Radiopharmaceutical therapy (RPT), the administration of a radioactive element coupled with a targeting vector, is one of the most promising innovations in oncology, supported by clinical trials. A theranostic approach—the pairing of diagnostic and therapeutic RPTs sharing the same target—facilitates selective delivery of therapeutic radiation to cancer cells. Its advantages and limitations are determined by the molecular targeting mechanisms employed, as well as the types of ionising radiation emitted. Therefore, understanding the biology of cell-surface targets and molecular mechanisms governing target expression in cancers is critical to the development and clinical use of these agents. This review provides an overview of the latest advances in the application of targeted RPTs within oncology, as discussed at the Fourth Transatlantic Exchange in Oncology, a hybrid conference held in March 2025 that brought together experts from Dana-Farber Cancer Institute (Boston, MA, USA) and Gustave Roussy (Paris, France). Key topics included the targeting of prostate-specific membrane antigen (PSMA) for both imaging and therapy purposes in prostate cancer. In particular, PSMA-based imaging—encompassing both positron emission tomography (PET) and single-photon emission computed tomography (SPECT)—has become a fundamental tool for patient selection, evaluation of treatment response, and personalisation of therapeutic strategies. While theranostic approaches continue to pose challenges, they should increasingly enable improved treatment selection for patients with cancer, and more effective prediction of response and toxicity. Lessons learned from PSMA may apply to other emerging theranostic targets in prostate cancer and other tumour types, expanding the future potential of RPT applications. Beyond current achievements, new molecules and intensive translational research programs may optimise, potentiate and direct RPT. The impact of the expanding use of RPTs on healthcare systems was also addressed, defining strategies to overcome barriers and provide broader access to innovations in RPT in both clinical and research settings. Physicians now recognise that an improved understanding of the molecular differences and biology of treatment targets on cells can have therapeutic implications in patients with cancer. Radiopharmaceuticals are radioactive drugs that can be used for certain imaging tests and for treating specific types of cancer. The term ‘theranostics’ is a concept that includes the use of both diagnostic and therapeutic radio-pharmaceuticals with the same target. Imaging, such as positron emission tomography, is initially performed using a diagnostic radiopharmaceutical to determine if the target of interest is sufficiently present to proceed with the therapeutic radiopharmaceutical. This review paper provides an overview of the latest advances in the application of targeted radiopharmaceutical therapies within oncology in prostate and beyond prostate cancer, as discussed at the Fourth Transatlantic Exchange in Oncology, which brought together leading experts from Dana-Farber Cancer Institute, Boston, USA, and Gustave Roussy, Paris, France, in March 2025. Theranostic approaches continue to evolve rapidly. Imaging remains a cornerstone—enabling precise patient selection, real-time monitoring of treatment response, and personalisation of therapeutic strategies. Advances in target discovery, novel radiopharmaceutical design, and translational research programs are opening new avenues to optimise efficacy, mitigate toxicity, and expand indications to a growing number of tumour types. Physicians are increasingly convinced that these combined advances will transform the management of patients with cancer. To fully realise this potential, healthcare systems need to be more prepared to provide access to innovations in radiopharmaceutical therapy in both clinical and research settings.

The advent of [18F]fluorocholine (FCH) positron emission tomography (PET)/computed tomography (CT) or magnetic resonance (MR) imaging has enhanced the diagnostic performance of preoperative imaging in patients with primary and renal hyperparathyroidism (HPT) during the past decade [1, 2]. Numerous studies and meta-analyses have confirmed the excellent performance of FCH PET, including in complex cases (i.e., inconclusive or negative results on parathyroid scintigraphy, recurrence, renal hyperparathyroidism (HPT), multiple endocrine neoplasia type 1 (MEN1)-related pHPT), with diagnostic accuracy consistently exceeding 95

Le carcinome parathyroïdien (CP) est d’une extrême rareté, touchant 1 % des hyperparathyroïdies primaires. Pour cette raison, sa prise en charge est peu codifiée et doit être effectuée en centre expert. Le CP est génétiquement déterminé dans un quart à un tiers des cas, impliquant notamment le gène CDC73 codant pour la parafibromine. Le diagnostic de malignité repose depuis 2004 sur des critères d’invasion non seulement macroscopiques mais également microscopiques, rappelés dans la classification histopathologique de l’OMS 2022. La chirurgie est un temps essentiel de la prise en charge. L’exérèse doit être carcinologique, après correction médicale première d’une hypercalcémie souvent sévère et s’appuyer sur des examens d’imagerie pour guider le geste chirurgical. Après une résection incomplète sans possibilité de réintervention, la radiothérapie externe adjuvante doit être discutée compte tenu d’un risque élevé de récidive locale, même si son intérêt fait débat. Le taux de rechute du CP est de 30 à 67 %. La survie globale à 5 ans varie de 60 % à 95 %. En cas de rechute localisée ou oligométastatique, les traitements locorégionaux sont privilégiés. Il n’existe pas de standard pour le traitement de la maladie métastatique, mais l’examen de la littérature fait apparaître un bénéfice possible des thérapies ciblées anti-angiogéniques. Un génotypage tumoral étendu est conseillé à la recherche de cibles thérapeutiques activables. Tous les cas de CP doivent être examinés en réunion de concertation multidisciplinaire spécialisée. Les patients opérés d’une tumeur parathyroïdienne atypique ou d’une tumeur parathyroïdienne avec perte d’expression de la parafibromine en immunohistochimie requièrent également une surveillance au long cours.

The EMBARK trial demonstrated improved survival with enzalutamide plus androgen deprivation therapy (ADT) in non-metastatic hormone-sensitive prostate cancer patients with high-risk biochemical recurrence (BCR), although staged using conventional imaging. Given the higher sensitivity of PSMA-PET, many of these patients could harbor metastatic disease. We retrospectively analyzed 587 patients with first BCR after radical treatment who underwent PSMA-PET. Patients were stratified according to EMBARK criteria for high-risk BCR. 169 patients (29%) met EMBARK criteria. They more often showed PSMA-PET positivity for any localization (82% vs 39%; p < 0.001) and metastatic disease (46% vs 15%; p < 0.001). Median PSA was higher and PSA doubling-time (PSADT) shorter (2.23 vs 0.43 ng/mL; 4.3 vs 9 months). Most High-risk BCR patients have a positive PSMA-PET, and many of these harbor metastatic disease at molecular imaging. Given the survival benefit from intensified systemic treatment with ARPI in this cohort, how to best combine systemic therapy with PSMA-PET guided metastases-directed-treatments remains an important future area of research.

Parathyroid carcinoma is extremely rare, affecting 1% of cases of primary hyperparathyroidism. For this reason, management is poorly codified and requires expertise in specialized center. PC is genetically determined in a quarter to a third of cases, notably involving the CDC73 gene coding for parafibromin. Since 2004, malignancy has been diagnosed on both macroscopic and microscopic invasion criteria, as set out in the WHO 2022 histopathological classification. Surgery is an essential part of treatment. Resection must be oncological, after prior medical treatment for hypercalcemia that are often severe, and be supported by imaging studies to guide the surgical procedure. After incomplete resection with no possibility of reoperation, adjuvant external radiotherapy should be discussed, given the high risk of local recurrence, even if its value is debated. The recurrence rate for PC is 30-67%. Overall 5-year survival ranges from 60% to 95%. In cases of localized or oligometastatic recurrence, locoregional treatments are preferred. There is no standard treatment for metastatic disease, but the literature review suggests possible benefit from targeted anti-angiogenic therapy. Extensive tumor genotyping is recommended to screen for targetable alterations in driver genes. All parathyroid carcinoma cases should be reviewed in a specialized tumor board. Patients operated on for atypical parathyroid tumors or parathyroid tumors with loss of immunohistochemical expression of parafibromin also require long-term monitoring.

Background/Objectives: Multiple myeloma (MM) is a complex hematologic malignancy characterized by abnormal plasma cell proliferation in the bone marrow. [18F]FDG PET/CT has emerged as a key imaging modality, demonstrating high sensitivity and specificity for the detection of metabolically active disease compared with conventional imaging techniques. This review examines the role of PET/CT imaging in evaluating therapeutic response in symptomatic myeloma, including minimal residual disease (MRD) assessment. Methods: We surveyed the literature published between 2014 and 2024 across PubMed, Scopus, Web of Science, and the Cochrane Library for peer-reviewed articles evaluating PET imaging in the assessment of treatment response in multiple myeloma. Results: [18F]FDG PET/CT provides a whole-body assessment of disease burden, extramedullary involvement detection, and early metabolic response evaluation. Standardized response assessment criteria (Deauville, IMPeTUs, IMWG) have enhanced the reproducibility and accuracy of treatment monitoring. Semiquantitative parameters including SUVmax and metabolic tumor volume (MTV) provide useful prognostic information with PET negativity correlating with improved progression-free and overall survival. The integration of PET/CT with bone marrow assessment techniques (next-generation flow cytometry and sequencing) optimizes MRD evaluation and patient stratification. Conclusions: PET/CT represents a valuable imaging tool for improving therapeutic decision making and risk stratification in MM management. Emerging radiotracers beyond FDG, including [11C]choline, [11C]methionine, and targeted agents like [68Ga]pentixafor and CD38-targeted immunoPET tracers, hold promise for enhanced diagnostic capabilities in specific clinical contexts.

OBJECTIVE:Assess the accuracy of preoperative PET-CT in detecting para-aortic nodal metastasis in patients with locally-advanced cervical cancer, using routine laparoscopic para-aortic lymphadenectomy and evaluate its impact on patient outcomes. METHODS:We retrospectively analyzed a cohort of 320 patients with locally advanced cervical cancer patients (2007-2020). All patients had negative para-aortic PET-CT findings and underwent staging laparoscopic para-aortic lymphadenectomy up to the left renal vein. Collected data included patients and tumors' characteristics, surgical procedures, and complications. The association between nodal status, size of metastatic nodes and survivals were also analyzed. RESULTS:Twenty-nine (9%) patients had para-aortic nodal metastases: 11 < 5 mm and 18 > 5 mm. The rates of false negative results for para-aortic nodal metastases were significantly correlated with the pelvic lymph node status on PET-CT imaging: 3.3% in patients without pelvic uptake compared to 16.9% in patients with pelvic uptake (p < 0.001), but not significantly linked with its laterality, uni or bilateral uptake. Patients with nodal metastases ≤5 mm did not have a different survival from pN0 patients but those with metastases >5 mm had an increased risk of death (HR = 2.79 (95%CI [1.19-6.54], p = 0.02). Among 12 patients in whom para-aortic nodal metastases location is known, 4 (33%) had isolated nodes above the inferior mesenteric artery). CONCLUSION:Para-aortic lymphadenectomy may be omitted in locally advanced cervical cancer patients without pelvic lymph node uptake on PET-CT. It remains valuable in patients with pelvic uptake. If performed, dissection up to the left renal vein allows for an accurate assessment of the para-aortic area.

BackgroundRevolution of chemo-immunotherapy (CT-IO) in the first-line treatment of metastatic non-small-cell lung cancers (NSCLC) without actionable genomic alterations (AGAs) has dramatically improved prognosis, providing long response in a subset of patients. Due to the highly heterogeneous nature of the disease, most of patients do not show long term benefit. Long axial field of view positron emission tomography (LAFOV-PET) scanner is a new emerging system allowing dynamic whole-body imaging with higher sensitivity, representing unique opportunity for oncological applications. The aim of this study is to determine whether 18F-fluorodeoxyglucose positron emission (18F-FDG) LAFOV-PET derived parameters might have prognostic and predictive potential for CT-IO outcomes in NSCLC.MethodsPROFIL-1 (NCT06738680) is a multicentre, prospective single-arm biomarker pilot study investigating the prognostic and predictive potential of multiparametric 18F-FDG LAFOV-PET for first-line CT-IO efficacy in advanced NSCLC, with a planned enrolment of 120 patients at 2 French sites. Adult patients with treatment-naïve advanced non-squamous or squamous NSCLC without AGAs and eligible for first-line CT-IO will be recruited for PROFIL-1. Patients will undergo baseline LAFOV-PET before treatment (optional second dynamic LAFOV-PET after CT-IO induction). The primary objective is to evaluate the prognostic and predictive potential of a whole-body multiparametric analysis (radiomics and dynamics) derived from LAFOV-PET for first-line CT-IO efficacy, using the rate of disease progression or death at one year as the primary endpoint, assessed by investigators according to RECIST v1.1 criteria. Secondary endpoints included correlations between imaging parameters and clinico-pathological characteristics, comparison between direct Patlak and indirect Patlak reconstruction methods to determine dynamic parameters such as Ki (the net influx rate) and distribution volume (DV), number of detected tumor lesions and signal-to-noise ratio (vs. SAFOV-like imaging), objective response rate, overall survival and safety. The study opened for enrolment in January 2025. Duration of inclusions: 2 years.Clinical trial informationNCT06738680.

BACKGROUND:To our knowledge, no randomised trial with peptide receptor radionuclide therapy has been done in patients with metastatic pancreatic neuroendocrine tumours. We aimed to evaluate the antitumour activity and safety of [177Lu]Lu-dota-tate in this setting. METHODS:OCLURANDOM is a randomised, open-label, non-comparative, phase 2 trial conducted in ten academic centres in France. Patients aged 18 years and older with pretreated, progressive, somatostatin receptor-positive, metastatic pancreatic neuroendocrine tumours and an Eastern Cooperative Oncology Group performance status of 0-2 were randomly assigned (1:1) using web-based software to receive intravenous [177Lu]Lu-dota-tate (7·4 GBq every 8 weeks up to four cycles) with concomitant amino acid infusion or oral sunitinib (37·5 mg once daily). Amino acid infusion was for at least 4 h starting 30 min before [177Lu]Lu-dota-tate infusion and included 16·8 g of arginine and 22 g of lysine in 2 L until May, 2018, and, from that date, a solution of 25 g of arginine and 25 g of lysine in 2 L. Randomisation was stratified according to Ki-67, liver involvement, and previous therapies. The primary endpoint was progression-free survival at 12 months assessed by real-time central review using Response Evaluation Criteria in Solid Tumours version 1.1 in the intention-to-treat population. Cross-over was allowed. Adverse events in the as-treated population were assessed continuously during the active phase of treatment and then every 3 months. Patients and the public were not involved in the design, conduct, reporting, or dissemination plans of this research. This trial was registered with ClinicalTrials.gov, NCT02230176, and is closed to enrolment. FINDINGS:Between Feb 13, 2015, and July 16, 2020, 84 patients were enrolled and randomly assigned to the [177Lu]Lu-dota-tate group (n=41) or the sunitinib group (n=43). 44 (52%) patients were women and 40 (48%) were men. Median follow-up was 72·5 months (IQR 61·4-88·4). Progression-free survival rate at 12 months was 33 (80·5% [90% CI 67·5-89·9]) of 41 patients in the [177Lu]Lu-dota-tate group versus 18 (41·9% [29·1-55·5]) of 43 patients in the sunitinib group. Grade 3-4 adverse events occurred in 18 (44%) of 41 patients in the [177Lu]Lu-dota-tate group and 31 (72%) of 43 patients in the sunitinib group. The most common grade 3-4 adverse events for all treatment groups were neutropenia (two [5%] of 41 in the [177Lu]Lu-dota-tate group vs 13 [30%] of 43 in the sunitinib group) and hypertension (four [10%] in the [177Lu]Lu-dota-tate group vs eight [19%] in the sunitinib group). Drug-related serious adverse events occurred in six (15%) patients in the [177Lu]Lu-dota-tate group (transaminase increase, neutropenia, thrombosis, and fever) and ten (23%) in the sunitinib group (gastrointestinal, general disorders, and sepsis). There was a 10·3-point (95% CI 2·4-18·2) difference in the Global Health Status score between the two groups in favour of [177Lu]Lu-dota-tate. Late adverse events (grade 2 or worse) were reported in 24 (60%) patients in the [177Lu]Lu-dota-tate group and in three (43%) of seven patients in the sunitinib group. One treatment-related death (acute leukaemia) occurred in the [177Lu]Lu-dota-tate group. INTERPRETATION:Using sunitinib as an internal control, our results show clinically significant antitumour efficacy of [177Lu]Lu-dota-tate in pretreated, progressive, somatostatin receptor-positive, metastatic pancreatic neuroendocrine tumours, and a better quality of life during the treatment phase. Late adverse events were reported in the [177Lu]Lu-dota-tate group that might affect the tolerance of subsequent lines of treatment. FUNDING:French Ministry of Health, through the National Institute for Cancer.

Radioligand therapy (RLT) with [177Lu]Lutetium-PSMA (prostate specific membrane antigen) has become a pillar of prostate cancer treatment; however, resistance and PSMA-negative disease remain as unmet needs. The α-emitting radionuclides represent a paradigm shift, with physical properties suited to overcome β-emitter resistance. [225Ac]Actinium-PSMA (prostate specific membrane antigen) has shown promising retrospective results, and ongoing trials are refining its sequencing and safety. Astatine-211 and lead-212 may further improve dosimetry and supply scalability. Beyond PSMA, emerging targets could extend theranostics to PSMA-negative and neuroendocrine diseases. Biomarker-stratified trials will be essential to personalize RLT in prostate cancer. PATIENT SUMMARY: This review highlights future directions in radioligand therapy for advanced prostate cancer, including α-therapy, and the identification of novel targets that may open new therapeutic options for prostate-specific membrane antigen-negative disease.

5067 Background: 177Lu-PSMA radioligand therapy is now a standard treatment for patients (pts) with mCRPC. Dual-tracer FDG/PSMA PET imaging mismatch (i.e. FDG+ and PSMA- lesions) is currently the main selection criterion used to predict 177Lu-PSMA response. However, this approach is time-consuming, resource-intensive and may not fully capture tumor biological aggressiveness. More accessible and biologically informative biomarkers are therefore needed. Methods: This retrospective, single-center study included pts diagnosed with mCRPC who underwent FDG and PSMA PET for 177Lu-PSMA screening and circulating tumor DNA next-generation sequencing (ctDNA) as part of the STING program (NCT04932525) at Gustave Roussy. A tumor suppressor gene alterations (TSalt) signature was defined by ≥ 2 alterations among TP53, PTEN and/or RB1 . Univariate logistic and linear regression models were used along with area under the curve (AUC) to assess associations between genomic and mismatch as well as PET-derived parameter. Progression-free survival (PFS, PCWG3 criteria) and overall survival (OS) were analyzed using univariate Cox models. Results: Among the 110 pts with available ctDNA and dual-tracer imaging, 18 (16.4%) exhibited mismatch. TSalt+ tumors were identified in 24 pts (21.8%) and were enriched in the mismatch group (50.0 vs 16.3%, p = 0.004) and in case of liver metastases (33.3% vs 10.5%, p = 0.011). TSalt was associated with mismatch (p = 0.003, AUC = 0.625). TSalt predicted higher total lesion glycolysis (TLG; p < 0.001, AUC = 0.720), increased ratio TLG/total lesion activity (TLA; p = 0.008, AUC = 0.657), larger FDG+ tumor volume (p = 0.008, AUC = 0.720), and lower PSMA+ tumor volume (p < 0.001, AUC = 0.725). TSalt+ pts had significantly shorter OS compared with TSalt- pts (median 5.7 vs 16.5 months; HR 3.31, 95% CI [1.93–5.69], p < 0.001). Similarly, pts with mismatch had inferior OS (median 4.7 vs 16.3 months; HR 3.17, 95% CI [1.69–5.95], p < 0.001). Among the 79 pts treated with 177Lu-PSMA, TSalt+ status (n = 14, 17.7%) was associated with shorter median PFS (3.5 vs 5.1 months; HR 2.37, 95% CI [1.29–4.34], p = 0.004) and OS (5.5 vs 15.3 months; HR 4.19, 95% CI [2.17–8.10], p < 0.001). Patients with mismatch (n = 3, 3.8%) also experienced inferior outcomes, with shorter PFS (2.5 vs 4.9 months; HR 3.80, 95% CI [1.14–12.7], p = 0.02) and OS (5.6 vs 15.1 months; HR 4.97, 95% CI [1.48–16.7], p = 0.004). Conclusions: The TSalt genomic signature was associated with FDG/PSMA PET mismatch, adverse metabolic imaging features, and poorer survival in patients with mCRPC, including those treated with 177Lu-PSMA. These findings suggest that ctDNA genomic profiling may help identify molecular imaging mismatch, associated with biologically aggressive disease, such as lineage plasticity phenotypes. Prospective studies are warranted to validate its clinical utility.

Metastases from meningioma are very rare and occur predominantly in WHO grade II and III tumors, with the lungs being the most common site. The increasing use of 68Ga-DOTA-peptides PET/CT has improved the detection of primary and secondary tumor sites. This imaging modality, evaluating the tumor expression of somatostatin receptors (SSTR), not only refines the diagnostic accuracy but also can guide a subsequent peptide receptor radionuclide therapy (PRRT). We report a case of meningioma brain tumor becoming refractory after initial neurosurgery and stereotactic radiotherapy. Meningioma has progressed to lung metastases displaying high expression of SSTR, and hence suitable for PRRT.

Fever of unknown origin (FUO) presents a significant diagnostic challenge because of its wide range of potential causes. The role of [18F]FDG PET/CT in this complex clinical scenario is not yet fully understood. This multicenter retrospective observational study aimed to investigate the diagnostic value and clinical impact of [18F]FDG PET/CT in patients with FUO and to identify specific factors linked to a positive [18F]FDG PET/CT scan. Methods: We retrospectively included 929 patients from 12 centers who underwent [18F]FDG PET/CT for FUO. The final diagnosis for each patient was established on the basis of laboratory, imaging, histopathologic or pathologic examinations, and at least 6 mo of clinical follow-up data. Final diagnoses were classified into 4 categories: infectious diseases, noninfectious inflammatory diseases, malignancies, and unknown causes (no diagnosis). Moreover, the impact of [18F]FDG PET/CT on clinical management, as well as its association with clinical, epidemiologic, and biochemical parameters were analyzed. Results: The final diagnoses included infectious diseases in 332 patients (36%), noninfectious inflammatory diseases in 281 (30%), and malignancies in 103 (11%). The cause of FUO remained undiagnosed in 213 patients (23%). [18F]FDG PET/CT scans had positive results for 549 (59%) patients and negative for the remaining 380 patients. The overall [18F]FDG PET/CT sensitivity was 72% (95% CI, 69%-75%), specificity was 85% (95% CI, 79%-89%), positive predictive value was 94% (95% CI, 92%-96%), negative predictive value was 47% (95% CI, 44%-51%), and accuracy was 75% (95% CI, 72%-78%). Predictive markers for a positive PET/CT scan were high C-reactive protein, high erythrocyte sedimentation rate, high neutrophil-to-lymphocyte ratio, the presence of fever at the time of PET, and short duration of prior antibiotic therapy. Moreover, [18F]FDG PET/CT findings directly influenced the clinical management of approximately 75% of patients. Conclusion: [18F]FDG PET/CT is a high-yield diagnostic tool that directly influenced clinical management of approximately 75% of patients with FUO, with optimal performance in patients with elevated inflammatory markers, fever at the time of imaging, and limited prior antibiotic use.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from neural crest-derived chromaffin tissue, marked by clinical heterogeneity and substantial genetic underpinnings. With up to 70

Radiopharmaceutical therapy (RPT) delivers protracted, low absorbed dose rate radiation over time, with cellular DNA repair capacity potentially limiting its efficacy. This article explores how lessons from radiobiology-particularly regarding DNA damage response (DDR)-inform the rational design of 177Lu-labeled RPT (177Lu-RPT)-based clinical trials, with emphasis on combinations with DDR inhibitors and replication stress response (RSR) inhibitors. Methods: We integrate preclinical and clinical data on both the induction and repair of DNA damage in the context of 177Lu-RPT and on their combination with inhibitors of DDR/RSR pathways. Results: At the low absorbed dose rates typical of 177Lu-RPT (<0.1 Gy/h), sublethal DNA damage is largely repaired during exposure, minimizing the quadratic component (β) of the linear quadratic model and making intrinsic radiosensitivity (α) the main determinant of cell killing. This raises questions regarding the biologic factors underlying intrinsic radiation sensitivity, as well as the influence of the activity administered per cycle and the number of treatment cycles. Conclusion: Despite the attenuated β-component, the efficacy of 177Lu-RPT could be improved by combining it with DDR and RSR inhibitors to disrupt the DNA repair processes that occur simultaneously with irradiation, provided that such combinations are rationally designed and sequenced. Optimal combinations will require integration of tumor- and patient-specific radiosensitivity profiles and incorporation of dosimetry and biomarker endpoints into trial designs.

Prostate cancer is one of the most common cancers among men, and accurate detection and diagnosis are crucial for effective treatment planning. Diagnostic prostate biopsy plays a pivotal role in the detection and characterization of prostate cancer. Recent advancements in molecular imaging, particularly with Positron Emission Tomography (PET) using radiolabelled Prostate-Specific Membrane Antigen (PSMA) tracers, have shown significant improvements in enhancing prostate cancer detection. PSMA PET, when combined with magnetic resonance imaging (MRI) in hybrid PET/MRI systems, provides improved sensitivity and specificity, enabling more precise localization of clinically significant prostate cancer (csPCa) lesions. This narrative review explores the evolving role of PET/CT and PET/MRI-guided prostate biopsy. We examine the integration of PET with MRI for the detection of prostate cancer, highlighting key studies that have demonstrated improved diagnostic outcomes. Additionally, we discuss the current limitations, including the high costs and longer scan times associated with PET/MRI, as well as the challenges in data interpretation. The review also considers emerging technologies, such as promising molecular probes for prostate PET imaging, such as gastrin-releasing peptide receptor (GRPR) and fibroblast activation protein inhibitor (FAPI). Finally, the present work provides the clinician with a comprehensive yet concise up-to-date review of the literature to easily evaluate the possibilities currently offered by hybrid imaging technologies of personalized imaging-guided biopsy for prostate cancer patients.

e17077 Background: [ 177 Lu]Lu-PSMA-617 was approved for metastatic castration-resistant prostate cancer, but only 46% of patients achieved a PSA response in the phase 3 VISION trial. Identifying patients unlikely to benefit from PSMA-targeted therapeutic radiopharmaceuticals is an urgent unmet need. Methods: Patients with mCRPC who progressed on taxane-based chemotherapy and ARSI, received baseline [ 68 Ga]Ga-PSMA-11 PET/CT, were VISION-eligible, and underwent [ 177 Lu]Lu-PSMA-617 or [ 177 Lu]Lu-PSMA-I&T were prospectively enrolled at 2 academic institutions. We report here the interim results of the University of Grenoble-Alpes cohort only (IRB: CEMEN 202406). Primary outcome was the prognostic value of an artificial intelligence-based technology (SelectPSMA, NucsAI) for PSA50 (≥50% decline from baseline), PSA progression-free survival (PSA-PFS; time to PSA progression by PCWG3), and overall survival (OS) after [ 177 Lu]Lu-PSMA radiopharmaceuticals. The Fisher's exact test and Kaplan-Meier analysis with log-rank test were used to test associations between SelectPSMA output and outcome data. Results: Of 72 mCRPC patients screened, 60 (83%) were enrolled between August 2023 and September 2024 and received [ 177 Lu]Lu-PSMA. 57/60 (95%) patients were treated previously with taxanes, while all 60 patients had received ARSIs. The median follow-up in survivors was 9.5 (IQR 7.1-15.1) mo and 47/60 (78%) patients achieved PSA progression at last follow-up. 38/60 (63%) patients achieved PSA50, the median (95%CI) PSA-PFS was 5.1 (3.3-7.1). 9/60 (15%) patients were classified by SelectPSMA as non-responders (PSMA-NR) and 51/60 (85%) as likely responders (PSMA-R). PSMA-NR was associated with significantly lower likelihood to achieve PSA50 (22% vs 71%; p=0.009) and shorter PSA-PFS (median (95%CI): 1.2 (0.7-NR) vs 6.6 (4.6-9.5) mo; p<0.001) compared to PSMA-R. At the time of this analysis, OS data was immature with low number of events in PSMA-NR group (n=4). Conclusions: Preliminary results show that SelectPSMA, an AI-based technology, identified patients with lower likelihood of PSA response and shorter progression-free survival after [ 177 Lu]Lu-PSMA radiopharmaceuticals. Results of multi-centric analysis including mature OS data will be presented at the conference. Clinical trial information: CEMEN 202406 .