{"id":614924,"date":"2026-09-05T03:44:18","date_gmt":"2026-09-05T03:44:18","guid":{"rendered":"https:\/\/www.newsbeep.com\/ie\/614924\/"},"modified":"2026-09-05T03:44:18","modified_gmt":"2026-09-05T03:44:18","slug":"prostic26-lutetium-psma-in-oligometastatic-disease","status":"publish","type":"post","link":"https:\/\/www.newsbeep.com\/ie\/614924\/","title":{"rendered":"ProsTIC26: Lutetium PSMA in Oligometastatic Disease"},"content":{"rendered":"

(UroToday.com)\u00a0The 2026 ProsTIC annual meeting featured a Lutetium-177 session and a presentation by Dr. Amar Kishan discussing Lutetium PSMA in oligometastatic disease. Oligometastatic prostate cancer is generally characterized by the presence of 1\u20135 detectable metastatic lesions. However, this clinical definition likely encompasses a biologically heterogeneous group of patients. Oligometastatic disease may represent genuinely indolent biology with limited potential for polymetastatic progression, aggressive disease identified relatively early in its natural history, or disease that historically would have remained subclinical but is now detectable because of increasingly sensitive imaging modalities such as PSMA PET.<\/p>\n


\n <\/p>\n

The strength of the metastasis directed therapy data was highlighted by the WOLVERINE individual patient data meta-analysis of six randomized phase II trials comprising 472 patients with a median follow-up of 40.7 months.1 Across these studies, metastasis directed therapy demonstrated robust benefits in progression free survival (HR 0.44, 95% CI 0.35-0.56), radiographic progression free survival (HR 0.60, 95% CI 0.42-0.85), and castration resistant free survival (HR 0.58, 95% CI 0.37-0.92), with a trend toward an overall survival (HR 0.63, 95% CI 0.39-1.00) benefit:<\/p>\n

<\/p>\n

\"\"<\/p>\n

<\/p>\n

These findings reinforce the clinical activity of metastasis directed therapy while also providing an important foundation for considering whether outcomes can be further improved through treatment intensification.<\/p>\n

<\/p>\n

Despite these favorable data, patterns of failure following metastasis directed therapy remain important. Long-term durable disease control with metastasis directed therapy alone is relatively uncommon. Patients experiencing subsequent oligoprogression may undergo repeat metastasis directed therapy; however, repeated episodes of oligoprogression ultimately tend to transition toward polyprogressive disease.2 This pattern strongly suggests that occult systemic disease may already be present despite apparently limited metastatic burden on imaging:<\/p>\n

<\/p>\n

\"image-1.jpg\"<\/p>\n

<\/p>\n

The role of hormonal therapy in this setting also remains nuanced. In WOLVERINE, the use of ADT, or ADT + an androgen receptor pathway inhibitor (ARPI), did not modify the effect of metastasis directed therapy on any endpoint within the castration sensitive prostate cancer subgroup. Although RADIOSA demonstrated a progression free survival benefit with the addition of six months of ADT to metastasis directed therapy,3 the median time to testosterone recovery was nine months. When outcomes were evaluated using eugonadal progression free survival, there was no significant difference, and castration recurrence free survival was similarly not different. These observations raise the clinically relevant question of whether alternative forms of intensification might improve disease control without requiring prolonged hormonal suppression.<\/p>\n

<\/p>\n

This provides the rationale for PSMA-directed radioligand therapy. Agents combining lutetium-177 with PSMA-targeting ligands have demonstrated improved progression free survival in men with advanced prostate cancer. To date, however, the observed benefit of PSMA-directed radioligand therapy has largely been attributed to its effect on macroscopic disease. The LUNAR trial tested a different hypothesis: whether adding 177Lu-PNT2002 to metastasis directed stereotactic body radiation therapy in patients with oligorecurrent prostate cancer could improve progression free survival by treating occult microscopic disease that is not visualized on PSMA PET.4 The LUNAR study enrolled patients with 1\u20135 lesions outside the prostate or prostate bed identified on PSMA PET\/CT. Patients were randomized 1:1, stratified by N1\/M1a versus M1b disease and by the number of lesions (1 versus 2\u20133 versus 4\u20135). Patients assigned to the experimental arm received 177Lu-PNT2002 at 6.8 GBq (\u00b110%) intravenously for two cycles administered eight weeks apart. PSMA PET\/CT was performed 4\u20136 weeks after the second cycle, followed by stereotactic body radiation therapy to all PSMA PET\/CT-defined disease. The comparator arm received stereotactic body radiation therapy to all sites of PSMA PET\/CT-defined disease. The primary endpoint was progression free survival, defined by progression on scheduled or triggered PSMA PET\/CT, initiation of salvage hormonal therapy, or death:<\/p>\n

<\/p>\n

\"image-2.jpg\"<\/p>\n

<\/p>\n

Between September 2, 2022 and November 9, 2023, 87 patients were randomized, including 42 to stereotactic body radiation therapy alone and 45 to 177Lu-PNT2002 + stereotactic body radiation therapy. The median age was 70.2 versus 69.7 years, respectively, and the median PSA at randomization was 1.2 versus 1.1 ng\/mL. Radical prostatectomy had been the prior definitive treatment in 71.4% and 73.3% of patients, respectively, while radiotherapy had been used in 29.3% and 26.7%. Prior ADT exposure was reported in 38.1% versus 55.6%, prior ARPI exposure in 21.4% versus 17.8%, prior chemotherapy in 7.1% versus 6.7%, and prior metastasis directed therapy in 38.1% versus 28.9%. By conventional imaging, 69.0% and 75.6% of patients were N0M0, while N0M1b disease was present in 21% and 20.0%, respectively:<\/p>\n

<\/p>\n

\"image-3.jpg\"<\/p>\n

<\/p>\n

LUNAR demonstrated a substantial improvement in progression free survival with 177Lu-PNT2002 + stereotactic body radiation therapy. The median progression free survival increased from 7.4 months (95% CI 6.0\u201313.5 months) with stereotactic body radiation therapy alone to 17.6 months (95% CI 15 months\u2013not reached) with 177Lu-PNT2002 + stereotactic body radiation therapy (HR 0.37, 95% CI 0.22\u20130.61; p < 0.0001):<\/p>\n

<\/p>\n

\"image-4.jpg\"<\/p>\n

<\/p>\n

Importantly, 98% of progression events (64\/65) were driven by the development of new lesions rather than failure at previously treated sites. On a per-lesion basis, in-field progression occurred in only 2 of 91 lesions (2%) treated with stereotactic body radiation therapy alone and 0 of 96 lesions (0%) treated with 177Lu-PNT2002 + stereotactic body radiation therapy.<\/p>\n

<\/p>\n

This benefit also extended to hormonal therapy free survival. The median hormonal therapy free survival increased from 14.1 months (95% CI 10.1 months\u2013not reached) with stereotactic body radiation therapy alone to 24.3 months (95% CI 18 months\u2013not reached) with 177Lu-PNT2002 + stereotactic body radiation therapy:<\/p>\n

<\/p>\n

\"image-5.jpg\"\u00a0<\/p>\n

<\/p>\n

Of the 47 patients who ultimately received salvage hormonal therapy, 46 had developed new lesions on PSMA PET\/CT. Repeat metastasis directed therapy without hormonal therapy was delivered to 17 patients.<\/p>\n

<\/p>\n

The improvement in disease control did not come with a significant overall increase in adverse events with 177Lu-PNT2002. Grade 1 anemia occurred in 21.4% with stereotactic body radiation therapy alone versus 31.1% with 177Lu-PNT2002 + stereotactic body radiation therapy. Grade 1, 2, and 3 lymphopenia occurred in 14.3%, 9.5%, and 4.8% versus 31.1%, 17.8%, and 6.7%, respectively. Grade 1 thrombocytopenia occurred in 9.5% versus 13.3%. Grade 1 fatigue was reported in 76.5% versus 64.3%, while grade 2 fatigue occurred in 0% versus 4.8%. Dry mouth was uncommon (5.6% versus 6.8%), as were dry eyes (0% versus 4.4%). Grade 1 nausea occurred in 14.3% versus 8.9%, and grade 2 nausea in 2.9% versus 0%, respectively:<\/p>\n

<\/p>\n

\"image-6.jpg\"<\/p>\n

<\/p>\n

Dr. Kishan then discussed the BULLSEYE trial,5 which provided an important complementary perspective to LUNAR. BULLSEYE randomized 58 men with \u22645 metastatic lesions, including at least one lesion with SUVmax \u226515, to 2\u20134 cycles of 177Lu-PSMA-I&T at 7.4 GBq administered six weeks apart versus observation. The median PSA was >3.8 ng\/mL in both arms, and approximately 50% of patients in each arm had 4\u20135 lesions. The primary endpoints were the proportion of patients experiencing disease progression and progression free survival. Progression could be defined by the treating physician, radiographic progression free survival, or a 100% increase in PSA. At a median follow-up of 27 months, disease progression occurred in 52% of patients receiving 177Lu-PSMA-I&T compared with 97% of patients in the observation arm. The median progression free survival was 25 months versus 5 months, respectively (HR 0.07, 95% CI 0.03-0.17, p < 0.0001):<\/p>\n

<\/p>\n

\"image-7.jpg\"<\/p>\n

<\/p>\n

Seven patients (24%) achieved a complete biochemical response. From a safety perspective, no significant toxicities were identified beyond a clear increase in fatigue. However, the BULLSEYE results also raise a critical question regarding whether radioligand therapy should replace or complement metastasis directed therapy. PSMA PET\/CT at progression in BULLSEYE was performed at physician discretion. Among patients progressing after 177Lu-PSMA-I&T who underwent PSMA PET (60% of those who progressed), 75% demonstrated local progression, and 92% had metastatic disease. Given the fundamental premise of metastasis directed therapy, the demonstrated benefit of metastasis directed therapy even in the setting of concurrent ADT in EXTEND,6 and biological evidence supporting metastasis-to-metastasis spread,7 these findings suggest that metastasis directed therapy may remain critical for eliminating gross disease even when systemic PSMA-directed radioligand therapy is incorporated. In this framework, radioligand therapy and metastasis directed therapy may be complementary rather than competing strategies: radioligand therapy targeting occult microscopic disease and metastasis directed therapy consolidating visible macroscopic disease.<\/p>\n

<\/p>\n

Several important future questions emerge from these studies:<\/p>\n


\n
\nWhat is the longer-term adverse event risk of radioligand therapy in patients with substantially longer life expectancy than those historically treated in advanced prostate cancer?
\nWhich patients actually require treatment intensification?
\nWhat is the most appropriate endpoint for future trials?
\nWhat is the optimal radioligand for the micrometastatic disease setting?
\n <\/p>\n

The adverse event question is particularly important as radioligand therapy moves earlier in the disease course. In this setting, short-term tolerability must be considered alongside the possibility of delayed toxicities that may emerge with longer follow-up. Dr. Kishan highlighted contemporary data evaluating adverse events following radioligand therapy,8 emphasizing the need for careful longitudinal assessment as these agents are deployed in patients with oligometastatic disease and potentially prolonged survival:<\/p>\n

<\/p>\n

\"image-8.jpg\"<\/p>\n

<\/p>\n

One specific area of concern is clonal hematopoiesis of indeterminate potential (CHIP). Clonal hematopoiesis represents a precursor state associated with an increased risk of hematologic malignancies and may potentially be increased by radioligand therapy exposure. A post hoc analysis of TheraP among patients with docetaxel-refractory mCRPC identified treatment-emergent clonal hematopoiesis in 62% of patients receiving 177Lu-PSMA-617 compared with 40% of patients receiving docetaxel:9<\/p>\n

<\/p>\n

\"image-9.jpg\"<\/p>\n

<\/p>\n

While the clinical implications of these findings in earlier-stage disease remain uncertain, they underscore the importance of understanding late hematologic effects when radioligand therapy is considered for patients with considerably longer anticipated survival.<\/p>\n

<\/p>\n

The next major question is determining which patients require intensification beyond metastasis directed therapy. A nomogram was developed using 586 patients treated with metastasis directed therapy without ADT and a median follow-up of 37 months, with subsequent validation in an additional 131 patients. Patients with 3-5 lesions and those with high risk disease had worse outcomes:<\/p>\n

<\/p>\n

\"image-10.jpg\"<\/p>\n

<\/p>\n

Such risk-stratification approaches may ultimately help distinguish patients who can achieve durable disease control with metastasis directed therapy alone from those whose clinical phenotype suggests a greater burden of occult systemic disease and therefore a greater potential benefit from systemic intensification.<\/p>\n

<\/p>\n

Beyond conventional clinical risk factors, there is an emerging opportunity for biomarker-driven patient selection for treatment intensification. Potential strategies highlighted included somatic mutational signatures, germline mutational signatures, PSMA-positive extracellular vesicles, and digital histopathology. Incorporating these biomarkers with clinical features could ultimately provide a more biologically informed definition of oligometastatic disease and help rationally allocate intensification rather than treating all patients with the same approach.<\/p>\n

<\/p>\n

The optimal endpoint for trials in this setting also warrants reconsideration. PSMA PET-driven metastasis free survival is unlikely to represent a surrogate for overall survival and may more closely resemble an event free survival endpoint because of the sensitivity of contemporary molecular imaging. In presented data at SNMMI 2026, conventional imaging metastasis free survival (HR 4.09) and OS (HR 3.2) were shorter among patients with >5 lesions compared with those with 1\u20135 lesions on PSMA PET, representing a potential \u201cpolymetastatic PSMA-metastasis free survival\u201d phenotype. Dr. Kishan suggested that freedom from clinical detriment may ultimately represent a more patient-centric endpoint for future studies.<\/p>\n

<\/p>\n

Finally, the optimal radioligand itself remains an open question. Beta emitters may not be ideal for micrometastatic disease because of their relatively long path length. Higher linear energy transfer particles, including alpha particles and Auger electrons, may theoretically be better suited for targeting microscopic deposits. Conversely, tumor dose with high-LET particles may be limited in the setting of heterogeneous PSMA expression, and toxicity may ultimately become dose limiting. The next-generation LUNAR study, ANDROMEDA (NCT07150715), is directly addressing this question by evaluating one cycle of 225Ac-PSMA-617 versus two cycles of 177Lu-PSMA-617 prior to stereotactic body radiation therapy.<\/p>\n

<\/p>\n

\u00a0Dr. Kishan concluded his presentation discussing Lutetium PSMA in oligometastatic disease with the following take home messages:<\/p>\n


\n
\nWhile metastasis directed therapy improves outcomes, occult disease remains a concern
\nRadioligand therapy may act on occult disease (as seen in LUNAR)
\nMetastasis directed therapy can consolidate local control (as implied by the BULLSEYE results)
\nNumerous important questions remain, including the adverse event profile and how to rationally allocate intensification
\n <\/p>\n

Presented by: Amar Kishan, MD, University of California \u2013 Los Angeles, Los Angeles, CA<\/p>\n

<\/p>\n

Written by: Zachary Klaassen, MD, MSc \u2013 Urologic Oncologist, Augusta, GA, @zklaassen_md on Twitter during\u00a0the 2026 ProsTIC Annual Meeting, Melbourne, Australia, Fri, Sept 3 \u2013 Sat, Sept 4, 2026. <\/a><\/p>\n

<\/p>\n

References:<\/p>\n


\n
\nTang C, Sherry AD, Hwang H, et al. Metastasis-directed therapy and standard of care versus standard of care for oligometastatic prostate cancer (WOLVERINE): A systematic review and individual patient data meta-analysis from the X-MET collaboration. Lancet Oncol. 2026 Feb;27(2):181-190.
\nDeek MP, Taparra K, Dao D, et al. Patterns of Recurrence and Modes of Progression after Metastasis-Directed Therapy in Oligometastatic Castration-Sensitive Prostate Cancer. Int J Radiat Oncol Biol Phys. 2021 Feb 1;109(2):387-395.
\nMarvaso G, Corrao G, Zaffaroni M, et al. ADT with SBRT versus SBRT alone for hormone-sensitive oligorecurrent prostate cancer (RADIOSA): A randomized, open-label, phase 2 clinical trial. Lancet Oncol. 2025 Mar;26(3):300-311.<\/a>
\nKishan AU, Valle LF, Wilhalme H, et al. 177Lu-Prostate-Specific Membrane Antigen Neoadjuvant to Stereotactic Ablative Radiotherapy for Oligorecurrent Prostate Cancer (LUNAR): An open-label, randomized, controlled, phase II study. J Clin Oncol. 2025 Dec 20;43(36):3812-3821.<\/a>
\nPrive BM, Noordzij W, Mueselaers CHJ, et al. [177Lu]-PSMA-617-PSMA-617 in oligometastatic hormone sensitive prostate cancer (BULLSEYE): An open-label, randomized, phase 2 study. Lancet Oncol. 2026 Apr;27(4):461-469.<\/a>
\nTang C, Sherry AD, Haymaker C, et al. Addition of metastasis-directed therapy to intermittent hormone therapy for oligometastatic prostate cancer: The EXTEND phase 2 randomized clinical trial. JAMA Oncol. 2023 Jun 1;9(6):825-834.<\/a>
\nGundem G, Van Loo P, Kremeyer B, et al. The evolutionary history of lethal metastatic prostate cancer. Nature. 2015 Apr 16;520(7547);353-357.
\nAbdlkadir AS, Al-Adhami D, Moghrabi S, et al. Beyond [177Lu]Lu-PSMA: A meta-analysis of safety and efficacy of emerging PSMA radioligand therapy agents. BMC Cancer. 2026 Mar 23;26(1):551.
\nMunzur AD, Herberts C, Kwan EM, et al. Clonal hematopoiesis after 177Lu-PSMA-617 Radioligand Therapy in Prostate Cancer. Clin Cancer Res. 2026 Jul 1;32(13):2644-2652.<\/a> <\/p>\n","protected":false},"excerpt":{"rendered":"(UroToday.com)\u00a0The 2026 ProsTIC annual meeting featured a Lutetium-177 session and a presentation by Dr. Amar Kishan discussing Lutetium…\n","protected":false},"author":2,"featured_media":614925,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[10],"tags":[103,61,60],"class_list":["post-614924","post","type-post","status-publish","format-standard","has-post-thumbnail","category-health","tag-health","tag-ie","tag-ireland"],"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/posts\/614924","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/comments?post=614924"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/posts\/614924\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/media\/614925"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/media?parent=614924"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/categories?post=614924"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/ie\/wp-json\/wp\/v2\/tags?post=614924"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}