Elevating PSMA-Targeted Radioligand Therapy: Introducing New Lutetium-177 EB-PSMA-617 Option

Summary: The emergence of Lutetium-177 EB-PSMA-617, a China-developed analogue of the well-established PSMA-617 radioligand, marks an intriguing development in the domain of molecular targeted therapy for metastatic castration-resistant prostate cancer (mCRPC). By incorporating a truncated Evans Blue (EB) molecule and employing a DOTA chelator, ¹⁷⁷Lu-EB-PSMA-617 seeks to optimise tumour retention and biodistribution. Although considered a “me-too” agent in relation to the more advanced ¹⁷⁷Lu-Vipivotide tetraxetan, early clinical findings have demonstrated a promising safety and tolerability profile. Evaluated through carefully designed Phase I/II trials, this radiopharmaceutical targets the same patient population as its Western counterparts, offering an alternative therapeutic approach. With further investigation, ¹⁷⁷Lu-EB-PSMA-617 could contribute to refining personalised nuclear medicine strategies, enhancing patient outcomes, and adding to the rapidly evolving field of radioligand therapy.

Keywords: Metastatic castration-resistant prostate cancer; PSMA-targeted therapy; ¹⁷⁷Lu-EB-PSMA-617; Radioligand therapy; Evans Blue conjugation; Nuclear medicine innovation.

Introduction to Prostate Cancer

Prostate cancer remains a formidable health challenge, representing one of the most common malignancies among men worldwide. Treatment options, ranging from radical prostatectomy to systemic therapies, have improved patient survival and quality of life, yet the landscape remains complex. As patients progress to castration-resistant stages, limited durable options pose clinical dilemmas, stimulating ongoing research into precision therapeutics. Radioligand therapy (RLT), particularly those targeting the prostate-specific membrane antigen (PSMA), has emerged as a potent strategy. By delivering targeted radionuclides that bind selectively to PSMA-expressing cancer cells, clinicians can offer a more personalised, minimally invasive, and effective treatment, even in advanced stages.

One of the established players in this domain is ¹⁷⁷Lu-PSMA-617, also known as 177Lu-Vipivotide tetraxetan, which has garnered global attention. Its impressive track record paved the way for the development of variants and analogues seeking to refine its pharmacokinetics and tumour-targeting capabilities. Among these, Lutetium-177 EB-PSMA-617 has emerged as a noteworthy contender. Developed in China, it adopts a similar mechanism and target population as ¹⁷⁷Lu-Vipivotide tetraxetan. Its inclusion of a truncated Evans Blue (EB) molecule is hypothesised to enhance tumour retention, potentially prolonging the therapeutic window. Now explored in Phase I/II trials, this “me-too” product may add to the toolbox of therapeutic radiopharmaceuticals and deepen our understanding of PSMA-targeted therapies.

Background on PSMA-Targeted Therapies in Prostate Cancer

Prostate-specific membrane antigen (PSMA) is a transmembrane protein that is abundantly expressed on the surface of prostate epithelial cells, with expression levels significantly elevated in prostate cancer cells, particularly in advanced and metastatic disease. This makes PSMA an attractive target for diagnostic imaging and RLT. Over the last decade, significant progress has been made in leveraging PSMA-binding ligands radiolabelled with isotopes such as gallium-68 for positron emission tomography (PET) imaging, and lutetium-177 for therapy.

With the clinical introduction and subsequent approvals of ¹⁷⁷Lu-Vipivotide tetraxetan, patients experiencing mCRPC who have progressed after multiple lines of standard therapy have found renewed hope. Encouraging survival benefits, tolerable side-effect profiles, and improved quality of life have been reported, further validating PSMA-targeted therapies. The quest now is to refine and improve upon these gains, potentially enhancing tumour retention, optimising dosing regimens, and ultimately producing superior outcomes.

Development of Lutetium-177 EB-PSMA-617

Lutetium-177 EB-PSMA-617 was conceived as an analogue to the successful PSMA-617 radioligand. PSMA-617 consists of a PSMA-binding motif conjugated to a chelator for lutetium-177. In the case of ¹⁷⁷Lu-EB-PSMA-617, researchers in China sought to introduce a truncated Evans Blue (EB) moiety into the structure. Evans Blue is a dye known for its albumin-binding properties; by incorporating a truncated version of this molecule, the aim is to leverage albumin-binding and increase the circulation time of the radioligand in the bloodstream. Extended circulation could theoretically allow more ligand molecules to interact with tumour tissues, thereby improving the radioligand’s tumour-to-background ratio and prolonging its residence in malignant lesions.

In parallel, the DOTA chelator ensures stable complexation with lutetium-177, providing a reliable platform for delivering beta-electron radiation directly to tumour cells. The synergy of PSMA-targeting, albumin-binding properties of truncated EB, and a robust chelation system is the central innovation behind ¹⁷⁷Lu-EB-PSMA-617.

Mechanism of Action

The therapeutic mechanism of Lutetium-177 EB-PSMA-617 begins with the targeting of PSMA, a membrane protein heavily overexpressed on prostate cancer cells. When administered intravenously, the radiopharmaceutical travels through the body and preferentially binds to PSMA-expressing tumour cells. The truncated EB moiety, by interacting with serum albumin, aims to increase the ligand’s plasma half-life. This prolonged circulation time can increase the accumulation of the radioligand in tumour sites, potentially improving the absorbed radiation dose delivered to the cancer cells over time.

Following cellular internalisation of the PSMA-ligand complex, the conjugated lutetium-177 emits beta particles (β– radiation). These particles induce DNA double-strand breaks and other forms of lethal cellular damage within the tumour. As the emission range of β– particles is relatively short (a few millimetres), the collateral damage to surrounding healthy tissues is minimised. The net effect is targeted radiation delivery, effectively destroying malignant cells while preserving normal tissues as much as possible.

Clinical Trials and Results

In 2018, the first Phase I clinical study evaluating Lutetium-177 EB-PSMA-617 was completed. Patient selection was guided by ⁶⁸Ga-PSMA-617 PET imaging, ensuring that only those with significant PSMA expression and therefore the highest likelihood of benefit were enrolled. This imaging-based selection strategy aligns with the growing trend in personalised oncology, where molecular profiling and diagnostic imaging guide therapy choices.

The Phase I study primarily aimed to assess safety, tolerability, and optimal dosing. Preliminary findings indicated that ¹⁷⁷Lu-EB-PSMA-617 had a safety and tolerability profile similar to that of ¹⁷⁷Lu-Vipivotide tetraxetan. Patients experienced manageable side effects, commonly mild-to-moderate in severity. These might have included fatigue, mild thrombocytopenia, or transient liver enzyme elevations, all of which are anticipated and manageable within the area of radioligand therapies. Encouragingly, no unexpected or severe toxicities emerged that would preclude further clinical evaluation.

Beyond safety endpoints, early data suggested that the radioligand localised effectively within PSMA-positive lesions. Although the Phase I study was not designed to draw definitive conclusions on efficacy, the signals of potential anti-tumour activity justified the transition into Phase II trials, where investigators aim to determine clinical benefit, progression-free survival, and ultimately overall survival outcomes.

Comparison with ¹⁷⁷Lu-Vipivotide tetraxetan

¹⁷⁷Lu-Vipivotide tetraxetan (formerly known as ¹⁷⁷Lu-PSMA-617) represents the gold standard against which novel PSMA-targeted ligands are measured. Having undergone extensive evaluation in multiple clinical trials, ¹⁷⁷Lu-Vipivotide tetraxetan is now a recognised therapy for mCRPC. In this context, ¹⁷⁷Lu-EB-PSMA-617 must be considered a “me-too” agent, meaning it targets the same patient population and employs a similar approach.

Where the novel agent attempts to differentiate itself is through the EB conjugation, which may alter pharmacokinetics and tumour retention. Whether these modifications translate into superior therapeutic indices or improved patient outcomes remains to be conclusively proven. Early clinical data show comparable safety profiles, and while it is encouraging that no added toxicity burden has been found, the field now looks to efficacy endpoints. If Lutetium-177 EB-PSMA-617 can demonstrate enhanced tumour uptake, prolonged retention, or improved lesion response rates, it may carve out a meaningful niche. Conversely, if its performance mirrors that of ¹⁷⁷Lu-Vipivotide tetraxetan without surpassing it in meaningful ways, its role might remain as an alternative for settings where the established therapy is not available or accessible.

Advantages and Limitations

Advantages:

• Potential for improved tumour uptake and retention: The inclusion of truncated EB within the molecular structure may allow for prolonged circulation time and potentially better tumour accumulation. This, in theory, could improve the therapeutic window and possibly enhance therapeutic efficacy.
• Stable and well-known chelator system (DOTA): The use of the DOTA chelator ensures stable complexation with lutetium-177, reducing the risk of free radionuclide release, which could cause off-target radiation.
• Established targeting mechanism (PSMA): By relying on PSMA, a well-validated target, Lutetium-177 EB-PSMA-617 circumvents the need to identify and validate new tumour markers. Clinicians are already familiar with PSMA-targeted strategies, facilitating integration into current treatment protocols.
• Similar safety profile to ¹⁷⁷Lu-Vipivotide tetraxetan: Early clinical findings indicate that adding EB to the structure has not introduced new toxicities. This builds physician confidence and lowers barriers to clinical adoption, should the agent prove efficacious.

Limitations:

• “Me-too” status: ¹⁷⁷Lu-EB-PSMA-617 enters a field where ¹⁷⁷Lu-Vipivotide tetraxetan is already established and proven. For it to secure a role, it must demonstrate meaningful advantages. Without clear superiority, it may be viewed as redundant.
• Limited data: While Phase I data look promising, robust efficacy data are still lacking. Until Phase II or III trials are completed, clinicians and patients must remain cautious about expecting superior outcomes.
• Dependence on proper patient selection: As with all PSMA-targeted therapies, patient selection based on imaging and receptor expression is critical. Those with low PSMA expression might not experience the same benefits, limiting the agent’s utility.
• Economic and accessibility considerations: Should ¹⁷⁷Lu-Vipivotide tetraxetan remain widely available and cost-effective, the incentive to adopt an alternative may be reduced unless Lutetium-177 EB-PSMA-617 can provide a distinctive clinical edge.

Future Perspectives

The introduction of Lutetium-177 EB-PSMA-617 exemplifies the spirit of innovation and refinement driving modern nuclear medicine. The future of this radiopharmaceutical will hinge on several factors:

• Results from Ongoing Phase II Trials: Robust data demonstrating improved objective response rates, prolonged progression-free survival, or even survival benefits over ¹⁷⁷Lu-Vipivotide tetraxetan would mark a crucial turning point. These trials will also ascertain whether the pharmacokinetic modifications introduced by truncated EB indeed confer a clinical advantage.
• Combination Strategies: In the evolving treatment landscape of mCRPC, monotherapy approaches may be just one piece of a larger puzzle. Combining radioligand therapy with androgen receptor signalling inhibitors, chemotherapy, PARP inhibitors, or immunotherapy might amplify anti-tumour effects. Exploring combinations that incorporate ¹⁷⁷Lu-EB-PSMA-617 could reveal synergistic effects, opening doors to treatment intensification for patients with aggressive disease.
• Personalised Dosimetry and Imaging Advances: Improvements in imaging and dosimetry could refine how ¹⁷⁷Lu-EB-PSMA-617 is administered. Patient-specific dosimetry ensures that patients receive an optimal radiation dose, balancing efficacy with toxicity. Imaging biomarkers, including next-generation PSMA PET tracers, might better identify which patients will derive the greatest benefit from ¹⁷⁷Lu-EB-PSMA-617 therapy.
• International Collaboration and Harmonisation: By examining how different regions integrate this therapy, valuable insights can be gained. Collaboration between Chinese researchers and international colleagues will ensure that if ¹⁷⁷Lu-EB-PSMA-617 proves beneficial, it can be adopted widely and responsibly. Benchmarking its performance against established standards will clarify its place in the global treatment algorithm.
• Long-Term Toxicity and Survivorship Data: Understanding the long-term safety profile, late toxicities, and impact on patients’ quality of life will be essential for establishing Lutetium-177 EB-PSMA-617 as a standard therapy. Extended follow-up studies, registries, and real-world data collection will contribute to a complete understanding of its role in managing mCRPC.

Broader Context in Radioligand Therapy

The development and investigation of ¹⁷⁷Lu-EB-PSMA-617 occur within a broader context of expanding radioligand therapy applications. Various tumour types expressing molecular targets are now being considered for similar treatments, including neuroendocrine tumours (NETs) treated with ¹⁷⁷Lu-DOTATATE, and potentially other solid tumours, should suitable targets and ligands be identified. Lessons learned from the refinement of PSMA-targeted therapies, including EB-based modifications, may guide the development of new ligands for different targets.

Furthermore, the increasing availability of novel radionuclides—each with unique physical properties—adds another layer of complexity and opportunity. Auger electron emitters, alpha particles, and other radionuclides with distinctive radiation ranges and energies could be combined with improved ligands to enhance specificity and potency. In that regard, Lutetium-177 EB-PSMA-617 is part of a vanguard pushing the boundaries of what is possible in targeted radiotherapy.

Implications for Patients and Clinicians

For patients living with mCRPC, treatments like ¹⁷⁷Lu-EB-PSMA-617 represent hope. Traditional options often yield diminishing returns, leading many to consider experimental therapies. For clinicians, new agents expand the therapeutic toolkit, allowing for more nuanced and patient-tailored strategies. However, clinicians must remain judicious, carefully weighing potential benefits against uncertainties. Until larger and more definitive trials complete, the drug’s true place in therapy will remain somewhat speculative.

Still, the mere presence of contenders to established treatments is beneficial. Competition fosters progress, encourages thorough comparisons, and motivates innovators to improve upon existing solutions. In the best-case scenario, patients benefit from an optimised therapy derived from lessons learned across multiple analogous agents.

Conclusion

Lutetium-177 EB-PSMA-617, as a China-developed PSMA-617 analogue enhanced with truncated Evans Blue, represents an incremental evolution in the field of PSMA-targeted RLT. Early-phase trials conducted in 2018 established its safety and tolerability, aligning it with the now well-known ¹⁷⁷Lu-Vipivotide tetraxetan. While currently positioned as a “me-too” therapy, its EB conjugation suggests the possibility of improved tumour retention and potentially better therapeutic indices.

The road ahead for ¹⁷⁷Lu-EB-PSMA-617 involves rigorous clinical evaluation in well-powered Phase II and III trials, careful analysis of its pharmacodynamics, and head-to-head comparisons where feasible. Should it demonstrate superior efficacy, durable responses, or a significantly improved therapeutic index, it could earn a place as a valuable alternative or even a preferred option in some scenarios.

Even if it ultimately provides incremental rather than revolutionary improvements, its development contributes to the collective understanding of how best to harness PSMA-targeted therapies. Each new radioligand refines the art and science of nuclear medicine, pushing the field closer to an era where we can confidently match specific drugs to specific patients for optimal outcomes. In this way, Lutetium-177 EB-PSMA-617 is more than a “me-too” treatment—it is a stepping stone towards a future where patients with mCRPC benefit from truly individualised and effective radiopharmaceutical therapies.

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