An Expert Report on 177Lu-PSMA-R2: Development, Clinical Evaluation, and Strategic Evolution in PSMA-Targeted Radioligand Therapy

Executive Summary

This report provides a comprehensive analysis of 177Lu-PSMA-R2, a second-generation, urea-based radioligand therapy developed for the treatment of metastatic castration-resistant prostate cancer (mCRPC). The agent was originated by Johns Hopkins University and advanced into clinical development by Advanced Accelerator Applications (AAA), a Novartis company, as a patent-protected successor to the first-generation agent, 177Lu-PSMA-617 (Pluvicto™).[1] The development of 177Lu-PSMA-R2 was predicated on a ligand design, PSMA-R2, that demonstrated a potentially superior safety profile, particularly with lower uptake in the salivary glands, aiming to mitigate the dose-limiting toxicity of xerostomia seen with other PSMA-targeted agents.[3]

The agent entered a Phase I/II clinical trial, known as the PROter study (NCT03490838), to evaluate its safety, radiation dosimetry, and preliminary efficacy.[6] However, after enrolling 27 patients, the trial was terminated by the sponsor in July 2022.[1] Critically, this discontinuation was not due to safety concerns but was a strategic decision reflecting the rapid technological advancements in the field of nuclear medicine.[1] Novartis pivoted its strategy to focus on a more potent, next-generation construct, 225Ac-PSMA-R2, which pairs the same promising PSMA-R2 ligand with an alpha-emitting radionuclide, Actinium-225.[9] This successor agent is now under investigation in the SatisfACtion clinical trial (NCT05983198).[10]

The developmental trajectory of 177Lu-PSMA-R2 serves as a critical case study in the dynamic and highly competitive landscape of PSMA-targeted theranostics. It illustrates how a promising clinical candidate can be rendered strategically obsolete by the pursuit of more powerful radionuclide technologies and optimized therapeutic indices. This report details the scientific rationale for 177Lu-PSMA-R2's development, analyzes the available clinical data from its terminated trial, and elucidates the strategic pivot toward its alpha-emitting successor, placing its story within the broader context of the evolving fight against prostate cancer.

The Theranostic Landscape: PSMA-Targeted Radioligand Therapy in Prostate Cancer

The Significance of PSMA as a Theranostic Target

The foundation of modern radioligand therapy (RLT) for prostate cancer rests upon the identification of an ideal molecular target: the Prostate-Specific Membrane Antigen (PSMA). PSMA, also known as glutamate carboxypeptidase-II (GCP-II), is a type II transmembrane glycoprotein that is highly overexpressed on the cell surface of the vast majority of prostate cancer cells.[2] Its expression levels have been shown to correlate directly with tumor aggressiveness, metastatic progression, and androgen-independent disease states, making it an excellent biomarker for advanced prostate cancer.[4] Furthermore, upon binding with a ligand, the PSMA-ligand complex is rapidly internalized by the cancer cell.[13] This unique combination of high, cancer-specific expression and efficient internalization makes PSMA an exceptional target for theranostics—an approach that combines diagnostic imaging and therapeutic action using the same molecular target. This allows for the selection of patients most likely to benefit from therapy and the subsequent delivery of a cytotoxic payload directly to the tumor cells, thereby maximizing efficacy while minimizing systemic toxicity.[3]

Principles of Radioligand Therapy

RLT operates on the principle of targeted radiation delivery. A targeting molecule, or ligand, is designed to bind with high affinity to a receptor on cancer cells. This ligand is chemically linked, via a chelator, to a radioactive isotope (radionuclide).[13] The choice of radionuclide is critical as it determines the nature and potency of the therapeutic effect.

• Beta (β−) Emitters: Radionuclides like Lutetium-177 (177Lu) are beta-emitters. They release beta particles (electrons) that travel a few millimeters in tissue (up to 2 mm).[17] This relatively long path length creates a "crossfire effect," where radiation can kill adjacent tumor cells that may not have bound the ligand, which is advantageous for treating larger, heterogeneous tumors. The primary mechanism of cell kill is through the induction of single-strand DNA breaks.[18] The success of 177Lu-PSMA-617 (Pluvicto™) established beta-emitters as the first-generation standard in PSMA-targeted RLT.[9]
• Alpha (α) Emitters: Radionuclides such as Actinium-225 (225Ac) are alpha-emitters. They release high-energy alpha particles (helium nuclei) that have a very short path length in tissue (typically <100 µm, or only a few cell diameters).[11] This short range confines the radiation damage very precisely to the target cells and their immediate neighbors, sparing more distant healthy tissue. Alpha particles possess a high linear energy transfer (LET), depositing a large amount of energy over a short distance. This results in complex, difficult-to-repair double-strand DNA breaks, making them significantly more potent and cytotoxic than beta particles.[9] This high potency is particularly advantageous for treating small tumor clusters or micrometastatic disease and has shown efficacy in patients who have become resistant to beta-emitter therapies.[21]

The Clinical Precedent: 177Lu-PSMA-617 (Pluvicto™)

The field of PSMA-targeted RLT was validated by the landmark success of 177Lu-PSMA-617, marketed as Pluvicto™ by Novartis. The pivotal Phase III VISION trial demonstrated that for patients with heavily pretreated mCRPC, the addition of 177Lu-PSMA-617 to standard of care resulted in a statistically significant and clinically meaningful improvement in both radiographic progression-free survival (rPFS) and overall survival (OS).[20] The FDA approval of Pluvicto in March 2022 marked a paradigm shift in the management of advanced prostate cancer, establishing PSMA-targeted RLT as a new pillar of care and setting a high clinical and commercial benchmark for all subsequent agents in this class.[20]

The development of 177Lu-PSMA-R2 was not undertaken in a scientific vacuum but was a direct strategic response to the proven efficacy of the PSMA-617 ligand. It represents a classic "fast-follower" strategy, aiming to improve upon a validated therapeutic concept while securing a new, distinct intellectual property position.[2] The simultaneous exploration of more potent alpha-emitters by the broader research community created a dynamic environment where developers like Novartis had to weigh the benefits of launching an incrementally improved beta-emitter against the potential of leapfrogging the technology with a next-generation alpha-emitter. This strategic tension ultimately dictated the developmental fate of 177Lu-PSMA-R2.

177Lu-PSMA-R2: Profile of a Second-Generation Radioligand

Development and Corporate History

The foundational science for the PSMA-R2 ligand was developed at Johns Hopkins University, a leading academic center in PSMA research.[1] The clinical and commercial development rights were advanced by Advanced Accelerator Applications (AAA), a specialist in nuclear medicine. With the acquisition of AAA by Novartis, 177Lu-PSMA-R2 was integrated into the Novartis oncology pipeline alongside 177Lu-PSMA-617.[1] The agent was explicitly developed as a patent-protected alternative to 177Lu-PSMA-617, with the strategic intent of offering potential improvements in the therapeutic profile.[2]

Molecular and Radiochemical Properties

177Lu-PSMA-R2 is a targeted radiopharmaceutical classified as an antineoplastic radioisotope.[1] It is a radioconjugate composed of two key components:

1. The Ligand (PSMA-R2): A small, urea-based molecule engineered to bind with high affinity and specificity to the enzymatic pocket of the PSMA protein.[2] The PSMA-R2 ligand was designed with linker technology intended to optimize its pharmacokinetics and biodistribution, with a particular focus on reducing uptake in non-target tissues.[11]
2. The Radionuclide (Lutetium-177): The therapeutic payload, 177Lu, is a beta-emitting radioisotope. It is securely held by a chelator that is covalently attached to the PSMA-R2 ligand. 177Lu has a physical half-life of 6.7 days, which is well-suited for targeting solid tumors, and its beta emissions are responsible for its cytotoxic effect.[17]

Mechanism of Action

Upon intravenous administration, the PSMA-R2 targeting moiety of the conjugate circulates through the body and selectively binds to PSMA expressed on the surface of prostate cancer cells.[11] Following this high-affinity binding, the entire radioligand-receptor complex is internalized into the cell.[16] This process concentrates the 177Lu radionuclide directly within or adjacent to the cancer cells. As 177Lu decays, it emits beta particles, which deposit energy in the surrounding tissue, causing single- and double-strand DNA breaks and inducing apoptosis (programmed cell death) in the targeted tumor cells.[13]

Preclinical Data and Dosimetry of the Diagnostic Analogue (68Ga-PSMA-R2)

The theranostic partner for 177Lu-PSMA-R2 is 68Ga-PSMA-R2, where the therapeutic isotope 177Lu is replaced with the positron-emitting diagnostic isotope Gallium-68 (68Ga). The PROfind study was conducted to evaluate the safety, biodistribution, and imaging performance of 68Ga-PSMA-R2.[6] The results from this study offered the first clinical insights into the behavior of the PSMA-R2 ligand in humans.

Dosimetry analysis revealed a biodistribution profile largely consistent with other PSMA-targeted agents, with the highest absorbed radiation doses being delivered to the urinary bladder wall and the kidneys, reflecting the primary routes of clearance and physiologic expression.[3] However, a key finding of potential clinical significance was the favorably low radiation dose delivered to the salivary glands (mean of 0.016 mGy/MBq) and lacrimal glands (0.008 mGy/MBq).[3] This was a critical observation, as xerostomia (severe dry mouth) resulting from off-target radiation to the salivary glands is a well-documented and often dose-limiting toxicity for other PSMA radioligands.[5] The data suggested that the PSMA-R2 ligand was successfully engineered to have a better safety profile in this regard. Furthermore, preliminary imaging results from the PROfind study showed that 68Ga-PSMA-R2 PET/CT was able to detect a greater number of lesions compared to conventional imaging methods, confirming its utility as a sensitive diagnostic tool for patient selection.[3]

The primary differentiating feature of the PSMA-R2 ligand, based on this early clinical data, was its potential for an improved safety profile, specifically concerning off-target radiation to the salivary glands. This was a clear attempt to engineer a "me-better" solution to address a known clinical challenge of first-generation PSMA RLTs. A superior safety profile could theoretically allow for higher or more frequent dosing, thereby improving the therapeutic index. However, a critical gap in the available information is the lack of direct preclinical data comparing the therapeutic efficacy and tumor retention of 177Lu-PSMA-R2 against the benchmark, 177Lu-PSMA-617. Without compelling evidence of at least non-inferior efficacy, the safety advantage alone may not have been sufficient to justify a competitive market position, likely influencing Novartis's ultimate decision to pivot to the more powerful alpha-emitter platform.

The PROter Clinical Trial (NCT03490838): A Detailed Examination

The clinical development of 177Lu-PSMA-R2 was centered on the PROter study, an integrated Phase I/II trial designed to rigorously evaluate its potential in mCRPC.

Table 1: Overview of the PROter Clinical Trial (NCT03490838)

Trial Attribute	Details	Source Snippet(s)
Title	PROter: 177Lu-PSMA-R2 in Patients With PSMA Positive Progressive, Metastatic, Castration Resistant Prostate Cancer	6
Identifier	NCT03490838; EudraCT 2017-004034-29	1
Phase	Phase I/II	1
Sponsor	Advanced Accelerator Applications (a Novartis company)	1
Design	Open-label, multi-center, dose-escalation/expansion	6
Target Enrollment	~96 patients	2
Actual Enrollment	27 patients	7
Primary Objectives	Safety, tolerability, radiation dosimetry, Maximum Tolerated Dose (MTD) determination (Phase I); Radiographic Progression-Free Survival (rPFS) (Phase II)	6
Final Status	Terminated (Sponsor's strategic decision, not due to safety concerns)	1

Study Design and Endpoints

The PROter study was structured in two parts to systematically assess the drug's profile.[6]

• Phase I (Dose Escalation): This initial phase was designed to establish the safety, tolerability, and optimal dosing of 177Lu-PSMA-R2. It employed a complex dose-escalation schema that explored not only different activity levels per cycle but also different numbers of cycles. Cohorts were planned to receive regimens ranging from three cycles at 100 mCi (3.7 GBq) up to multiple cycles at 500 mCi (18.5 GBq).[30] The primary endpoints for this phase were the incidence of Dose-Limiting Toxicities (DLTs) and the overall safety profile, with the goal of determining the Maximum Tolerated Dose (MTD) and/or the Recommended Phase 2 Dose (RP2D).[8] The intricate design, investigating both dose level and cycle number, reflects a sophisticated attempt to define the optimal therapeutic index—the balance between delivering a tumor-killing radiation dose and minimizing toxicity to healthy organs.
• Phase II (Dose Expansion): Following the determination of the RP2D, this phase was planned to enroll approximately 60 patients to gather preliminary evidence of anti-tumor activity.[6] The primary efficacy endpoint for this part of the study was designated as radiographic progression-free survival (rPFS).[6] Key secondary endpoints were robust and included standard oncology metrics such as Prostate-Specific Antigen (PSA) response rate (defined as a ≥50% decline from baseline), Objective Response Rate (ORR) based on RECIST 1.1 criteria, time to PSA progression, and Overall Survival (OS).[7] Patient-reported outcomes were also a focus, with quality-of-life assessments using tools like the EORTC QLQ-C30 and a specific questionnaire for xerostomia, underscoring the importance of the drug's anticipated safety benefit.[7]

Trial Status and Termination

The PROter study began enrolling patients in mid-2018.[2] However, after enrolling 27 of the planned 96 participants, the sponsor, Novartis, halted recruitment and terminated the study in July 2022.[1] It is crucial to note that regulatory filings and company statements explicitly clarify that this termination was a strategic business decision and was not precipitated by any safety concerns observed in the trial.[1] Patients who were already enrolled at the time of the decision were allowed to complete their treatment and the required one-year safety follow-up as per the protocol.[8]

The decision to terminate a Phase I/II trial in a high-value indication like mCRPC after enrolling only 28% of the target population, and in the absence of safety signals, is a strong indicator of a fundamental strategic shift within the developing company. It suggests that the projected clinical or commercial value of 177Lu-PSMA-R2 was superseded by that of another asset in the pipeline. The PROter program was rendered strategically obsolete before it could be fully evaluated, not because of its own failings, but because of the greater perceived promise of its successor.

The Strategic Pivot: From Beta to Alpha with the PSMA-R2 Ligand

The termination of the PROter trial was a direct consequence of Novartis's strategic decision to prioritize the development of a more potent, next-generation alpha-emitting radiopharmaceutical. This move reflects a broader industry trend toward leveraging the superior cytotoxic potential of alpha particles.

The Rationale for Alpha-Emitters

The shift from beta- to alpha-emitters is driven by fundamental radiobiology. Alpha particles, such as those released by Actinium-225 (225Ac), are significantly more powerful than beta particles from 177Lu.[9] Their high LET and short tissue penetration range allow for the delivery of highly concentrated, lethal radiation doses directly to cancer cells while largely sparing adjacent healthy tissue.[18] This precision is particularly valuable for eradicating micrometastatic disease. Most importantly, alpha-emitters have demonstrated the ability to induce responses in patients whose tumors have become resistant to beta-emitter therapy, offering a new line of treatment for a patient population with otherwise limited options.[21]

The Successor: 225Ac-PSMA-R2

Novartis's clinical development pipeline clearly illustrates this strategic pivot. The company is now advancing 225Ac-PSMA-R2, a compound that utilizes the same proprietary PSMA-R2 ligand from the discontinued program but is armed with the more potent 225Ac radionuclide.[9] This next-generation agent is being evaluated in the

SatisfACtion trial (NCT05983198), a Phase I/II study in men with metastatic hormone-sensitive prostate cancer (mHSPC) and heavily pre-treated mCRPC.[10]

The design of the SatisfACtion trial is telling; it explicitly includes cohorts of patients who have and have not received prior 177Lu-PSMA therapy.[9] This directly positions 225Ac-PSMA-R2 as a potential treatment for patients who have progressed on or after Pluvicto™, creating a new, valuable market segment and extending the lifecycle of the company's PSMA-targeted franchise.

This strategic maneuver was not a repudiation of the PSMA-R2 ligand but rather an affirmation of its perceived value. Novartis deemed the ligand promising enough to pair it with the higher-risk, higher-reward alpha-emitter platform. Instead of launching a second beta-emitter that would compete with its own blockbuster drug (Pluvicto) on a potentially modest safety advantage, Novartis chose to leverage its proprietary ligand to create a technologically superior product. This leapfrogging strategy aims to address the next major unmet need in prostate cancer: resistance to beta-emitter RLT. This decision was likely also influenced by the significant logistical challenge of securing a stable supply of medical-grade 225Ac, a factor that would have dictated the timing and feasibility of committing to a large-scale alpha-emitter program.[11]

Competitive and Comparative Landscape

The development of 177Lu-PSMA-R2 occurred within an intensely competitive environment, with multiple companies striving to develop superior PSMA-targeted radioligands. Understanding this landscape is key to appreciating the strategic context of the PROter trial's termination.

Table 2: Comparative Landscape of Key PSMA-Targeted Radioligands

Agent Name	Ligand Type	Radionuclide	Developer	Key Differentiator / Development Status	Source Snippet(s)
177Lu-PSMA-617 (Pluvicto™)	PSMA-617	Beta (177Lu)	Novartis	FDA Approved; The established clinical and commercial benchmark.	9
177Lu-PSMA-R2	PSMA-R2	Beta (177Lu)	Novartis	Discontinued (Phase I/II); Developed for improved safety profile (low salivary uptake).	1
225Ac-PSMA-R2	PSMA-R2	Alpha (225Ac)	Novartis	Phase I/II (SatisfACtion trial); Next-gen alpha-emitter successor to 177Lu-PSMA-R2.	9
177Lu-PSMA-I&T	PSMA-I&T	Beta (177Lu)	Curium	Phase III (ECLIPSE trial met primary endpoint); Competing beta-emitter.	32
177Lu-rhPSMA-10.1	rhPSMA-10.1	Beta (177Lu)	Blue Earth Therapeutics	Phase II; Radiohybrid ligand designed for higher tumor radiation dose and improved therapeutic index.	36

The entire field is engaged in a race to optimize the therapeutic index—that is, to maximize the radiation dose delivered to tumors while minimizing exposure to healthy organs, particularly the kidneys and salivary glands. Each competitor is pursuing this goal through different technological approaches.

• 177Lu-PSMA-617 (Pluvicto™) serves as the established baseline against which all others are measured.[20]
• 177Lu-PSMA-R2 aimed to improve the therapeutic index by modifying the ligand (PSMA-R2) to reduce off-target binding, specifically in the salivary glands, thereby lowering the risk of xerostomia.[3]
• 177Lu-PSMA-I&T, developed by Curium, represents a direct competitor in the beta-emitter class. Its successful Phase III ECLIPSE trial positions it as a potential option in the pre-chemotherapy mCRPC setting.[33]
• 177Lu-rhPSMA-10.1, from Blue Earth Therapeutics, utilizes a novel "radiohybrid" linker technology. Preclinical intrapatient comparisons against 177Lu-PSMA-I&T suggest that rhPSMA-10.1 can deliver a significantly higher absorbed radiation dose to tumor lesions, potentially leading to greater efficacy.[40]

The promising dosimetry data from competitors like Blue Earth Therapeutics raised the competitive bar for efficacy. For 177Lu-PSMA-R2 to succeed, it would have needed to demonstrate not just a safety benefit but also at least comparable, if not superior, anti-tumor activity. In an environment where competitors were demonstrating potentially higher tumor doses with their beta-emitters, the strategic appeal of pivoting to a much more potent alpha-emitter, which offers a fundamentally different and more powerful mechanism of cell killing, becomes clear.

Conclusion

177Lu-PSMA-R2 was a rationally designed, second-generation PSMA-targeted radiopharmaceutical developed by Novartis (via AAA) as a proprietary successor to the pioneering agent, 177Lu-PSMA-617. Its development was underpinned by a promising ligand, PSMA-R2, which in its diagnostic form (68Ga-PSMA-R2) demonstrated a favorable biodistribution profile with notably low uptake in the salivary glands, suggesting a potential solution to the clinically significant problem of xerostomia.

The clinical evaluation of 177Lu-PSMA-R2 in the PROter trial was initiated to confirm its safety, dosimetry, and efficacy. However, the program was terminated not due to clinical failure or safety issues, but as a result of a calculated strategic decision by its sponsor. This pivot reflects the remarkably rapid pace of innovation within the radiopharmaceutical field. Faced with a landscape of competing beta-emitters and the emergence of highly potent alpha-emitter technology, Novartis opted to leverage its promising PSMA-R2 ligand to create a next-generation alpha-therapeutic, 225Ac-PSMA-R2, rather than pursue an incremental improvement in the beta-emitter class.

The legacy of 177Lu-PSMA-R2 is therefore not one of failure, but of strategic evolution. It served to clinically validate the PSMA-R2 ligand, paving the way for its use in the more advanced 225Ac-PSMA-R2 program currently underway in the SatisfACtion trial. The story of 177Lu-PSMA-R2 is a compelling illustration of how, in the competitive arena of modern drug development, a promising candidate can be superseded by the relentless pursuit of superior technology and a forward-looking lifecycle management strategy. The focus of the oncology community now rightly shifts to the clinical data that will emerge from the 225Ac-PSMA-R2 program to determine if this strategic pivot will ultimately deliver a new, more powerful weapon against advanced prostate cancer.

Works cited

1. Lutetium-177 PSMA-R2 - AdisInsight - Springer, accessed June 18, 2025, https://adisinsight.springer.com/drugs/800051164
2. Lu-177-PSMA-R2 - Oncidium Foundation, accessed June 18, 2025, https://www.oncidiumfoundation.org/molecule/lu-177-psma-r2/
3. Ga]Ga-PSMA-R2 as an Imaging Agent in Patients with Biochemical Recurrence or Metastatic Prostate Cancer - Journal of Nuclear Medicine, accessed June 18, 2025, https://jnm.snmjournals.org/content/early/2025/02/20/jnumed.124.268318.full.pdf
4. Safety, Dosimetry, and Feasibility of [68Ga]Ga-PSMA-R2 as an Imaging Agent in Patients with Biochemical Recurrence or Metastatic Prostate Cancer - PubMed Central, accessed June 18, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11876733/
5. Safety, Dosimetry, and Feasibility of [68Ga]Ga-PSMA-R2 as an Imaging Agent in Patients with Biochemical Recurrence or Metastatic Prostate Cancer | Journal of Nuclear Medicine, accessed June 18, 2025, https://jnm.snmjournals.org/content/early/2025/02/06/jnumed.124.268318
6. Advanced Accelerator Applications Announces First Patients Dosed in Two Clinical - Amazon S3, accessed June 18, 2025, https://s3-eu-west-1.amazonaws.com/s3-adacap-staging/wp-content/uploads/2019/01/03085008/AAA-PSMA-R2-Press-Release-2018-06-22-FINAL-2.pdf
7. 177Lu-PSMA-R2 in Patients With PSMA Positive Progressive, Metastatic, Castration Resistant Prostate Cancer - Cancer Trial Results, accessed June 18, 2025, https://clin.larvol.com/trial-detail/NCT03490838
8. 177Lu-PSMA-R2 in Patients With PSMA Positive Progressive, Metastatic, Castration Resistant Prostate Cancer - NCI, accessed June 18, 2025, https://www.cancer.gov/clinicaltrials/NCT03490838?cid=eb_govdel
9. Novartis's post-Pluvicto plan materialises | ApexOnco - Clinical Trials news and analysis, accessed June 18, 2025, https://www.oncologypipeline.com/apexonco/novartiss-post-pluvicto-plan-materialises
10. Phase I/II Study of [225Ac]Ac-PSMA-R2 in PSMA-positive Prostate Cancer, With/Without Prior 177Lu-PSMA RLT | Novartis, accessed June 18, 2025, https://www.novartis.com/clinicaltrials/study/nct05983198
11. 225Ac-PSMA-R2 - Wikipedia, accessed June 18, 2025, https://en.wikipedia.org/wiki/225Ac-PSMA-R2
12. PSMA Theranostics in prostate cancer - Radboud Repository, accessed June 18, 2025, https://repository.ubn.ru.nl/bitstream/handle/2066/252883/252883.pdf?sequence=1&isAllowed=y
13. PSMA-Targeting Radioligand Therapy in Prostate Cancer | Published in healthbook TIMES Oncology Hematology, accessed June 18, 2025, https://onco-hema.healthbooktimes.org/article/133537-psma-targeting-radioligand-therapy-in-prostate-cancer
14. Current status of PSMA-targeted imaging and therapy - PMC - PubMed Central, accessed June 18, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10803481/
15. Current status of PSMA-targeted imaging and therapy - Frontiers, accessed June 18, 2025, https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1230251/full
16. Synthesis and Preclinical Evaluation of a Bispecific PSMA-617/RM2 Heterodimer Targeting Prostate Cancer | ACS Medicinal Chemistry Letters, accessed June 18, 2025, https://pubs.acs.org/doi/10.1021/acsmedchemlett.4c00324
17. Precision strikes: PSMA-targeted radionuclide therapy in prostate cancer – a narrative review - PMC, accessed June 18, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10687416/
18. Design of 225Ac-PSMA for targeted alpha therapy in prostate cancer - AME Publishing Company, accessed June 18, 2025, https://cdn.amegroups.cn/journals/amepc/files/journals/16/articles/122280/public/122280-PB3-5569-R2.pdf
19. PSMA-Targeted Radiopharmaceuticals in Prostate Cancer: Current Data and New Trials | The Oncologist | Oxford Academic, accessed June 18, 2025, https://academic.oup.com/oncolo/article/28/5/392/7046245
20. PSMA-Targeted Radiopharmaceuticals in Prostate Cancer: Current Data and New Trials, accessed June 18, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10166155/
21. Small Molecule PSMA-Targeted Alpha Therapy - NIH RePORTER - National Institutes of Health (NIH), accessed June 18, 2025, https://reporter.nih.gov/search/8OnSa5SP-EetpglyKYQWWw/project-details/11063953
22. PSMA-Targeted Radiopharmaceuticals in Prostate Cancer: Current Data and New Trials, accessed June 18, 2025, https://www.researchgate.net/publication/368647249_PSMA-Targeted_Radiopharmaceuticals_in_Prostate_Cancer_Current_Data_and_New_Trials
23. Predictors and Real-World Use of Prostate-Specific Radioligand Therapy: PSMA and Beyond, accessed June 18, 2025, https://ascopubs.org/doi/pdf/10.1200/EDBK_350946
24. Renal and Multiorgan Safety of 177Lu-PSMA-617 in Patients with Metastatic Castration-Resistant Prostate Cancer in the VISION Dosimetry Substudy | Journal of Nuclear Medicine, accessed June 18, 2025, https://jnm.snmjournals.org/content/65/1/71
25. The PSMA-Targeting Era: A Game-Changer for Men with Prostate Cancer Worldwide, accessed June 18, 2025, https://www.hopkinsmedicine.org/news/articles/2021/11/the-psma-targeting-era-a-game-changer-for-men-with-prostate-cancer-worldwide
26. 177Lu-PSMA-R2 / Novartis - LARVOL DELTA, accessed June 18, 2025, https://delta.larvol.com/Products/ceb44f8c8ef844f7bee719942861363d/177LuPSMAR2/1/6b83c459fd734a09b004b265cef1ee03/Security/Default.aspx
27. The Development of Lutetium-177 PSMA-R2: A Novel Therapeutic Agent for Prostate Cancer - Open MedScience, accessed June 18, 2025, https://openmedscience.com/the-development-of-lutetium-177-psma-r2-a-novel-therapeutic-agent-for-prostate-cancer/
28. Definition of lutetium Lu-177 PSMA-R2 - NCI Drug Dictionary - National Cancer Institute, accessed June 18, 2025, https://www.cancer.gov/publications/dictionaries/cancer-drug/def/lutetium-lu-177-psma-r2
29. PSMA Theranostics: Current Landscape and Future Outlook - PMC - PubMed Central, accessed June 18, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC8391520/
30. EudraCT Number 2017-004034-29 - Clinical trial results, accessed June 18, 2025, https://www.clinicaltrialsregister.eu/ctr-search/trial/2017-004034-29/results
31. PROter/LU-PSMA - A206T-G01-001 - NHS Health Research Authority, accessed June 18, 2025, https://www.hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/proterlu-psma-a206t-g01-001/
32. Eclipse Clinical Trial, accessed June 18, 2025, https://eclipseclinicaltrial.org/
33. Curium Announces ECLIPSE Trial Has Met Primary Endpoint, Demonstrating a Statistically Significant and Clinically Meaningful Benefit for Patients With PSMA-Positive Metastatic Castration Resistant Prostate Cancer, accessed June 18, 2025, https://www.curiumpharma.com/2024/11/13/eclipse-tiral-psma-prostate-cancer/
34. 177Lu-PSMA-I&T for Metastatic Castration-Resistant Prostate Cancer - Cancer Trial Results, accessed June 18, 2025, https://clin.larvol.com/trial-detail/NCT05204927
35. 177Lu-PSMA-I&T Meets rPFS End Point in PSMA+ mCRPC - OncLive, accessed June 18, 2025, https://www.onclive.com/view/177lu-psma-i-t-meets-rpfs-end-point-in-psma-mcrpc
36. Blue Earth Therapeutics initiates Phase 2 Clinical Trial evaluating the efficacy and safety of Lutetium (177Lu) rhPSMA-10.1 Injection in metastatic castrate resistant prostate cancer - BioSpace, accessed June 18, 2025, https://www.biospace.com/press-releases/blue-earth-therapeutics-initiates-phase-2-clinical-trial-evaluating-the-efficacy-and-safety-of-lutetium-177lu-rhpsma-10-1-injection-in-metastatic-castrate-resistant-prostate-cancer
37. Blue Earth Therapeutics Reports Key Results from Lutetium (177Lu) rhPSMA-10.1 Injection Phase 1 Clinical Trial - PR Newswire, accessed June 18, 2025, https://www.prnewswire.com/news-releases/blue-earth-therapeutics-reports-key-results-from-lutetium-177lu-rhpsma-10-1-injection-phase-1-clinical-trial-302400601.html
38. Blue Earth Therapeutics starts Phase 2 trial for Lutetium (177Lu) rhPSMA-10.1 in metastatic castration-resistant prostate cancer - Patsnap Synapse, accessed June 18, 2025, https://synapse.patsnap.com/article/blue-earth-therapeutics-starts-phase-2-trial-for-lutetium-177lu-rhpsma-101-in-metastatic-castration-resistant-prostate-cancer
39. Blue Earth Therapeutics initiates Phase 2 Clinical Trial evaluating the efficacy and safety of Lutetium (177Lu) rhPSMA-10.1 Injection in metastatic castrate resistant prostate cancer - 1stOncology, accessed June 18, 2025, https://www.1stoncology.com/blog/blue-earth-therapeutics-initiates-phase-2-clinical-trial-evaluating-the-efficacysafety-of-lutetium-177lu-rhpsma-10-1-injection-in-metastatic-castrate-resistant-prostate-cancer1234652463/
40. An Intrapatient Dosimetry Comparison of 177 Lu-rhPSMA-10.1 and 177 Lu-PSMA-I&T in Patients with Metastatic Castration-Resistant Prostate Cancer | Request PDF - ResearchGate, accessed June 18, 2025, https://www.researchgate.net/publication/374268101_An_Intrapatient_Dosimetry_Comparison_of_177_Lu-rhPSMA-101_and_177_Lu-PSMA-IT_in_Patients_with_Metastatic_Castration-Resistant_Prostate_Cancer
41. ECLIPSE trial: 177Lu-PSMA-I&T extends rPFS vs hormone therapy in mCRPC, accessed June 18, 2025, https://www.urologytimes.com/view/eclipse-trial-177lu-psma-i-t-extends-rpfs-vs-hormone-therapy-in-mcrpc
42. An Intrapatient Dosimetry Comparison of 177Lu-rhPSMA-10.1 and 177Lu-PSMA-I&T in Patients with Metastatic Castration-Resistant Prostate Cancer - PubMed, accessed June 18, 2025, https://pubmed.ncbi.nlm.nih.gov/37770108/