From lutetium to terbium: a new era in PSMA-targeted radioligand therapy for mCRPC patients

Abstract

Terbium-161 (¹⁶¹Tb) is emerging as a promising theranostic radionuclide for prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) in metastatic castration-resistant prostate cancer (mCRPC). Compared with lutetium-177 (¹⁷⁷Lu), ¹⁶¹Tb emits additional high-linear energy transfer Auger and internal conversion electrons, enabling superior tumor cell kill in micrometastatic disease. Early clinical studies demonstrate favorable safety, dosimetry, and efficacy profiles for ¹⁶¹Tb-labeled PSMA ligands. Ongoing trials and production advancements are critical to fully realizing the therapeutic potential of ¹⁶¹Tb-based RLT.

The integration of diagnostic and therapeutic capabilities, known as theranostics, has gained increasing importance in clinical nuclear medicine. This advancement highlights the critical role of radioligand therapy (RLT) in cancer management, particularly in achieving personalized treatment strategies [1-3]. To fulfill the dual functions of therapy and imaging, radionuclides with appropriate physical and chemical properties, such as those emitting therapeutic alpha or beta particles alongside diagnostic gamma or positron emission, are essential.

Terbium-161 (¹⁶¹Tb) has emerged as a promising novel radionuclide for RLT. With a physical half-life of 6.89 days, it closely resembles lutetium-177 (¹⁷⁷Lu), a well-established therapeutic radionuclide (half-life: 6.65 days). Despite this similarity, ¹⁶¹Tb differs significantly from ¹⁷⁷Lu in terms of radiation emission characteristics, offering distinct radiophysical advantages, particularly in the treatment of micrometastases and minimal residual disease. Both ¹⁶¹Tb and ¹⁷⁷Lu emit low-linear energy transfer (LET) β^- particles with comparable mean energies (154.3 keV for ¹⁶¹Tb vs. 133.3 keV for ¹⁷⁷Lu) and similar tissue penetration depths (~1.5 mm). However, a defining feature of ¹⁶¹Tb is its copious emission of short-range, high-LET particles: each decay produces, on average, approximately 1.4 internal conversion electrons and 11 Auger electrons, compared to only 0.15 and 1, respectively, for ¹⁷⁷Lu [4]. These electrons, with ranges spanning from ~97 nm to ~13 µm, are capable of inducing concentrated energy deposition at the subcellular level, particularly in proximity to nuclear DNA. This spatially confined damage enhances tumor cell killing while minimizing collateral damage to healthy tissue. This unique emission profile positions ¹⁶¹Tb as a compelling alternative to ¹⁷⁷Lu, especially for indications requiring precision radiotoxicity, such as targeting disseminated tumor cells or treatment-resistant populations. A growing body of in vitro and in vivo evidence demonstrates that ¹⁶¹Tb-labeled radiopharmaceuticals consistently outperform their ¹⁷⁷Lu-labeled counterparts in therapeutic efficacy when administered at equivalent activity levels [5,6]. Moreover, for the same injected activity, ¹⁶¹Tb delivers a higher absorbed dose to tumor tissue, further contributing to its enhanced therapeutic potential [7,8] (Figure 1).

Figure 1.

Overview of the therapeutic mechanism of ¹⁶¹Tb and highlighting the potential advantages of Auger electrons. The two main components of the ¹⁶¹Tb-PSMA. Abbreviations: LET, linear energy transfer.

In recent years, considerable effort has been directed toward the development of novel ¹⁶¹Tb-based therapeutic radiopharmaceuticals. However, the challenges associated with large-scale production of ¹⁶¹Tb have limited the number of compounds that have advanced to human clinical trials. Notable among these are ¹⁶¹Tb-DOTA-LM3 (NCT05359146) in patients with gastroenteropancreatic neuroendocrine tumors, as well as ¹⁶¹Tb-SibuDAB (NCT06343038), ¹⁶¹Tb-PSMA-I&T (NCT05521412), ¹⁶¹Tb-NYM032 (NCT06827080), and ¹⁶¹Tb-PSMA-617, the latter currently being investigated in the German REALITY registry study (NCT04833517), all in the context of metastatic castration-resistant prostate cancer (mCRPC).

Due to the chemical similarity between ¹⁶¹Tb and ¹⁷⁷Lu, most of these agents utilize ligands originally developed for and validated with ¹⁷⁷Lu-based radiopharmaceuticals. PSMA-617 [9,10] and PSMA-I&T [11,12] are two such ligands extensively studied in mCRPC treatment. Andrea et al. recently conducted the first comparative dosimetric analysis of ¹⁶¹Tb-PSMA-617 and ¹⁷⁷Lu-PSMA-617 in six patients with mCRPC [13] (Figure 2A). PSMA-617 is known for its physiological accumulation in salivary glands and kidneys, leading to xerostomia as a prominent adverse effect, and revealing considerable inter-patient variability in renal absorbed dose. Their findings revealed that ¹⁶¹Tb-PSMA-617 delivered, on average, 2.4 times higher radiation doses to tumor lesions compared to ¹⁷⁷Lu-PSMA-617. In contrast, the increase in absorbed dose to normal organs was relatively modest: 1.18-fold in kidneys and 1.10-fold in parotid glands. The study also employed the therapeutic index (TI), defined as the ratio of tumor absorbed dose to that of dose-limiting organs (e.g., kidneys or salivary glands), as proposed by Feuerecker et al. [14]. Notably, the mean TI for the kidney was 2.19 times higher with ¹⁶¹Tb-PSMA-617 compared to ¹⁷⁷Lu-PSMA-617, while the TIs for the salivary and submandibular glands were 1.34 and 1.70 times higher, respectively. These results support ¹⁶¹Tb-PSMA-617 as a promising candidate for prostate-specific membrane antigen (PSMA)-targeted RLT, offering improved tumor targeting with a favorable dosimetric profile.

Figure 2.

The representative examples of SPECT-CT at different times for ¹⁶¹Tb-PSMA-617 (A) and ¹⁶¹Tb-PSMA-I&T (B). Reprinted from [13,15].

¹⁶¹Tb-PSMA-I&T has advanced to Phase II clinical evaluation following a Phase I trial conducted at the Peter MacCallum Cancer Centre in Australia, which enrolled 30 patients with mCRPC [15,16] (Figure 2B). The dose-escalation component followed a standard 3 + 3 design to assess the safety of three predefined activity levels (4.4, 5.5, and 7.4 GBq). Twelve patients were enrolled in this phase: three each at 4.4 and 5.5 GBq, and six at 7.4 GBq. Subsequently, 18 additional patients received 7.4 GBq in the dose-expansion phase. The results confirmed that ¹⁶¹Tb-PSMA-I&T is safe and well tolerated at a maximum dose of 7.4 GBq, with a low incidence of grade 3-4 adverse events and evidence of encouraging antitumor activity. Based on these outcomes, the study protocol was amended to include a subsequent expansion cohort receiving 9.5 GBq to further explore safety and therapeutic efficacy. Although this study was conducted as a single-arm trial and did not directly compare ¹⁶¹Tb with ¹⁷⁷Lu, the findings clearly establish the safety and feasibility of ¹⁶¹Tb-PSMA-I&T in mCRPC patients, supporting its continued development within the broader context of precision oncology.

¹⁶¹Tb-based RLT continues to demonstrate advantages over time, particularly due to its unique emission profile that enables enhanced tumor cell kill via high-LET Auger and conversion electrons. The clinical relevance of ¹⁶¹Tb-labeled PSMA ligands is gaining recognition as their development accelerates. However, several challenges must be addressed to fully realize the clinical potential of ¹⁶¹Tb-based therapies. The most pressing is the limited availability and chemical purity of enriched target materials necessary for large-scale ¹⁶¹Tb production [17]. Off-target uptake in salivary glands and kidneys remains a clinical concern, contributing to xerostomia and limiting tolerable dosages. Nonetheless, these limitations should not overshadow the significant promise of ¹⁶¹Tb-PSMA radioligand therapy in mCRPC treatment. As the field moves toward increasingly personalized cancer therapies, it is imperative to support both the development of novel PSMA-targeting ligands and the scale-up of ¹⁶¹Tb production to fully harness the capabilities of this emerging radionuclide.

Disclosure of conflict of interest

None.