Emerging radiotracers in prostate cancer: opportunities and challenges

The past decade has seen a rapid expansion of prostate cancer (PCa) theranostics, driven largely by the success of prostate-specific membrane antigen (PSMA) imaging and [177Lu]Lu-PSMA-617 radioligand therapy (RLT). This progress has been transformative for advanced disease states, but several limitations remain – heterogenous PSMA expression, therapy-limiting xerostomia, and a global dependence on a single isotope placing strain on supply chains. These limitations have sparked interest in the next generation of radiotracers. While emerging isotopes may offer greater potency, improved sensitivity, or more practical production pathways, they also introduce limitations that must be considered prior to adoption (Table 1). The challenge for the urological field is to balance innovative therapies with pragmatism and avoid repeating the pattern of premature enthusiasm that has previously challenged emerging PCa therapeutics. α-emitting isotopes illustrate this conundrum most clearly. [225Ac]Actinium-225 has shown meaningful activity in patients with metastatic castration-resistant prostate cancer (mCRPC) who progress despite [177Lu]Lu-PSMA-617 therapy [1]. Benefits include high linear energy transfer producing high tumour-cell kills, and multicentre series reporting PSA responses in pre-treated cohorts. However, limitations remain, including xerostomia, which often leads to treatment cessation, bone marrow and renal toxicities, and attenuated responses in visceral metastatic deposits due to the short range of α particles. The greatest limitation is the difficulty in sourcing 225Ac particles, their global scarcity, and their high cost. In its current form, [225Ac]Actinium-225 is a powerful RLT option for select patients but remains impractical for more widespread use. Emerging alternative therapies include [211At]Astatine-211 and [212Pb]Lead-212, which attempt to retain the potency of α therapy while reducing toxicity and improving availability [2, 3]. The shorter half-life of [211At]Astatine-211 reduces prolonged radiation exposure, and production capacity is expanding, making it an α emitter with a realistic pathway to scalable distribution. Nonetheless, the short half-life restricts transport distance and evidence remains preliminary. [212Pb]Lead-212 offers a balanced profile, with early studies demonstrating tolerable toxicity, but implementation remains constrained by a lack of mature supply chains, limited clinical experience, and an absence of long-term safety data. The next generation of β-emitting tracers have their own distinct appeals. [161Tb]Terbium-161 offers an appealing approach as it emits both β particles and Auger electrons that improve the efficacy of RLT. Importantly, it can be deployed using existing [177Lu]Lu-PSMA-617 infrastructure, giving it a realistic pathway to prompt uptake. The findings of the VIOLET trial suggest that [161Tb]Terbium-161 is efficacious and safe [4]. Nonetheless, despite early success, no phase III has demonstrated a distinct advantage, or non-inferiority, to [177Lu]Lu-PSMA-617 and toxicity profiles remain similar. [161Tb]Terbium-161 represents an attractive potential successor to [177Lu]Lu-PSMA-617 but expectations should be tempered until higher-level evidence emerges. [67Cu]Copper-67 provides an attractive alternative, as unlike [177Lu]Lu-PSMA-617, which relies on a reactor, [67Cu]Copper-67 can be generated using electron accelerators which may provide a more sustainable global supply chain [5]. While copper-based therapies have a promising future, they remain in early development and need investigation in more clinical trials. The other issue that emerging diagnostic isotopes aim to solve is improving the sensitivity and logistic feasibility of PSMA-positron emission tomography (PET) imaging. Copper-64 has demonstrated some advances with high tumour uptake and manufacturing flexibility owing to a 48-h self-life. This logistical advantage may enable centralised production and long-distance distribution, which would be transformative for hospitals without access to on-site gallium generators. Nonetheless, drawbacks include higher background signal and increased cost, which may be acceptance trade-offs where sensitivity or accessibility are prioritised. Zirconium-89 offers a more specialised diagnostic role because it remains in the body longer than 68Ga, imaging can be performed over several days, and it can facilitate better selection of patients for RLT. Early studies suggest that 89Zr-PSMA can reveal lesions not detected by 68Ga-PSMA [6]. However, the higher radiation dose and logistic issues of multi-day scanning limit its practical implementation. Thus, 89Zr-PSMA is likely to be reserved for select cases for treatment planning. The expanding field of radiotracers has revealed a pattern – scientific progress is accelerating more rapidly than the clinical infrastructure necessary to support it. For α therapy, toxicities remain significant, especially xerostomia, which is an ongoing threat to its sustainability. The evidence base for most isotopes remains in its early phase, and limited evidence exists comparing RLTs to define optimal sequencing or patient selection. The logistical realities of producing these tracers continues to restrict uptake. Furthermore, the increasing number of tracers risks overcomplicating clinical pathways that are already difficult for patients and clinicians to navigate. Nonetheless, the future of radiotracers appears to be positive. The expanding portfolio of α, β and diagnostic isotopes offers an exciting opportunity to personalise therapy, improve diagnostic precision, and overcome the limitations of existing PSMA-based approaches. However, evidence-driven adoption remains crucial. Randomised trials, long-term toxicity data, and clear guidelines for tracer selection are necessary to support this emerging space. If the field can prioritise robust clinical validation, the next generation of radiotracers may deliver on their promise to meaningfully improve outcomes for men with high-risk PCa. The authors have no relevant disclosures.