufolastat F-18 may be the preferred imaging agent: the evaluation of patients with biochemical recurrence following radical prostatectomy. While its performance is likely comparable to other PSMA-PET agents for staging distant disease, its distinct advantage in the pelvic region represents a powerful differentiator for guiding crucial salvage therapy decisions in the post-surgical setting. The initiation of a head-to-head, intra-patient comparative trial (NCT06604442) specifically designed to quantify this difference in urinary radioactivity versus Piflufolastat F-18 indicates a clear strategic effort to generate high-level evidence to solidify this specific use case and establish a claim of superiority in this important clinical scenario.[49]

Table 5: Comparative Profile of FDA-Approved PSMA-PET Radiopharmaceuticals

Attribute	Ga-68 PSMA-11 (e.g., Illuccix®)	Piflufolastat F-18 (Pylarify®)	Flotufolastat F-18 (Posluma®)
Radioisotope	Gallium-68 ($^{68}Ga$)	Fluorine-18 ($^{18}F$)	Fluorine-18 ($^{18}F$)
Half-Life	~68 minutes	~110 minutes	~110 minutes
Production	On-site generator	Centralized cyclotron	Centralized cyclotron
Image Resolution	Good	Very Good (shorter positron range)	Very Good (shorter positron range)
Urinary Excretion	High	High	Low to Medium
Key Clinical Advantage	Generator-based accessibility	Logistical flexibility, high resolution	Low urinary activity improving pelvic visualization, high resolution
Information synthesized from sources.5

Future Directions and Ongoing Research

The approval of Flotufolastat F-18 is a significant milestone, but research continues to further define its role, optimize its use, and explore the full potential of its underlying radiohybrid technology.

Current Clinical Trials

Several ongoing and recruiting clinical trials are designed to expand the evidence base for Flotufolastat F-18 and investigate its utility in additional clinical contexts. Key studies include:

• NCT06604442: A completed Phase 4 study that performed a direct, intra-patient comparison of urinary radioactivity between Flotufolastat F-18 and Piflufolastat F-18 in men with low-PSA biochemical recurrence. This trial aims to provide definitive evidence for the lower urinary excretion profile of Flotufolastat F-18.[49]
• NCT07115277: A recruiting study focused on further evaluating the diagnostic efficacy and safety of Flotufolastat F-18 in the setting of biochemical recurrence.[51]
• NCT07185165: An active Phase 2 trial investigating the effectiveness of Flotufolastat F-18 PET/CT for detecting residual or recurrent disease in the challenging patient population that has undergone focal therapy (such as cryotherapy or HIFU) for prostate cancer.[9]
• A previously planned pilot study (NCT05707182) intended to explore its role in patients on active surveillance was withdrawn before enrollment, but this remains an area of potential future investigation.[53]

Theranostic Potential

The most compelling future direction for the technology underlying Flotufolastat F-18 lies in the field of theranostics. The radiohybrid (rh) PSMA platform was engineered from its inception with this dual purpose in mind.[13] The same core ligand that is labeled with F-18 for diagnostic PET imaging can be readily labeled with therapeutic radionuclides, such as the beta-emitter Lutetium-177 ($^{177}Lu$) or the more potent alpha-emitter Actinium-225 ($^{225}Ac$).[13]

This capability paves the way for a complete diagnostic-therapeutic ecosystem that represents a pinnacle of personalized medicine in oncology. In this paradigm, a patient with advanced prostate cancer would first undergo a diagnostic scan with Flotufolastat F-18 PET. This scan would serve multiple purposes:

1. It would confirm that the patient's tumors express the PSMA target, identifying them as a suitable candidate for PSMA-targeted therapy.
2. It would precisely map the location and extent of all PSMA-positive disease throughout the body.
3. The quantitative data from the PET scan could be used for dosimetry calculations, helping to predict the radiation dose that would be delivered to both tumors and healthy organs during therapy, thereby personalizing the treatment dose.

Following this diagnostic workup, the same patient could then be treated with the exact same targeting molecule, but this time labeled with a therapeutic isotope like $^{177}Lu$. This "image and treat" approach ensures that therapy is directed only to patients who are most likely to benefit, and it allows for a highly precise correlation between the diagnostic image and the subsequent therapeutic response. The commercialization of Flotufolastat F-18 is likely the first public step in a broader corporate strategy to develop and launch a companion therapeutic agent, creating a proprietary and powerful diagnostic-therapeutic pair that could significantly impact the management of prostate cancer, from initial diagnosis through to late-stage, metastatic disease.

Conclusion

Flotufolastat F-18 (Posluma®) is a highly effective, next-generation PSMA-targeted radiopharmaceutical for the diagnostic imaging of prostate cancer. Its approval by the U.S. FDA was based on robust data from the pivotal LIGHTHOUSE and SPOTLIGHT trials, which demonstrated its high specificity for initial staging in high-risk patients and its high detection rate in patients with biochemical recurrence, even at very low PSA levels. The agent is well-tolerated, with a favorable safety profile and a modest patient radiation dose.

While sharing the logistical and image-resolution advantages of other F-18 labeled agents, Flotufolastat F-18 distinguishes itself through a unique and clinically significant pharmacokinetic profile characterized by lower urinary excretion. This property enhances visualization of the prostate bed and pelvic lymph nodes, carving out a specific clinical niche where it may be the preferred agent, particularly for guiding salvage therapy decisions in post-prostatectomy patients.

Beyond its immediate diagnostic utility, the radiohybrid technology underlying Flotufolastat F-18 holds immense promise for the future of prostate cancer care. Its design as a theranostic platform, capable of being labeled with both diagnostic and therapeutic isotopes, positions it as a key component of a personalized medicine strategy that seamlessly integrates diagnosis, patient selection, and targeted radioligand therapy. As ongoing research further refines its clinical applications and explores its therapeutic potential, Flotufolastat F-18 and the rhPSMA platform are poised to play an increasingly integral role in the multidisciplinary management of prostate cancer.

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