The Expanding Horizon of PSMA: A Comparative Clinical Review of Theranostics in Prostate Cancer and Beyond

Abstract 

The emergence of theranostics has revolutionized precision oncology, with PSMA therapy at the forefront of this paradigm shift. While prostate-specific membrane antigen (PSMA) has been the cornerstone of advanced prostate cancer treatment, its expression is now recognized in the tumor neovasculature and parenchyma of numerous other malignancies, presenting a broader therapeutic opportunity. This review provides a comparative clinical analysis of the application of PSMA-targeted radioligand therapy (RLT) in metastatic castration-resistant prostate cancer (mCRPC) and its nascent role in other PSMA-positive cancers, such as salivary gland and thyroid carcinomas. For mCRPC, extensive Phase III data, particularly from the VISION and PSMAfore trials, demonstrate that Lu-177 PSMA significantly extends radiographic progression-free survival and improves quality of life in heavily pretreated patients. This success is built upon a well-established theranostics model, where pre-treatment PSMA imaging (e.g., Ga-68 PSMA PET) is a critical tool for patient selection and response assessment. In contrast, the application of PSMA therapy in non-prostate malignancies is still largely confined to early-phase clinical trials and compassionate use cases. The therapeutic rationale in these other cancers, such as thyroid carcinoma, often targets the highly expressed PSMA in tumor neovasculature rather than the tumor cells themselves, representing a key difference in mechanism. While side-effect profiles, most notably xerostomia, are shared due to physiological PSMA expression, efficacy and patient selection criteria remain distinct. This review aims to equip US healthcare professionals with a nuanced understanding of PSMA therapy as a tailored tool, highlighting its proven role in prostate cancer treatment and its expanding, yet investigational, horizon in a broader spectrum of PSMA-positive cancers.

Introduction 

Oncological disease management is undergoing a profound transformation driven by the principles of precision oncology. The traditional "one-size-fits-all" approach to systemic therapy is giving way to targeted treatments that exploit unique molecular vulnerabilities within a patient's tumor. At the vanguard of this revolution is theranostics, a portmanteau of "therapeutics" and "diagnostics," which leverages a single molecular target for both diagnostic imaging and targeted therapy. The most successful clinical application of this model to date is centered on prostate-specific membrane antigen (PSMA), a transmembrane protein overexpressed on the surface of prostate cancer cells. PSMA therapy, specifically radioligand therapy with Lutetium-177 (Lu-PSMA), has recently emerged as a standard of care for late-stage metastatic castration-resistant prostate cancer treatment. 

However, the term "prostate-specific" is a misnomer. While PSMA is highly concentrated in prostate cancer, its expression is also found in the neovasculature of many other solid tumors, including salivary gland, thyroid, renal cell, and some forms of lung and breast cancer. This broader PSMA expression presents a compelling, albeit less-explored, opportunity to apply the successful theranostic model to a wider spectrum of malignancies. The key distinction lies in the mechanism of action: in prostate cancer treatment, the therapy targets the tumor cells directly, whereas in other cancers, it often targets the blood vessels that supply the tumor, a form of vascular-targeted therapy. 

This review will provide a comparative analysis of the clinical application of PSMA therapy across different oncological disorders, with a primary focus on its well-established role in prostate cancer treatment and a secondary exploration of its nascent use in other PSMA-positive cancers. We will delve into how the diagnostic use of PSMA imaging (e.g., Gallium-68 PSMA PET) is a prerequisite for patient selection in all cases and how the therapeutic approach and expected outcomes vary based on the specific disease. 

The implications of this comparative perspective for US healthcare professionals are profound. It is no longer sufficient to view PSMA therapy as a singular treatment for a single disease. Clinicians in urology, medical oncology, and nuclear medicine oncology must understand the nuanced differences in patient selection, efficacy, and side-effect profiles across various tumor types. The proven success of Lu-177 PSMA in mCRPC provides a powerful proof-of-concept for radioligand therapy, but its rational application beyond the prostate will require a sophisticated understanding of tumor biology and the specific therapeutic goal, whether it is direct tumor cell killing or vascular disruption. This article aims to be a valuable resource for guiding evidence-based discussions and clinical decision-making in this dynamic and exciting new era of precision oncology.

Literature Review 

The literature on PSMA therapy presents a clear dichotomy: a robust, evidence-based paradigm for prostate cancer treatment contrasted with an emerging, yet largely investigational, application in other PSMA-positive cancers. This review examines the key findings that define this clinical landscape, highlighting the distinct therapeutic strategies and outcomes for each disease.

PSMA Therapy in Prostate Cancer: The Gold Standard

The use of Lu-177 PSMA in metastatic castration-resistant prostate cancer (mCRPC) is the most clinically advanced and well-studied application of theranostics. The success is predicated on the high and selective overexpression of PSMA on prostate cancer cells, which increases with disease progression, a characteristic of PSMA expression that makes it an ideal target.

• Diagnostic Prequel: PSMA Imaging: A cornerstone of this approach is pre-therapy PSMA imaging using agents like Gallium-68 ([⁶⁸Ga]Ga-PSMA) PET. This diagnostic step is crucial for identifying patients with a high tumor burden that expresses PSMA, ensuring they are likely to respond to radioligand therapy. This "see what you treat" model minimizes exposure to an ineffective treatment, a key principle of precision oncology.

• Therapeutic Outcomes: The landmark Phase III VISION trial established Lu-177 PSMA as a new standard of care. The trial demonstrated that in patients with PSMA-positive mCRPC who had progressed on prior treatments, the addition of Lu-177 PSMA to standard care significantly improved overall survival by 4.0 months and radiographic progression-free survival (rPFS) by 5.3 months compared to standard care alone. The more recent Phase III PSMAfore trial further cemented this success by showing a significant rPFS benefit in a pre-chemotherapy setting, with Lu-177 PSMA achieving a median rPFS of 12.0 months compared to 5.59 months for a change in androgen receptor pathway inhibitor. These results confirm the profound impact of PSMA therapy on prostate cancer treatment and provide robust evidence for its efficacy.

• Side Effect Profile: The most common side effect is xerostomia (dry mouth) due to physiological PSMA expression in the salivary glands. This is generally manageable, but the severity can vary. Other side effects include transient myelosuppression (anemia, thrombocytopenia) and fatigue, which are well-documented and typically manageable in a specialized nuclear medicine oncology setting.

PSMA Therapy Beyond Prostate Cancer: An Emerging Frontier

While the success in prostate cancer is clear, the application of PSMA therapy in other PSMA-positive cancers is in a much earlier phase of development. These investigations are primarily driven by the observation that PSMA is also expressed in the neovasculature of many tumors.

• Salivary Gland Carcinomas: Salivary gland tumors are a natural target for PSMA therapy due to the physiological expression of PSMA in healthy salivary glands. This led to the hypothesis that PSMA-positive salivary gland carcinomas, particularly adenoid cystic carcinomas, could be a target.

  • Therapeutic Mechanism: In contrast to the direct tumor cell targeting in prostate cancer, the mechanism here is often a combination of direct targeting of tumor cells and targeting of the supporting tumor vasculature. The high PSMA expression in both healthy and malignant salivary glands makes these tumors highly avid on PSMA imaging, a critical step for patient selection.

  • Clinical Evidence: The evidence for efficacy is currently limited to small case series and compassionate use reports. These studies have shown encouraging signs of tumor response and symptom palliation, but large, prospective trials are needed to establish safety and efficacy for PSMA-positive cancers beyond the prostate.

• Thyroid Cancer: While iodine-131 is the standard radioligand therapy for differentiated thyroid cancer, PSMA therapy is being explored for more aggressive, iodine-refractory subtypes, particularly poorly differentiated and anaplastic thyroid cancers.

  • Therapeutic Mechanism: The therapeutic target in thyroid cancer is predominantly the neovascular PSMA expression. Anaplastic thyroid cancer is highly vascular, and this PSMA expression can be exploited for targeted radiotherapy. This mechanism is fundamentally different from both iodine therapy (which targets iodine uptake in the tumor cells) and the direct targeting of prostate cancer cells.

  • Clinical Evidence: The use of Lu-177 PSMA in this setting is highly investigational, with published data limited to a handful of case reports showing partial responses and stable disease in selected patients. The high uptake of PSMA on imaging provides a rationale for treatment, but standardized protocols and larger studies are non-existent.

Comparative Challenges and Future Directions

The stark contrast between the two categories highlights key challenges. For PSMA-positive cancers beyond prostate, a clear understanding of the specific therapeutic mechanism (tumor cell vs. vascular targeting) and the optimal patient selection criteria is lacking. Furthermore, the limited patient numbers and the rarity of some of these tumors make large-scale clinical trials difficult to conduct. The future of PSMA therapy will likely involve expanding its application through rigorous clinical trials and exploring its use in a multimodal fashion, combining it with other systemic therapies to enhance efficacy across a broader range of solid tumors.

Methodology

The objective of this comprehensive review article is to provide a critical, evidence-based analysis of the clinical application of PSMA therapy as a cornerstone of precision oncology, with a particular focus on its comparative use in prostate cancer treatment versus other malignancies. The target audience for this review is US healthcare professionals. To achieve this, a systematic and targeted review of the contemporary peer-reviewed and gray literature was conducted, with a strong emphasis on publications from the past five years to capture the most recent advancements in this rapidly evolving field.

Databases searched included PubMed, Scopus, the Cochrane Library, and major clinical trial registries (e.g., ClinicalTrials.gov), using a combination of keywords and Medical Subject Headings (MeSH) terms to ensure a comprehensive yet focused search. Key search terms included: "PSMA therapy," "prostate cancer treatment," "radioligand therapy," "nuclear medicine oncology," "Lu-177 PSMA," "PSMA-positive cancers," "theranostics," "precision oncology," "PSMA imaging," and "PSMA expression." Additional terms were used to identify specific clinical trial updates and real-world evidence, such as "VISION trial," "PSMAfore trial," "Expanded Access Program," "salivary gland cancer," and "thyroid cancer."

Inclusion criteria for the review were: publications in English focused on human studies or clinical trials, and articles that directly compared or provided data on the application of PSMA therapy in prostate cancer and non-prostate malignancies. Articles were excluded if they were exclusively focused on in vitro studies, animal models without translational data, or publications on other non-PSMA-targeted radioligands. Editorials, commentaries, and single case reports were also generally excluded to maintain a high level of evidence, though a limited number of well-documented case series were included to represent the emerging data for rare cancer types.

Data extraction from the selected articles focused on several key parameters for each disorder: the specific type of cancer, the therapeutic mechanism of action (e.g., direct cell targeting vs. vascular targeting), study design and phase, reported outcomes related to safety and efficacy, and details on patient selection and response assessment using PSMA imaging. This structured approach allowed for a direct, evidence-based comparison, highlighting the distinct challenges and promises of PSMA therapy as a tailored tool in modern oncological disease management.

Results 

The extensive review of the clinical literature on PSMA therapy reveals a clear and profound divergence in its application and maturity across different oncological disorders. The data on prostate cancer treatment is robust and definitive, while the evidence for other PSMA-positive cancers remains in its early, exploratory phase. This section presents a comparative synthesis of the key findings in efficacy, safety, and patient selection.

Comparative Efficacy: A Tale of Two Tiers

The efficacy data for Lu-177 PSMA in metastatic castration-resistant prostate cancer (mCRPC) is a success story for theranostics and precision oncology. The landmark Phase III VISION trial demonstrated a statistically significant improvement in overall survival (OS) by 4.0 months and radiographic progression-free survival (rPFS) by 5.3 months when Lu-177 PSMA was added to standard care. This was further validated by the more recent Phase III PSMAfore trial, which showed a significant rPFS benefit of 12.0 months in a pre-chemotherapy setting. Real-world evidence from the US Expanded Access Program (EAP) corroborates these findings, with patients experiencing a similar safety profile and PSA response rate, albeit with a slightly shorter OS, reflecting the more heavily pretreated nature of this patient population. This robust evidence has made PSMA therapy a standard of care.

In stark contrast, the efficacy data for PSMA-positive cancers outside of the prostate is highly limited. The literature consists predominantly of small case series and compassionate use reports. A systematic review of 40 cases of non-prostatic PSMA therapy revealed that while some patients, particularly those with salivary gland tumors, demonstrated encouraging responses, the overall outcomes are sporadic and not from large-scale, prospective trials. For thyroid cancer, particularly the aggressive anaplastic subtype, some case reports show a positive response, but the data is too sparse to draw any conclusions on efficacy. The primary benefit reported in these cases is disease stabilization and palliation rather than a definitive survival benefit.

Comparative Safety and Side Effects

The safety profile of Lu-177 PSMA is well-characterized in prostate cancer treatment. The most common adverse event across all major trials is xerostomia (dry mouth), a direct consequence of physiological PSMA uptake in the salivary glands. This is generally a low-grade, manageable toxicity. Other reported side effects include fatigue, nausea, and hematological toxicities such as anemia and thrombocytopenia. While these are also typically low-grade, they require careful monitoring, especially in patients with bone marrow infiltration.

For PSMA-positive cancers outside the prostate, the safety data is nascent but appears to be similar. Xerostomia remains a predictable side effect, confirming the ubiquity of PSMA expression in salivary glands. Given the limited patient numbers in the existing reports, a full spectrum of potential toxicities is not yet known. However, initial data suggests that the side effects are manageable, and researchers are generally using existing protocols from prostate cancer treatment trials. The safety profiles, though similar in reported adverse events, differ significantly in the level of long-term data available to a clinician considering treatment.

Comparative Patient Selection

Patient selection is a critical component of theranostics and a key differentiator between the two applications of PSMA therapy.

• Prostate Cancer: For mCRPC, patient selection is standardized and driven by PSMA imaging using agents like Ga-68 PSMA PET. The patient must have a high level of PSMA expression on their tumor metastases, as confirmed by the scan, to be eligible for radioligand therapy. This stringent selection process ensures that the radiation will be effectively delivered to the tumor cells, maximizing therapeutic benefit and minimizing futile treatment. The FDA's recent expanded indication now allows for earlier use in the patient journey, further solidifying the role of the PET scan as a critical diagnostic tool.

• Other PSMA-Positive Cancers: Patient selection for non-prostate cancers is still rudimentary and lacks standardization. While PSMA imaging is used to identify potential candidates, the criteria are often subjective and based on a visual assessment of uptake rather than established standardized criteria. Furthermore, the decision to proceed with treatment is often made on a compassionate use basis for patients with limited or no other treatment options. The lack of standardized protocols for dosimetry, patient selection, and response assessment is a major hurdle that must be overcome for PSMA therapy to gain wider acceptance in these indications.

Discussion 

The comparative analysis presented in this review underscores that PSMA therapy is a transformative force in nuclear medicine oncology, but its application is not a universal solution. The evidence clearly delineates a mature, highly effective paradigm for prostate cancer treatment from an early, investigational, and complex landscape for other PSMA-positive cancers. This duality has profound implications for US healthcare professionals as they navigate the evolving world of precision oncology.

The resounding success of Lu-177 PSMA in mCRPC, supported by the robust data from the VISION and PSMAfore trials, provides a powerful proof-of-concept for the entire field of theranostics. The FDA's expanded approval is a testament to this success and solidifies the role of PSMA imaging as a non-negotiable prerequisite for treatment. For the practicing oncologist, this means that for the appropriate patient, PSMA therapy should be a key consideration in the oncological disease management armamentarium. However, it also means that clinicians must be vigilant in educating patients on the importance of adhering to the evidence-based protocols and the risks of seeking unproven treatments from unregulated sources.

The nascent, and often anecdotal, evidence for the use of PSMA therapy in non-prostate cancers presents a distinct set of challenges. The lack of large-scale clinical trial data means that efficacy and safety are not yet established. The use of the therapy in these rare indications is currently a matter of expert consensus and compassionate use, not standard of care. This places a significant burden on the treating physician to ensure proper patient selection, informed consent, and careful monitoring, often using protocols adapted from prostate cancer treatment. The fact that the therapeutic target may be the tumor’s neovasculature rather than the cells themselves adds another layer of complexity, as this mechanism requires different dosimetry and response assessment strategies.

Looking to the future, the expansion of PSMA therapy beyond prostate cancer will depend on several key factors. First, the field requires dedicated, well-designed clinical trials for other PSMA-expressing tumors. These trials must establish clear patient selection criteria, standardized treatment protocols, and objective efficacy endpoints. Second, there is a growing interest in combining PSMA therapy with other treatment modalities, such as chemotherapy, immunotherapy, or targeted agents. This combination approach holds promise for overcoming resistance mechanisms and achieving more durable responses, particularly in tumors with lower PSMA expression.

In conclusion, PSMA therapy exemplifies the promise and complexity of precision oncology. Its proven efficacy and manageable safety profile in prostate cancer treatment have set a high bar for the rest of the field. However, its application in other malignancies is an ongoing journey that requires careful investigation, a nuanced understanding of disease-specific biology, and a steadfast commitment to evidence-based practice. For the US HCP, mastering this duality will be essential for delivering optimal patient care in this new era of targeted radioligand therapy.

Conclusion 

PSMA therapy has fundamentally reshaped prostate cancer treatment, establishing theranostics as a powerful tool in precision oncology. Supported by robust evidence from pivotal clinical trials and real-world data, Lu-177 PSMA is now a standard of care for metastatic castration-resistant prostate cancer, offering significant improvements in survival and quality of life.

However, this review highlights a crucial distinction: while PSMA therapy's role in prostate cancer is well-defined, its use in other PSMA-positive cancers remains highly investigational. The limited, albeit promising, data for conditions like salivary gland and thyroid tumors underscores a critical need for dedicated research to establish disease-specific protocols for patient selection, dosage, and efficacy. The future of nuclear medicine oncology will likely be defined by the expansion of this therapeutic concept, but it will require a nuanced, evidence-based approach and a continued commitment to rigorous clinical research to ensure that this powerful treatment is safely and effectively delivered to a broader spectrum of patients.

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