Mapping the Radiopharmaceutical Therapy Landscape for Prostate Cancer: Insights Into Global Clinical Trial Trends and Future Directions

To the Editor, prostate cancer (PCa) is the most frequently diagnosed malignancy of the male urinary system globally. With ongoing advancements in clinical treatment paradigms, radionuclide therapy has emerged as a promising novel therapeutic therapy for PCa [1, 2]. In recent years, significant advancements in radiopharmaceuticals research for PCa have been driven by substantial investments, technological breakthroughs, and increasing global collaboration [3]. Notably, Pluvicto, as the first FDA-approved radiopharmaceutical, achieved annual sales exceeding USD 1 billion in 2024, suggesting that the targeted delivery of radionuclides combined with disease-specific molecules may hold great potential in the PCa therapy. According to this background, we summarized the research status and characteristics of the clinical pipeline for PCa radiopharmaceuticals, hoping to provide potential directions for their research and development (R&D) in the future. To systematically collect high-quality information on the clinical trial progress of radiopharmaceuticals for PCa, we queried the Trialtrove database (https://clinicalintelligence.citeline.com/) using the search terms “Mechanism Of Action is Radioemitter” and “Disease is Oncology: Prostate”. Our search identified 372 clinical trials of radiopharmaceutical therapies listed up to March 8, 2026. Based on the “Treatment plan” in the original data, a total of 346 clinical trials were included in the analysis after excluding trials involving diagnostic radiopharmaceuticals (n = 17) and those not utilizing radionuclide agents (n = 9). We then examined trends in trial numbers, radionuclide diversity, targets, indications, combination strategies, geographic distribution, and funding sources to summarize the crucial characteristics of radionuclide therapies for PCa in clinical development. From January 2000 to March 2026, a total of 346 trials focused on radiopharmaceuticals for PCa treatment registered globally. Notably, we observed that the number of clinical trials assessing radiopharmaceuticals exhibited a gradually increasing trend (Figure 1A). However, most trials were in early clinical phases, with Phase I (46.5%) and Phase II (34.7%) predominating. Only a small fraction had advanced to Phase III (9.8%) and Phase IV (8.4%) (Figure 1B). This distribution implied that current R&D efforts in radiopharmaceuticals mainly remained in the early stage which were focused on the assessment of drug safety and efficacy. Therefore, the application of radiopharmaceuticals in PCa treatment may yield significant potential for further development and optimization. Comprehensive landscape of radiopharmaceutical R&D for prostate cancer: evolution of clinical trials, radionuclides, targets, and mechanisms (2000–2026). (A) Annual distribution of clinical trials by phase (2000–2026). (B) Trial phase distribution analysis of radiopharmaceutical. (C) Proportion analysis of radionuclides used in radiopharmaceutical research and development. (D) Annual distribution of clinical trials by radionuclide type (2000–2026). (E) Trial phase distribution across 13 radionuclides. (F–H) Comparative analysis of radiopharmaceutical R&D pre-2017 and post-2017, including trial numbers, radionuclide type distribution, and target distribution. (I) Proportional representation of radiopharmaceutical targets. (J) Annual clinical trial distribution by target type (2000–2026). (K) Distribution of clinical trial phases by different targets. (L) Mechanism of action distribution and delivery molecule classification of radiopharmaceuticals. (M) Proportional representation of radiopharmaceutical delivery molecules. (N) Mechanism of action distribution analysis for biological-targeted radiopharmaceuticals. (O) Mechanism of action distribution analysis for organ-targeted radiopharmaceuticals. (P, Q) delivery molecules distribution analysis for biological-targeted and organ-targeted radiopharmaceuticals. To further characterize the developmental landscape, we analyzed radionuclide types, therapeutic targets, and mechanisms of action based on the fields of “Primary Tested Drug: Mechanism Of Action, Target, Drug Type” in the original data. Interestingly, the diversity of radionuclides showed an increasing trend similar to the number of clinical trials (Figure 1C–D). Currently, 13 distinct radionuclides were under clinical investigation, whereas only six (e.g., Lu-177) had reached advanced Phase III/IV trials (Figure 1E). Additionally, we found a notable shift in the radionuclides application mode around 2017 from organ-targeted therapies such as those aimed at bone metastases toward biologically targeted radionuclide drug conjugates (RDCs). This transformation might be facilitated by the regulatory approval and commercial success of Novartis's Lutathera, the first EMA-approved RDC launched in the same year [4]. To date, the proportion of RDC drugs, predominantly represented by Lutathera, has risen to 78.5% (n = 208) within the clinical trial pipeline, whereas the organ-targeting trial pipeline, primarily represented by RaCl2, showed a declining trend (21.5%, 57 trials) (Figure 1F–H). Therefore, it is suggested that biological targeted RDCs may be a critical direction of nuclear drug R&D in the future. It is well established that RDCs take effect by specifically binding to target molecules uniquely expressed on PCa cells, underscoring the necessity for diverse and highly specific targets [5]. However, prostate-specific membrane antigen (PSMA) remains overwhelmingly dominant (91.9%, 204 trials) targets in current RDCs, highlighting the need to diversify molecular targets to mitigate market homogeneity and provide more therapeutical options (Figure 1I–K). Mechanistically, β-ray-emitting radionuclides make up 61.8% (n = 214) of all experimental drugs, whereas α-ray-emitting radionuclides account for 38.2% (n = 132) (Figure 1L). Moreover, α-ray emitters agents predominate in organ-targeted drugs accounting for 75% (n = 93), whereas β-ray emitters rule that the RDC drugs make up 82.4% (n = 183) currently (Figure 1N–O). Notably, α particles exhibit a higher linear energy transfer (LET) and a shorter radiation range compared to β particles which may improve tumor selectivity and fewer systemic side effects of RDC, implying the next wave of innovation [6]. Currently, 39 clinical trials (17.6%) are investigating the application of α-emitters such as Ac-225 and At-211 in RDC drugs and some of which suggested that the α particles had better efficacy and fewer side effects. However, more research is warranted to confirm their superiority [7, 8]. In addition, although small molecules remain the predominant ligands (90.8%), novel ligands such as peptides and antibodies are gaining traction due to superior pharmacokinetic profiles [9] (Figure 1M, Figure 1P–Q). After clarifying the basic characteristics of radiopharmaceuticals, we further analyzed their indications and combination therapeutic strategies. Firstly, regarding indications, clinical trials were stratified in accordance with the National Comprehensive Cancer Network (NCCN) guidelines as well as the information presented in the “Trial Title” and “Patient Population”. It is observed that the majority of trials focused on metastatic castration-resistant prostate cancer (mCRPC), accounting for 76.6% of the included studies. However, the exploration of additional subtypes including metastatic hormone-sensitive prostate cancer (mHSPC, 4.3%), recurrent prostate cancer (RPC, 3.5%), localized prostate cancer (LPC, 3.2%), and neuroendocrine prostate cancer (NEPC, 1.2%) is increasing in recent years, which may indicate the gradually expanded indications for radiopharmaceuticals in PCa (Figure 2A,D). However, most of these expanded indication studies were primarily focused on RDC drugs (81%) and remained in early clinical phases (85.7%), emphasizing more evidence is warranted to enable precise and effective treatment in diverse clinical scenarios (Figure 2B–G). Meanwhile, combination therapy has increasingly been popular. By screening clinical trials with combination therapy based on the “Treatment Plan” field, our analysis showed that monotherapy accounted for 53.5% of radiopharmaceutical clinical trials, whereas combination therapy constituted 46.5%. Among the 161 clinical trials involving combination therapies, 17 distinct combination regimens were included, with the top five most prevalent being androgen receptor signaling inhibitors (ARSIs, 48 trials), chemotherapy (46 trials), radiotherapy (30 trials), androgen deprivation therapy (ADT, 18 trials), and immunotherapy (18 trials). Meanwhile, combination methods such as poly (ADP-ribose) polymerase inhibitors (PARPi, 9 trials) and S1009A inhibitor (1 trial) were incorporated into combination regimens, although their use was still relatively limited (Figure 2H, Supporting Information S1: Table S1). We speculated that the increased trials number of the combination therapy may be attributed to the goals such as enhancing drug therapeutic efficacy, addressing tumor heterogeneity, and overcoming drug resistance mechanisms [10]. Stereotactic body radiation therapy (SBRT) has improved the precision management of PCa by delivering high-dose, conformal radiation with submillimeter accuracy [11, 12]. Among the 30 clinical trials investigating combination radiotherapy regimens, six of them have investigated the integration of radiopharmaceuticals with SBRT, all of which were Phase I/II studies enrolling patients with locally advanced, oligometastatic, or oligorecurrent PCa. The LUNAR trial firstly reported that PSMA-targeted radiopharmaceutical therapy combined with SBRT significantly delayed disease progression and the initiation of ADT in patients with oligorecurrent disease [13]. By contrast, the RAVENS trial showed that Ra-223 plus SBRT did not significantly prolong progression-free survival (PFS) in oligometastatic PCa, although it identified HiRi mutation status and TCR diversity as potential prognostic biomarkers [14]. Several additional clinical trials which evaluated radiopharmaceutical therapy in combination with SBRT including the STARLiT and LUST trials are currently in active recruitment. Moreover, elective nodal radiotherapy (ENRT) was associated with improved metastasis-free survival in patients with oligometastatic lymph node recurrence after primary local treatment for PCa, although its roles still are required further validation in Phase III randomized controlled trials [15]. Furthermore, 11 trials explored different nuclide combinations, some of which showed that the tandem administration of 177Lu-PSMA-617 and 225Ac-PSMA-617 may exert synergistic anti-tumor effects [16]. However, the detailed synergistic effects and adverse events of nuclide combinations are still required to be explored. Clinical translation and implementation landscape: indications, therapeutic strategies, trial geography, and sponsors. (A) Annual clinical trial distribution by indications (2000–2026). (B) Trial phase distribution by indication types. (C) Trial status distribution by indication categories. (D–G) Proportional representation of therapeutic indications. (H) Combination therapy patterns between radiopharmaceuticals and other treatment pharmacological agents. Since some trials involved multiple combination therapies, the total number exceeded 161. ADT, androgen deprivation therapy; ARSI, androgen receptor signaling inhibitor; BAT, bipolar androgen therapy; HDACi, histone deacetylase inhibitors; PARPi, poly(ADP-ribose) polymerase inhibitors; PROTAC, Proteolysis-Targeting Chimera; TBK1i, TANK-binding kinase 1 inhibitor. (I) Geographical distribution of clinical trials. Dark blue is indicative of a higher number of studies, while gray is indicative of no studies. (J) Sponsor type classification of clinical trials. As some trials involved multiple funding sources, the total number exceeded 346. (K) Sponsor type distribution for biological-targeted radiopharmaceuticals. (L) Sponsor type distribution for organ-targeted radiopharmaceuticals. Beyond the aforementioned characteristics of radiopharmaceuticals, their global development and accessibility were also influenced by geographic distribution and funding patterns, which may also be crucial for understanding the current landscape and future potential of this field. Therapeutic radiopharmaceuticals possess potential in cancer treatment for its widely acknowledged precision and high efficiency [17]. However, widespread adoption is hindered by several challenges, including the limited radionuclide production, R&D constraints, specialized professional training needs, and regulatory framework optimization [18]. According to the “Trial Country” field, our analysis of the global distribution of the nuclear drug development pipeline revealed that the United States dominated this field with 150 clinical trials (43.4%), followed by the China (43 trials, 12.4%), Australia (39 trials, 11.3%), United Kingdom (35 trials, 10.1%), and France (34 trials, 9.8%), with remaining trials spreading across other nations (Figure 2I, Supporting Information S1: Table S2). These countries may benefit from the well-established nuclear infrastructures that significantly bolster radiopharmaceutical R&D [19]. Conversely, countries in Africa and Asia have lagged behind. Nonetheless, there has been a sharply increasing number of clinical trials (37 trials) in China driven by strategic governmental initiatives “the introduction of the Medium and Long-Term Development Plan for Medical Isotopes (2021–2035)” since 2021, suggesting the pivotal role of policy in radiopharmaceutical advancement. Meanwhile, further investigation based on the “Funding Type” field revealed that academic institutions and enterprises were the most active sponsors of clinical trials, contributing 45.9% and 44.6% of the total funding, respectively, whereas cooperative groups and governments each accounted for 4.6% and 3.0% (Figure 2J). Moreover, a detailed analysis of the funding distribution revealed that industry funding tends to favor RDC development (48.5%), whereas academia allocates more resources toward organ-targeted approaches (49.6%) (Figure 2K,L). Collectively, substantial funding provided by industries and academia may largely provide support for the R&D, practical application, and commercial value transformation of radiopharmaceuticals in the future. In conclusion, radiopharmaceutical therapy is a rapidly evolving and promising strategy for the PCa treatment. Based on the analysis of global clinical trial registry data, we observed a steady increase of trial number, with a clear shift toward biologically targeted RDCs. Most trials remained in early phases, and radionuclide types continued to be diverse, though therapeutic targets were still dominated by PSMA, highlighting the need for expanded target discovery to support more precise clinical applications. β emitting radionuclides are prevalent in current trials, whereas α emitting agents may be a potential next generation direction for theoretical advantages in tumor selectivity and thus warrant further investigation. Indications for radiopharmaceuticals are gradually expanding beyond mCRPC to include other disease states, yet most of these efforts are still in early clinical stages and require additional evidence to confirm clinical value. Combination strategies are increasingly adopted, which may aim to enhance treatment effects and address tumor heterogeneity. However, detailed clinical benefits remain to be validated. Geographically, clinical development is concentrated in a small number of countries with established nuclear medicine infrastructure, whereas China has shown rapid growth driven by national policy support. Academic institutions and industry are the primary funding sources, with distinct investment preferences between RDCs and organ targeted agents. Collectively, though substantial progress has been made in the clinical development of PCa radiopharmaceuticals, the field remains in an early phase of clinical translation. Continued improvements in radionuclide production, research infrastructure, and regulatory coordination may facilitate the widespread implementation of PCa radiopharmaceuticals. Furthermore, strengthening collaboration among academia, industry, and regulatory agencies may also be beneficial for accelerating innovation, optimizing the R&D of radiopharmaceuticals, and promoting their widespread application in clinical practice. This study was supported by the National Natural Science Foundation of China (Grant Nos. 82273373, 82573849), Yunnan Natural Science Foundation (Grant Nos. 202401AS070019, 202201AY070001-045), 535 Talent Project of First Affiliated Hospital of Kunming Medical University (Grant No. 2023535D15), and Yunnan Health Training Project of High-Level Talents (Grant No. D-2024028). The authors declare no conflicts of interest. Trialtrove database is a commercial, curated clinical intelligence platform rather than a public primary clinical trial registry. The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.