UCLA Health Andromeda Trial Compares Alpha v Beta PSMA Radioligand Therapies for Recurrent Prostate Cancer

UCLA Health Launches ANDROMEDA Trial Testing Dual PSMA-Targeted Radiopharmaceuticals in Recurrent Prostate Cancer

BLUF (Bottom Line Up Front): UCLA Health has initiated the ANDROMEDA trial, the first head-to-head comparison of two PSMA-targeted radioactive therapies—lutetium-177-PSMA-617 (Pluvicto) and the investigational actinium-225-PSMA-617—combined with precision radiation for men with oligorecurrent prostate cancer. This landmark Phase 2 study builds directly on the successful LUNAR trial results and could help determine which radioligand therapy works best for early recurrence while potentially delaying or avoiding hormone therapy and its associated side effects.

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A New Frontier in Precision Cancer Treatment

For men facing prostate cancer recurrence after initial treatment, the ANDROMEDA trial represents a significant milestone in precision medicine. Launched by UCLA Health's Jonsson Comprehensive Cancer Center under the leadership of Dr. Jeremie Calais, this Phase 2 clinical trial addresses a critical unanswered question: which PSMA-targeted radioactive therapy—when combined with stereotactic body radiotherapy (SBRT)—provides superior disease control for patients whose cancer has returned to a limited number of sites?

The study focuses on men with oligorecurrent disease, defined as cancer that has returned to one to five detectable spots as identified by advanced PSMA PET/CT imaging. By comparing FDA-approved lutetium-177-PSMA-617 with the investigational alpha-emitting actinium-225-PSMA-617, researchers aim to identify the optimal treatment strategy for this critical patient population where early, aggressive intervention may significantly alter disease trajectory.

Building on Breakthrough LUNAR Trial Results

The ANDROMEDA trial builds directly on the remarkable success of UCLA's recently completed LUNAR trial, which demonstrated that adding PSMA-targeted radioligand therapy to SBRT could more than double progression-free survival in men with oligorecurrent disease. Published in the Journal of Clinical Oncology in late 2025 and presented at the American Society for Radiation Oncology (ASTRO) Annual Meeting, the LUNAR trial randomized 92 patients to receive either SBRT alone or two cycles of investigational lutetium-177-PNT2002 followed by SBRT.

The results were striking: patients receiving the combination therapy achieved a median progression-free survival of 17.6 months compared to just 7.4 months with SBRT alone—a statistically significant improvement that met the trial's primary endpoint. Even more encouraging, the combination delayed the need for hormone therapy from a median of 14.1 months to 24.3 months, providing men with an additional 10 months free from the side effects of androgen deprivation therapy.

Dr. Amar Kishan, co-principal investigator of the LUNAR trial and professor at UCLA's Department of Radiation Oncology, emphasized the significance: "This is the first randomized trial to show that PSMA-targeting radioligand can significantly delay progression when added to metastasis-directed radiation. It suggests we may be able to intervene earlier with radioligand therapy and meaningfully change the course of disease."

Critically, 98% of disease progressions in the LUNAR trial were new metastases rather than regrowth at previously treated sites, confirming that the real challenge lies in occult microscopic disease that even advanced imaging cannot detect. This finding validates the rationale for combining systemic radioligand therapy (to address hidden disease throughout the body) with localized SBRT (to directly eliminate visible lesions).

Understanding PSMA-Targeted Radiopharmaceuticals: Beta vs. Alpha Emitters

Prostate-specific membrane antigen (PSMA) is a protein highly expressed on the surface of most prostate cancer cells, making it an ideal target for precision therapies. PSMA-targeted radiopharmaceuticals work by attaching radioactive particles to molecules that seek out and bind to PSMA, delivering cancer-killing radiation directly to tumor sites while minimizing damage to surrounding healthy tissue.

Lutetium-177-PSMA-617 (Pluvicto) received FDA approval in March 2022 for metastatic castration-resistant prostate cancer (mCRPC) patients who have progressed on androgen receptor pathway inhibitors and chemotherapy. This beta-emitting radiopharmaceutical demonstrated significant benefits in the landmark VISION trial, improving median overall survival by approximately four months (15.3 vs. 11.3 months) and radiographic progression-free survival by more than five months compared to standard care alone. Beta particles from lutetium-177 travel relatively longer distances (up to 2 millimeters) and deliver radiation over their path, which can be advantageous for treating larger tumor deposits but also carries some risk of affecting nearby healthy tissue.

Actinium-225-PSMA-617 is an investigational alpha-emitting radiopharmaceutical that has shown promising results in early studies, particularly in patients who have progressed on lutetium-177 therapy. Alpha particles travel much shorter distances (50-100 micrometers, roughly the diameter of 5-10 cells) but deliver significantly more concentrated energy than beta particles. According to recent meta-analyses, actinium-225-PSMA achieves PSA declines of 50% or greater in approximately 60% of patients—somewhat higher than the roughly 49% seen with lutetium-177 in similar heavily pretreated populations.

The physical differences between alpha and beta radiation are substantial. Alpha particles are approximately 8,000 times more massive than beta particles and deposit their energy over much shorter distances, creating dense ionization tracks that cause more complex, irreparable DNA damage. In vitro studies have demonstrated that alpha particles require fewer hits to kill cancer cells and may be particularly effective against hypoxic (oxygen-deprived) tumors and cells with lower PSMA expression, where beta emitters might be less effective.

However, these advantages come with important considerations. Multiple studies have documented that xerostomia (dry mouth) from salivary gland damage is significantly more common and severe with actinium-225 than with lutetium-177. A systematic review found that approximately 74% of patients receiving actinium-225-PSMA experience some degree of xerostomia, though most cases are grade 1 or 2. In some series, up to 23-25% of patients requested treatment discontinuation due to bothersome dry mouth symptoms. This occurs because salivary glands physiologically express PSMA, and the short-range, high-energy alpha particles can cause more concentrated damage to these glands compared to the longer-range beta particles.

Recent research has revealed that the salivary gland toxicity from actinium-225 may be compounded by its radioactive decay daughters. Actinium-225 decays through a chain that produces four alpha-emitting daughter nuclides, including bismuth-213 and francium-221. Studies using sophisticated imaging techniques have shown that some of these daughter products can redistribute from tumor tissue to salivary glands and kidneys, potentially increasing absorbed radiation doses to these organs by factors of 1.3 to 2.5 beyond what would be predicted from the initial actinium-225 uptake alone.

Critical Pharmacokinetic and Physical Differences: Why Location Matters

Beyond the basic distinction between alpha and beta radiation, there are several crucial pharmacokinetic and physical differences between lutetium-177 and actinium-225 that significantly impact their clinical effectiveness depending on metastasis location and patient characteristics.

Radioactive Half-Life and Time of Exposure

One of the most fundamental differences between these radiopharmaceuticals is their physical half-life—the time it takes for half of the radioactivity to decay:

• Lutetium-177: 6.6 days (approximately 160 hours)
• Actinium-225: 9.9 days (approximately 240 hours)

While these may seem similar, the biological implications are substantial. Lutetium-177-PSMA has a biological elimination half-life of approximately 41-72 hours, with 58% of the administered activity excreted in urine within 24 hours and 65% within 48 hours. This relatively rapid clearance means that unbound radioligand is quickly removed from the body, reducing exposure to normal tissues.

In contrast, actinium-225's longer physical half-life of nearly 10 days, combined with its decay chain producing four alpha-emitting daughter isotopes (francium-221, bismuth-213, polonium-213, and thallium-209), results in prolonged radioactive exposure. Importantly, recent research has shown that some daughter products can redistribute from tumor tissue to organs like salivary glands and kidneys, potentially increasing absorbed radiation doses to these organs by factors of 1.3 to 2.5 beyond what would be predicted from the initial actinium-225 uptake alone.

This difference in elimination kinetics has practical implications: patients receiving lutetium-177 therapy can typically be released from radiation safety restrictions within 48-72 hours, while those receiving actinium-225 may require longer precautionary periods. Radiation can be detected in urine for up to 30 days following lutetium-177 administration, and likely even longer with actinium-225.

Metastasis Location: Bone, Lymph Node, and Visceral Disease

Perhaps most critically for treatment selection, mounting evidence suggests that the type and location of metastases significantly influence treatment response to alpha versus beta emitters:

Bone Metastases (present in 80-90% of metastatic prostate cancer patients):

Multiple studies have documented that bone metastases may respond somewhat less robustly to lutetium-177-PSMA compared to soft tissue disease. This appears related to the "bystander effect" issue: the longer-range beta particles from lutetium-177 can deliver radiation to bone marrow adjacent to bone metastases, potentially causing hematologic toxicity in patients with heavy skeletal disease burden. Up to 10-25% of men with significant bone metastases experienced grade 1-2 reductions in hemoglobin or platelets with lutetium-177 therapy.

In contrast, actinium-225's very short-range alpha particles (50-100 micrometers vs. up to 2 millimeters for beta particles) largely spare adjacent bone marrow while delivering lethal radiation doses directly to tumor cells. Early studies have confirmed this relative bone marrow sparing with actinium-225-PSMA even in patients with extensive skeletal metastases. Preclinical studies using intratibial bone metastasis models showed that actinium-225-PSMA reduced tumor burden by approximately 81% compared to vehicle controls, demonstrating robust activity in the bone microenvironment.

Lymph Node Metastases (present in 70-75% of patients):

Both lutetium-177 and actinium-225 show good activity against lymph node metastases. In meta-analyses, patients without visceral metastases (typically those with primarily bone and lymph node disease) achieved PSA50 responses of approximately 69% with actinium-225 versus 61% in patients with visceral disease—a modest but meaningful difference.

Visceral Metastases (liver, lung; present in 20-22% of patients):

Visceral metastases represent a particularly poor prognostic factor and appear to respond differently to the two radiopharmaceuticals. Patients with liver metastases have shown significantly poorer outcomes with actinium-225 therapy. In one study, liver metastases were associated with dramatically shorter median PSA progression-free survival (1.9 vs. 4.0 months), clinical progression-free survival (1.8 vs. 5.2 months), and overall survival (4.3 vs. 10.4 months) compared to patients without liver involvement.

This may relate to the fact that liver metastases often indicate more aggressive, advanced disease, but it also raises questions about whether the short-range alpha particles are less effective in larger visceral tumors with potentially heterogeneous PSMA expression. Conversely, some preclinical models using intracardiac injection to create visceral metastases showed that actinium-225-pelgi achieved an 84% reduction in tumor burden in liver, lungs, and brain—suggesting the alpha emitter can be highly effective against micrometastatic visceral disease when PSMA expression is adequate.

Disease Burden and PSMA Expression Density

The physical properties of alpha versus beta radiation create different optimal scenarios:

Alpha emitters (actinium-225) may be particularly advantageous when:

• PSMA expression is lower or heterogeneous, as the high energy of alpha particles can kill cells with fewer "hits"
• Tumors are in hypoxic (low oxygen) environments, where alpha particles remain effective
• Disease is micrometastatic or consists of small tumor deposits
• Skeletal metastases dominate, to minimize bone marrow toxicity
• Patients have failed lutetium-177 therapy

Beta emitters (lutetium-177) may be preferable when:

• Larger tumor masses need treatment, as beta particles can deliver "crossfire" radiation to cells farther from the targeting site
• Disease is predominantly in soft tissues (lymph nodes)
• Patients have good bone marrow reserve
• PSMA expression is robust and homogeneous
• Minimizing salivary gland toxicity is a priority

Prior Treatment History Matters

Response rates to actinium-225-PSMA are significantly influenced by prior treatments. Meta-analyses have shown:

• Treatment-naive patients: 76% achieved PSA50 response
• Post-lutetium-177 patients: 54% achieved PSA50 response
• Post-chemotherapy patients: Lower response rates across both agents

This suggests that actinium-225 may be most effective when used earlier in the treatment sequence rather than reserved as salvage therapy after multiple prior lines. However, it has also demonstrated activity after lutetium-177 failure, with approximately half of heavily pretreated patients still achieving significant PSA reductions.

Practical Implications for Patient Selection

These pharmacokinetic and metastasis-location factors suggest that optimal radiopharmaceutical selection should consider:

1. Pattern of metastases: Predominantly bone disease may favor actinium-225; visceral metastases (especially liver) may favor lutetium-177
2. Disease burden: Micrometastatic disease may benefit from alpha particles; bulkier disease may benefit from beta particles' longer range
3. Bone marrow reserve: Extensive skeletal metastases with borderline marrow function may better tolerate actinium-225
4. Salivary gland tolerance: Patients particularly concerned about dry mouth may prefer lutetium-177
5. Treatment sequencing: Earlier use (when PSMA expression is typically higher) may maximize actinium-225 effectiveness

The ANDROMEDA trial's head-to-head comparison in the oligorecurrent setting—where patients have limited, PSMA-positive disease and have not been heavily pretreated—represents an ideal scenario to define which agent works best. By stratifying patients by metastasis location (N1/M1a vs. M1b) and number of lesions, the trial will provide crucial data about how these factors influence treatment selection.

The ANDROMEDA Trial Design and Rationale

The ANDROMEDA study represents the first randomized, head-to-head comparison of lutetium-177 and actinium-225 radiopharmaceuticals in the oligorecurrent setting. According to the trial design, participants will be randomly assigned to receive either:

• Two cycles of lutetium-177-PSMA-617 (the FDA-approved agent marketed as Pluvicto) followed by SBRT, or
• A single cycle of actinium-225-PSMA-617 (investigational) followed by SBRT

All patients will receive SBRT to all detectable tumors identified on PSMA PET/CT scans. Their progress will be tracked using follow-up imaging, blood tests measuring PSA levels, and patient-reported quality-of-life measures to capture not only disease control but also the impact on daily living.

This trial design is particularly significant for several reasons. First, it addresses early recurrence—a stage where intervention might have greater impact than waiting until disease becomes widespread. The oligorecurrent state represents a critical window where aggressive treatment could potentially achieve durable disease control or even cure in some patients.

Second, the trial directly compares different radiation physics (alpha vs. beta) in a standardized population, which will provide crucial data about which type of radiation works best in this setting. Previous studies have compared these agents only indirectly or in different patient populations, making it difficult to draw definitive conclusions.

Third, the dosing differs between arms—two cycles of lutetium-177 versus one cycle of actinium-225—reflecting real-world practice patterns based on the different radiation energies and toxicity profiles of these agents. This pragmatic approach will yield results directly applicable to clinical decision-making.

Dr. Calais, director of UCLA's Ahmanson Translational Theranostics Division's clinical research program, explained the study's goals: "By combining whole-body targeted radiopharmaceutical therapy with precise local radiotherapy, we hope to eliminate both visible tumors and microscopic disease. The ultimate goal is to improve long-term cancer control while preserving quality of life."

The Promise of Delaying Hormone Therapy

One of the most compelling aspects of both the LUNAR and ANDROMEDA trials is their potential to delay or avoid androgen deprivation therapy (ADT), the standard systemic treatment for recurrent prostate cancer. While ADT effectively suppresses testosterone and slows cancer growth, it comes with significant quality-of-life impacts that can be particularly burdensome for men who may live many years with their cancer.

The side effects of hormone therapy are well-documented and often life-altering: hot flashes affect up to 80% of men, fatigue can be severe and persistent, loss of muscle mass and gain of body fat alter body composition, cognitive changes ("chemo brain") affect memory and concentration, sexual dysfunction includes loss of libido and erectile function, and long-term risks include cardiovascular disease, diabetes, and osteoporosis with increased fracture risk.

For many men, especially those with early recurrence and limited disease burden, the prospect of delaying these side effects while maintaining disease control represents a transformative potential benefit. In the LUNAR trial, men receiving the combination therapy enjoyed a median of 24.3 months—more than two years—before needing hormone therapy, compared to 14.1 months with radiation alone. This difference of more than 10 months represents significant additional time with better quality of life and preserved testosterone levels.

If PSMA-targeted radiopharmaceuticals combined with SBRT can provide durable disease control in the oligorecurrent setting, patients may enjoy extended periods of what researchers call "treatment holiday"—time free from systemic therapy while still keeping their cancer in check. For men in their 50s, 60s, and even 70s who may have decades of life ahead, this represents not just quantity of life but quality of life.

The Broader Landscape of PSMA Radioligand Therapy Research

The ANDROMEDA trial is part of a rapidly expanding ecosystem of research investigating PSMA-targeted radiopharmaceuticals across the full spectrum of prostate cancer:

Moving Earlier in the Disease Course: Multiple phase 3 trials are now exploring PSMA radioligand therapy in earlier disease settings. The PSMAddition trial completed enrollment in 2023 and is evaluating whether adding lutetium-177-PSMA-617 to standard treatment (androgen receptor pathway inhibitors plus ADT) improves outcomes for newly diagnosed metastatic hormone-sensitive prostate cancer. Results are expected in early 2026. The PEACE-6 trial is investigating a similar question specifically for poor responders to initial treatment.

Pre-Chemotherapy mCRPC: The PSMAfore and SPLASH trials have demonstrated that lutetium-177-PSMA-617 significantly improves radiographic progression-free survival compared to switching androgen receptor pathway inhibitors in men with metastatic castration-resistant prostate cancer who haven't yet received chemotherapy. PSMAfore showed a median rPFS of 9.3 months with Lu-177-PSMA versus 5.6 months with an ARPI switch (hazard ratio 0.41, p<0.001).

Combination Strategies: The recently reported ENZA-p trial demonstrated a survival benefit for combining enzalutamide with Lu-177-PSMA-617 versus enzalutamide alone in first-line metastatic castration-resistant disease, with median overall survival of 34 months versus 26 months (hazard ratio 0.55). This represents one of the first successful combination approaches, suggesting that radioligand therapy may work synergistically with hormone therapy and other treatments.

Actinium-225 Trials: At least 11 prospective trials are evaluating actinium-225-PSMA therapy, including dose-finding studies, monotherapy versus combination approaches, and salvage therapy after lutetium-177 progression. The AcTIOn trial is assessing actinium-225 in patients who have progressed on lutetium-177, while trials like PSMAcTION are exploring it in treatment-naive settings.

Re-treatment Studies: The RE-LuPSMA trial at UCLA and similar studies are investigating whether patients who initially responded well to lutetium-177-PSMA can benefit from additional cycles upon progression, an important question given the generally good tolerability of the beta-emitting agent.

High-Risk Localized Disease: Seven trials are exploring neoadjuvant or adjuvant PSMA radioligand therapy in high-risk localized prostate cancer, including before or after surgery. The LUPUS trial is evaluating intra-arterial delivery of Lu-177-PSMA-617 before radical prostatectomy, while the NeoPSMA trial is studying it before surgery in oligometastatic disease.

Understanding Alpha-Beta Differences: What the Science Shows

Recent meta-analyses and systematic reviews have begun to clarify the relative benefits and risks of alpha versus beta emitters in PSMA-targeted therapy. A 2024 meta-analysis published in European Urology examined data from 100 studies involving 8,711 patients and found:

• PSA decline ≥50% occurred in approximately 49% of lutetium-177-PSMA-treated patients versus 60% of actinium-225-PSMA-treated patients
• Among patients naive to radioligand therapy, actinium-225 achieved PSA50 responses in 76% versus 54% in patients previously treated with lutetium-177
• Quality of life improved with lutetium-177 therapy but remained stable (not improved) with actinium-225 therapy
• Severe toxicities were more frequent with actinium-225, particularly xerostomia
• The presence of visceral metastases and baseline hemoglobin levels were key factors associated with treatment response and survival

A 2025 systematic review focused specifically on actinium-225 found that 73.9% of patients experienced xerostomia, though most cases were grade 1-2. Only one patient in the pooled analysis experienced grade 3 or higher dry mouth. However, the clinical impact was substantial—in some series, nearly one-quarter of patients discontinued treatment due to bothersome xerostomia despite ongoing cancer response.

Emerging research is exploring strategies to mitigate salivary gland toxicity with actinium-225. These include:

• Salivary gland protection methods such as scopolamine patches, chewing polyglutamate tablets, or intra-parotid botulinum toxin injections to reduce salivary flow during treatment
• Novel radioligand designs with albumin-binding domains that prolong circulation time and alter biodistribution to reduce salivary gland uptake while maintaining tumor targeting (such as BAY 3563254, currently in development)
• Antibody-based delivery using molecules like J591 or TLX592, which show much lower salivary gland uptake than small molecule ligands, though with trade-offs in terms of different toxicity profiles

Patient Eligibility and Trial Participation

Men with oligorecurrent prostate cancer who meet specific eligibility criteria may qualify for the ANDROMEDA trial. While detailed inclusion and exclusion criteria should be discussed with the UCLA research team, the trial generally seeks patients with:

• Biochemical recurrence after definitive treatment (surgery or radiation)
• Limited metastatic disease (oligorecurrent, typically 1-5 sites)
• PSMA-positive disease confirmed by PSMA PET/CT imaging
• No hormone therapy within the last 6 months or currently hormone-sensitive
• Adequate organ function and performance status
• No contraindications to SBRT or radiopharmaceutical therapy

Patients interested in participating can contact the UCLA trial team at:

• Email: sparmisano@mednet.ucla.edu
• Phone: 310-825-9775
• Additional information: ClinicalTrials.gov (search for "ANDROMEDA UCLA prostate")

It's important to note that actinium-225-PSMA-617 remains investigational and is only available through clinical trials. Lutetium-177-PSMA-617 (Pluvicto) is FDA-approved but only for metastatic castration-resistant disease after progression on other treatments, not yet for the oligorecurrent hormone-sensitive setting studied in ANDROMEDA.

What This Means for Patients and the Future

The ANDROMEDA trial addresses fundamental questions that could reshape treatment approaches for recurrent prostate cancer:

Treatment Selection and Personalization: By directly comparing alpha versus beta radiation in a standardized population, the trial may help identify which patients benefit most from each approach. Factors such as disease burden, PSMA expression levels, metastasis location (bone vs. lymph node vs. visceral), baseline salivary gland function, and prior treatments could all play roles in determining optimal therapy selection.

Timing of Intervention: Both LUNAR and ANDROMEDA test whether earlier intervention with radioligand therapy, when disease burden is still limited, provides better outcomes than waiting until more advanced stages. This represents a potential paradigm shift from using these therapies only as late-stage salvage options to incorporating them much earlier in the treatment sequence.

Quality of Life Preservation: If successful in delaying hormone therapy while maintaining disease control, this approach could preserve quality of life during extended periods—a crucial consideration for men who may live many years or even decades with their cancer. The LUNAR trial already demonstrated a median 10-month delay in starting hormone therapy, and ANDROMEDA will provide additional data on this critical endpoint.

Combination Strategy Optimization: The integration of SBRT with radioligand therapy represents an evolving paradigm—combining systemic and localized treatments to address both visible disease and potential micrometastases. The success of this approach in LUNAR validates the concept and provides a strong foundation for ANDROMEDA's comparative evaluation of different radioligand agents.

Understanding Toxicity Trade-offs: By collecting detailed quality-of-life data alongside efficacy outcomes, ANDROMEDA will help quantify the trade-offs between potentially greater efficacy (with alpha emitters) versus more favorable toxicity profiles (with beta emitters). This patient-centered approach recognizes that the "best" treatment must balance disease control with quality of life.

The Theranostics Revolution

The ANDROMEDA and LUNAR trials exemplify what researchers call "theranostics"—the integration of diagnostics and therapeutics using the same molecular target. Dr. Calais, a leading expert in PSMA theranostics, explains: "We leveraged PSMA PET imaging technology to guide SBRT targeting, which is more precise than other imaging methods. And we combined it with PSMA radioligand therapy to treat PSMA-expressing sites of disease, both the ones visible by PET but also the microscopic sites too small to be detected."

This represents a fundamentally different approach to cancer treatment. Rather than applying therapies broadly based on clinical staging, theranostics allows physicians to:

1. Identify patients whose tumors express the target (via PSMA PET imaging)
2. Quantify the degree of target expression
3. Deliver targeted therapy directly to cancer cells
4. Monitor response using the same imaging technology
5. Adjust treatment based on individual response patterns

UCLA and UCSF have been pioneers in PSMA theranostics, jointly obtaining FDA approval in 2020 for PSMA PET imaging—a rare achievement for academic institutions. This imaging technique has proven more effective than prior methods at detecting prostate cancer lesions, enabling better treatment planning and patient selection for trials like ANDROMEDA.

Looking Ahead: The Evolving Treatment Landscape

As results emerge from ANDROMEDA and the dozens of other PSMA radioligand therapy trials now underway, the prostate cancer treatment landscape will continue to evolve rapidly. Several key questions remain:

Optimal Sequencing: When should radioligand therapy be introduced—at first recurrence, first metastatic disease, first castration-resistance, or after other treatments fail? Multiple trials are addressing different time points along this continuum.

Best Combinations: Should radioligand therapy be combined with hormone therapy, immunotherapy, PARP inhibitors, chemotherapy, or other treatments? Early results with combinations are promising but require validation in larger studies.

Response Prediction: Can we identify biomarkers that predict which patients will respond best to which radioligand therapy? Factors under investigation include PSMA expression intensity, presence of visceral metastases, baseline hemoglobin, genetic variants, and immune system parameters.

Resistance Mechanisms: Why do some patients not respond or develop resistance to radioligand therapy? Understanding resistance mechanisms could lead to strategies to overcome or prevent resistance.

Novel Agents: Multiple next-generation radioligands are in development, including lead-212-PSMA, thorium-227-PSMA, improved actinium-225 compounds with better salivary gland sparing, and bispecific agents targeting multiple antigens simultaneously.

A Note on Clinical Trial Participation

The ANDROMEDA trial exemplifies why clinical trial participation matters. Every patient who enrolls contributes valuable data that will help future patients receive better, more personalized treatment. Clinical trials offer several potential benefits:

• Access to cutting-edge treatments not yet available outside of research settings
• Close monitoring by expert teams specializing in the disease
• Contribution to scientific knowledge that will help others
• Potential individual benefit from experimental therapies

However, participation also involves considerations such as more frequent visits, additional testing, the possibility of side effects from investigational treatments, and uncertainty about whether the experimental arm will prove superior to standard treatment.

Men considering trial participation should discuss thoroughly with their oncology team, understand the potential risks and benefits, consider logistics and travel requirements, and make informed decisions based on their individual circumstances and priorities.

Conclusion

The ANDROMEDA trial represents the cutting edge of precision medicine for prostate cancer. By directly comparing two fundamentally different types of radiation—alpha-emitting actinium-225 versus beta-emitting lutetium-177—in combination with precision stereotactic radiation, this study will provide crucial data to guide treatment selection for men with oligorecurrent disease.

Building on the remarkable success of the LUNAR trial, which demonstrated that adding radioligand therapy to SBRT can more than double progression-free survival, ANDROMEDA asks the next logical question: which radioligand works best? The answer will help physicians personalize treatment recommendations, balancing the potential for greater tumor kill against quality-of-life considerations, while taking into account critical factors like metastasis location, disease burden, and individual patient characteristics.

As Dr. Kishan noted in discussing the LUNAR results: "This is an important proof of principle. It suggests we may be able to intervene earlier with radioligand therapy and meaningfully change the course of disease." The goal remains constant across all these trials: achieving durable disease control while preserving quality of life. Studies like ANDROMEDA bring us closer to that objective, one patient at a time.

For men facing oligorecurrent prostate cancer, the expanding array of treatment options—including participation in groundbreaking trials like ANDROMEDA—offers hope for better outcomes and better lives.

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Note: This article is intended for educational purposes and should not replace consultation with qualified healthcare providers. Patients should discuss all treatment options, including clinical trial participation, with their oncology team to determine the most appropriate approach for their individual situation. The ANDROMEDA trial contact information: Email sparmisano@mednet.ucla.edu or call 310-825-9775.