In a groundbreaking clinical trial, researchers at the UCLA Health Jonsson Comprehensive Cancer Center have revealed promising results for men battling recurrent prostate cancer through an innovative combination therapy. This novel approach integrates PSMA-targeted radioligand therapy with stereotactic body radiotherapy (SBRT), offering more than double the progression-free survival compared to SBRT alone. These findings, unveiled at the 2025 American Society for Radiation Oncology (ASTRO) Annual Meeting, mark a significant advancement in treating oligorecurrent prostate cancer—where the disease returns in limited, detectable lesions.
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.
