Prostate cancer remains the second most prevalent malignancy among men globally, often presenting a formidable challenge when it recurs after initial treatment. Oligorecurrent prostate cancer, characterized by a small number of new metastatic lesions, demands precise and effective therapeutic interventions. SBRT, a form of high-precision radiation that targets tumors while sparing surrounding healthy tissue, has become the standard for managing these cases. However, many patients eventually experience relapse, primarily due to microscopic disease invisible on conventional imaging.

To address this, the UCLA-led LUNAR phase 2 trial investigated whether incorporating a PSMA-targeted radioligand, specifically the molecule 177Lu-PNT2002, prior to SBRT could better eradicate both visible and occult prostate cancer cells. Prostate-specific membrane antigen (PSMA) is a protein abundantly expressed on prostate cancer cells, making it an ideal target for radioligand therapies. Unlike traditional radiation, radioligand therapy delivers targeted radiation via radioactive isotopes linked to molecules that bind directly to cancer cells, minimizing collateral damage to healthy tissues.

The trial enrolled 92 men with oligorecurrent prostate cancer and randomly assigned them to two groups. The control arm received SBRT alone, while the experimental arm received two doses of 177Lu-PNT2002 before SBRT. Patients were monitored through prostate-specific antigen (PSA) blood tests and advanced PSMA PET imaging to evaluate disease progression. Remarkably, those treated with the combination therapy exhibited a median progression-free survival of 17.6 months, more than twice that of the SBRT-only group, which demonstrated 7.4 months.

This substantial improvement translated into a 63% reduction in the combined risk of cancer progression, initiation of hormone therapy, or death. Importantly, the addition of 177Lu-PNT2002 delayed the initiation of androgen deprivation therapy (ADT)—a cornerstone treatment for advanced prostate cancer known for its severe side effects such as fatigue, sexual dysfunction, and bone density loss. Men receiving the combination therapy enjoyed a median of 24.3 months before hormone therapy became necessary, compared to 14.1 months in the SBRT-alone cohort.

The success of this combined modality stems not only from its capacity to target PSMA-expressing cancer cells visible on PET scans but also from its potential to eradicate microscopic disease lingering beneath the detection threshold. By harnessing PSMA PET imaging to precisely guide SBRT targeting and coupling it with radioligand therapy, the researchers created a dual-attack strategy that addresses both macroscopic and microscopic cancer deposits.

Additionally, the LUNAR trial delved into biological markers that could predict patient responses to treatment. The researchers analyzed T cell receptor changes post-SBRT, immunological shifts associated with improved clinical outcomes. Furthermore, a gene expression signature encompassing 20 genes linked to immune function and DNA repair differentiated patients at higher risk of disease progression from those more likely to benefit from therapy, opening avenues toward personalized treatment approaches.

Despite the profound benefits observed, the trial underscored ongoing challenges, as 64% of men still experienced disease progression. This high relapse rate highlights the complexity of micrometastatic prostate cancer and suggests the need for further refinements in both therapeutic delivery and precision targeting.

Dr. Amar Kishan, the executive vice chair of radiation oncology and co-director of the cancer molecular imaging, nanotechnology, and theranostics program at UCLA, emphasized the significance of these findings: “Our research provides pivotal proof of principle that radioligand therapy can be effectively and safely integrated earlier in prostate cancer treatment, offering patients meaningful delays in disease progression and hormone therapy initiation without additional toxicity.”

Moreover, Dr. Jeremie Calais, the trial’s senior author and director of the Ahmanson Translational Theranostics Division, highlighted the synergy achieved through collaboration between radiation oncology and nuclear medicine. This interdisciplinary approach exemplifies the promise of theranostics—a field combining diagnostic imaging and targeted therapy—to revolutionize cancer care paradigms.

The safety profile of the combination therapy was also encouraging, with minimal adverse effects reported, reinforcing its potential for broader clinical application. Nevertheless, the investigators acknowledge the necessity for longer-term follow-up and exploration of strategies to enhance response rates, such as optimizing dosing schedules or combining with immunotherapies.

This study not only propels forward the clinical utility of PSMA-targeted radioligand agents beyond advanced metastatic settings but also redefines the therapeutic landscape for men with oligorecurrent disease. By extending progression-free survival and postponing hormone therapy, this approach promises to improve both survival and quality of life for countless patients worldwide.

Funded by Lantheus, the LUNAR trial represents a milestone in prostate cancer research, illuminating a new path for early intervention that leverages molecular targeting and state-of-the-art imaging to outmaneuver one of the most common and insidious cancers affecting men today.

Subject of Research: Prostate cancer treatment using PSMA-targeted radioligand therapy combined with stereotactic body radiotherapy (SBRT).

Article Title: New Radioligand Therapy Combined with Radiotherapy Doubles Progression-Free Survival in Recurrent Prostate Cancer

News Publication Date: 2025

Web References:

• UCLA Health Jonsson Comprehensive Cancer Center: https://www.uclahealth.org/cancer
• 2025 ASTRO Annual Meeting Session: https://amportal.astro.org/sessions/ct-01-21645/177-lutetium-psma-neoadjuvant-to-ablative-radiotherapy-for-oligorecurrent-prostate-cancer-pri-109077
• Dr. Amar Kishan Profile: https://www.uclahealth.org/providers/amar-kishan
• Dr. Jeremie Calais Profile: https://www.uclahealth.org/cancer/members/jeremie-calais

Keywords: Prostate cancer, PSMA-targeted radioligand therapy, stereotactic body radiotherapy, oligorecurrent disease, progression-free survival, androgen deprivation therapy, theranostics, prostate-specific membrane antigen, 177Lu-PNT2002, molecular imaging, cancer treatment innovations.

PSMA-targeted radioligand therapy (RLT) has revolutionized the treatment landscape for advanced prostate cancer by delivering radioactive isotopes directly to malignant cells expressing PSMA. Particularly, the tandem use of alpha-emitter ^225Ac-PSMA and beta-emitter ^177Lu-PSMA has demonstrated remarkable anti-tumor efficacy. However, an unfortunate consequence of this targeted therapy is the inadvertent radiation exposure and consequent damage to non-target tissues such as the salivary glands. Such toxicity manifests as xerostomia or chronic dry mouth, severely diminishing quality of life and potentially forcing patients to discontinue otherwise effective therapies.

Historically, attempts to mitigate salivary gland damage using methods such as applying cold packs, external cooling, or single-agent anticholinergic drugs have yielded limited success. The paramount challenge lies in selectively protecting the salivary glands without compromising the accumulation of radioligands in tumor tissues. Against this backdrop, the recent study from the National University of Singapore offers a beacon of hope through a dual-modality prophylactic intervention that harnesses the complementary pharmacological effects of Botox and scopolamine.

Botulinum toxin, a neurotoxic protein widely known for its neuromuscular blockade properties, is administered via ultrasound-guided injections into the major salivary glands – specifically the parotid and submandibular glands – on alternate sides of the body. By inhibiting acetylcholine release at the presynaptic neuromuscular junction, Botox effectively reduces salivary gland secretory activity and blood flow, likely diminishing the retention and uptake of PSMA-targeted radioligands in these tissues. Complementing this, transdermal scopolamine patches applied behind the ears serve as a systemic anticholinergic agent, further curbing parasympathetic stimulation and potentially enhancing glandular protection.

The study enrolled fourteen patients with metastatic castration-resistant prostate cancer scheduled for combined ^225Ac- and ^177Lu-PSMA RLT. Botox injections were administered three to four weeks prior to the initiation of therapy, allowing sufficient time for the neurotoxin to exert its effects on glandular function. Scopolamine patches were applied three days before treatment and maintained until two hours post-therapy. Molecular imaging assessments, including pre- and post-treatment PSMA PET/CT scans and SPECT/CT, quantitatively evaluated changes in radioligand uptake within the salivary glands.

Results revealed a significant and clinically meaningful reduction in PSMA tracer accumulation in treated salivary glands. Notably, Botox-injected parotid glands exhibited an average 30% decrease in radioligand uptake when compared to the contralateral untreated glands. Similarly, treated submandibular glands demonstrated a 17% reduction relative to their untreated counterparts. Importantly, despite this protective effect on non-target tissue, tumor uptake of PSMA radioligands remained unaffected, underscoring the therapeutic selectivity of the intervention.

Patients tolerated the combined Botox and scopolamine regimen remarkably well, with only mild localized injection discomfort reported and no serious systemic adverse events. Crucially, no participants discontinued radioligand therapy owing to xerostomia, suggesting a substantial improvement in treatment adherence and overall quality of life. This safety profile is particularly encouraging given that both Botox and scopolamine are already FDA-approved agents with well-characterized mechanisms of action and established clinical use in other settings.

The implications of these findings are far-reaching. Addressing salivary gland toxicity not only alleviates a debilitating side effect but also holds potential to broaden the therapeutic index of PSMA-targeted radiopharmaceuticals, especially those employing potent alpha emitters like ^225Ac. By mitigating dose-limiting toxicity, clinicians may be empowered to deliver higher or more frequent therapeutic doses, potentially enhancing oncologic outcomes without compromising patient well-being.

Dr. Jingjing Zhang, assistant professor at the Theranostics Centre of Excellence, emphasized the translational impact of the study: "Our approach leverages readily available, FDA-approved medications to pioneer a protective strategy against radiation-induced salivary gland damage. This innovation could rapidly be adopted in clinical centers equipped to perform PSMA radioligand therapy, thereby enhancing patient care on a global scale."

Mechanistically, the synergy between Botox’s local neuromuscular blockade and the systemic parasympathetic inhibition by scopolamine likely orchestrates a multifaceted reduction in salivary gland perfusion, secretion, and consequent PSMA radioligand uptake. This dual blockade represents a significant advancement over prior monotherapies or physical cooling methods that failed to achieve meaningful glandular protection.

Further research is warranted to optimize dosing, timing, and delivery parameters of this combined intervention, as well as to evaluate long-term outcomes and potential effects on salivary gland function recovery. Nonetheless, these promising early results chart a clear path forward toward integrating neurotoxin and anticholinergic agents into standard care protocols for patients undergoing PSMA-targeted therapies.

In conclusion, this innovative protective strategy opens new avenues to improve the therapeutic ratio of radioligand therapy in advanced prostate cancer. By proactively safeguarding salivary glands from radiation damage, the combined use of botulinum toxin and scopolamine holds great promise to enhance patient quality of life, maintain adherence to life-extending treatments, and ultimately improve clinical outcomes in this challenging oncologic arena.

Subject of Research: Protective strategies against salivary gland toxicity during PSMA-targeted radioligand therapy in metastatic prostate cancer patients.

Article Title: Botulinum Toxin Plus Scopalamine as a Protective Strategy Against Salivary Gland Toxicity in Patients Treated with 225Ac- and 177Lu- PSMA-Targeted Radioligand Therapy (TANDEM PSMA-RLT).

News Publication Date: 2025

Web References:
https://jnm.snmjournals.org/content/66/supplement_1/251452

Image Credits:
Images created by Tianzhi Zhao, Jingjing Zhang, et al., National University of Singapore, Singapore / Richard P. Baum et al., Curanosticum Wiesbaden-Frankfurt, Wiesbaden, Germany.

Keywords:
Personalized medicine, side effects, medical treatments, prostate cancer