Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) with 177-Lutetium-PSMA has significantly improved outcomes in advanced prostate cancer; however, optimising its clinical application requires a nuanced, individualised approach. This review outlines key principles for patient selection, therapeutic monitoring, and adaptive dosing strategies to maximise efficacy while limiting toxicity. Adaptive strategies, including dose escalation or fractionation informed by tumour volume, treatment pauces at exceptional response, and retreatment at relapse, offer opportunities to personalise and optimise therapy beyond the standard six-cycle regimen.Additionally, defining clinical, imaging, and molecular biomarkers for resistance and efficacy will improve patient selection and clinical outcomes. As novel radioisotopes and combination strategies emerge, optimising treatment approaches will be essential to realise the full potential of RLT in prostate cancer.

Prostate-specific membrane antigen (PSMA)-targeted PET/CT (PSMA PET/CT) has become the first-line imaging modality used for staging and restaging prostate cancer. Its utility after minimally invasive focal therapy (high-intensity focused ultrasound, laser ablation, cryoablation) remains unclear. This study evaluated PSMA PET/CT for detecting and localizing recurrence after focal therapy. Methods: This retrospective single-center study included patients with prior focal therapy for prostate cancer who underwent 68Ga-PSMA-11 PET/CT for suspected recurrence between 2016 and 2023 without intervening treatment. Three masked readers analyzed whole-body PET/CT images using a per-region (prostate, pelvic nodes, distant metastases) majority rule for per-patient positivity. Interreader agreement was determined using Fleiss κ. In a subcohort of 39 patients with both MRI and biopsy results available within 3 mo of PSMA PET/CT, per-patient and per-segment (12 prostate segments) accuracy was assessed. One masked reader evaluated PET/CT at 60 min (whole-body) and 90 min (pelvic) postinjection, and one prostate MRI expert independently read the MRI scans. Biopsy pathology-confirmed clinically significant prostate cancer, defined as International Society of Urological Pathology grade 2 or greater, served as the reference standard. Results: In total, 112 patients were included. PSMA PET/CT showed 82% positivity for intraprostatic recurrence, 15% for pelvic nodes, and 9% for distant metastases. Interreader agreement was moderate (κ = 0.4; 95% CI, 0.32-0.54). In the subcohort, per-patient sensitivity was 85% for PET vs. 82% for MRI. All cases with an SUVmax of 10 or greater had an ISUP grade group of 3 or greater. Conclusion: PSMA PET/CT effectively localizes prostate cancer recurrence after focal therapy, outperforming MRI on sensitivity.

Real-world disparities in access to PSMA-targeted theranostics are poorly characterized. We compared waiting times for PSMA PET/CT and 177Lu-PSMA therapy between centers in Brazil and Europe. Methods: This retrospective multicenter study included 91 patients (50 from Brazil, 41 from Europe) treated with 177Lu-PSMA. Outcomes were days from request to PSMA PET/CT completion (diagnostic access) and days from request to first therapy dose (therapeutic access). Groups were compared using the Mann-Whitney U test. Results: Diagnostic access was similar between Brazil (median, 17.5 d; interquartile range [IQR], 9-34 d) and Europe (median, 19 d; IQR, 14-23 d; P = 0.39). Therapeutic access was significantly delayed in Brazil (median, 59 d; IQR, 54.5-91) compared with Europe (median, 21 d; IQR, 17-31 d; P < 0.01), representing a 2.8-fold longer wait. Conclusion: Despite comparable access to PSMA PET/CT, initiation of 177Lu-PSMA therapy is nearly 3 times slower in Brazil than in Europe. Closing the therapeutic access gap requires targeted investments in radiopharmaceutical supply chains and regulatory efficiency.

This Systematic review provides a comprehensive framework for understanding current therapeutic options and future directions in prostate cancer treatment. It highlights ongoing efforts, focusing on AR signaling inhibitors (ARSi) and novel molecularly targeted therapies. Using PRISMA-ScR guidelines, we conducted a comprehensive literature search across significant databases (MEDLINE/PubMed, Embase, and Cochrane Library). Next-generation ARSi (enzalutamide, apalutamide, darolutamide) have demonstrated significant survival benefits across various stages of prostate cancer, as evidenced by pivotal trials (PROSPER, SPARTAN, ARAMIS). The emergence of promising therapeutic approaches for biomarker-defined patient subgroups, including PARP inhibitors (PROfound, TRITON2), radioligand therapy (VISION, TheraP), and immunotherapy (KEYNOTE-199, CheckMate 650), is increasingly clinically relevant. While significant advances have been made in AR-targeted therapies, emerging molecular-targeted approaches are reshaping the treatment landscape. Our data provide a comprehensive framework for understanding current therapeutic options and future directions in prostate cancer treatment, engaging the audience and making them feel part of the solution.

Radiopharmaceutical-based imaging and targeted radionuclide therapy are often limited by heterogeneous or absent molecular targets in tumors. Here, we present a stiffness-responsive mesenchymal stem cell (MSC)-assisted relayed tumor-targeting (SMART) platform that converts matrix stiffness into a programmable molecular entry point for radiotheranostics. Engineered MSCs sense elevated mechanical stiffness within the tumor microenvironment and induce localized expression of synthetic biomarkers, thereby enabling radiopharmaceutical targeting independent of endogenous target availability. As a proof of concept, SMART-driven expression of prostate-specific membrane antigen (PSMA) enables sensitive tumor detection by 68Ga-PSMA-617 positron emission tomography (PET) and effective treatment with 177Lu-AB-PSMA-617 across multiple tumor models, with improved sensitivity and reduced off-target uptake compared with conventional 18F-fluorodeoxyglucose PET. This platform is readily adaptable to alternative synthetic targets and induced pluripotent stem cell (iPSC)-derived MSCs. By translating a universal physical feature of tumors into an actionable molecular signature, SMART expands the scope of precision radiotheranostics beyond native biomarkers.

Prostate cancer disproportionately affects Sub-Saharan African men, who often present with aggressive, late-stage disease. This systematic review synthesizes contemporary evidence on the immunophenotyping and molecular patterns of prostate cancer in East Africa to inform regional screening and precision oncology strategies. Following PRISMA 2020 guidelines, a systematic search was conducted across PubMed, Scopus, and Web of Science for studies published between January 1, 2011 and December 31, 2025. The review protocol was preregistered in Open Science Framework (OSF Registration ID: https://doi.org/10.17605/OSF.IO/RJZFT). Eligible studies were original research articles involving histologically confirmed prostate cancer in East African countries as classified by the United Nations Geoscheme for Africa (Eastern Africa subregion), reporting on immunohistochemical markers or genomic alterations. Preclinical studies, in vitro/in silico studies, case reports, editorials, and meeting abstracts were excluded. Quality was appraised using Joanna Briggs Institute Critical Appraisal Tools. Seven original studies involving participants from Uganda, Sudan, Kenya, and Rwanda were included. Study designs comprised 5 analytical cross-sectional studies and 2 case-control studies. Patient ages ranged from 45 to 107 years (mean ∼70-74 years across cohorts). Dominant histopathological subtype was high-grade acinar prostatic adenocarcinoma. Findings reveal mean prostate-specific antigen levels reaching 434.06 ng/mL and high-grade malignancies (Gleason Score ≥ 8) in up to 82.4% of cases. Key biomarkers identified include Cyclin D1 expression (98.3%), ERG positivity (75.4%), and pathogenic variants at the 8q24 locus (rs72725854). Loss of BRCA1/2 was noted in high-grade tumors. All included studies demonstrated a low risk of bias, though confounding management remains a recurring methodological weakness. East African prostate cancer is defined by an aggressive molecular profile and systemic diagnostic delays. The identification of population-specific genetic drivers necessitates a shift from Western-derived risk models toward decolonized precision oncology and decentralized diagnostic infrastructure to improve early detection and patient outcomes.

To explore how core backbone modifications influence prostate-specific membrane antigen (PSMA) targeting, we synthesized a series of novel peptidomimetics replacing the classic urea linkage of established radiotracers with a carbamate functionality. This panel systematically varied side chain length (aspartic vs. aminoadipic acid), stereocenter configuration (S/S vs. S/R diastereomers), and the radiometal chelator (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid [DOTA] vs. N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid [HBED-CC]). In vitro binding assays in LNCaP cells revealed that the carbamate backbone severely compromised PSMA affinity (Ki) for short-chain aspartic acid derivatives, whereas long-chain aminoadipic acid conjugates successfully retained low-nanomolar potencies. Across all variations, S/S configurations displayed superior affinities over S/R counterparts, demonstrating that natural stereochemistry is essential for optimal binding pocket interactions. Although both conjugates showed high in vitro potency, high-temperature radiolabeling of the DOTA derivative with gallium-68 caused thermal degradation via hydrolytic cleavage and intramolecular cyclization of the carbamate backbone. Conversely, the companion HBED-CC conjugate, 37(S/S), was successfully radiolabeled at ambient temperature without structural compromise to yield the intact radiotracer, 40(S/S). In vivo positron emission tomography (PET) imaging and biodistribution studies of 40(S/S) in LNCaP tumor-bearing mice demonstrated high tumor uptake (∼12%ID/g) at 1 h post-injection, rapid renal clearance, and excellent tumor-to-background ratios (tumor-to-muscle: ∼23; tumor-to-bone: ∼36). These findings demonstrate that carbamate backbones can successfully mimic urea linkages in PSMA ligands, provided they are paired with precise side chain lengths and mild radiolabeling conditions.