Targeted radionuclide therapies for prostate cancer: clinical insights and innovation
- Open Access
- 05.12.2025
- Prostatakarzinom
- review
Summary
Background
Prostate cancer (PCa) remains one of the leading causes of cancer-related death in men, with its incidence continuing to rise [1]. Given its high prevalence, research efforts have focused on the development of precise diagnostic methods and various therapeutic strategies.
The primary standard-of-care treatment for localized PCa typically includes surgical radical prostatectomy (RPE), radiation therapy (including external beam radiation and internal radioactive seed implants) or active surveillance, depending on risk stratification. For patients with low-, intermediate- and high risk PCa, surgery and radiation generally achieve similar results in overall survival, although RPE might have a small advantage in certain intermediate and high-risk subgroups [2‐4].
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Despite these interventions, approximately up to 46% of patients experience an increase in prostate-specific antigen (PSA) levels after the primary curative approach, a condition referred to as biochemical recurrence (BCR) [5]. These individuals are at higher risk of developing metastatic disease and are generally associated with a poorer prognosis. Consequently, further treatments such as salvage radiotherapy or additional androgen deprivation therapy (ADT) are often initiated [6].
However, this disease eventually progresses to an advanced stage known as castration-resistant PCa (CRPC) after a median time of about 3 years. At this stage, tumor growth becomes independent of androgens, meaning that ADT is no longer effective. CRPC is frequently associated with poor outcomes and only a short overall survival [7]. Nowadays, various treatment options are available at this advanced stage of the disease, including taxane-based chemotherapeutic agents, as well as androgen receptor pathway inhibitors (ARPIs) and poly(ADP-ribose) polymerase (PARP) inhibitors. Given the limitations of these conventional therapies, including significant side effects and suboptimal response rates, radionuclide therapies have become increasingly important in clinical routine. These therapies target-specific receptors, often resulting in similar improved therapeutic responses with more favorable side effects.
[223Radium]Ra-dichloride
[223Radium]Ra was the first radionuclide therapy to receive U.S. Food and Drug Administration (FDA) approval for advanced PCa in May 2013. [223Radium]Ra-dichloride is an alpha-emitting radiopharmaceutical that targets areas of increased bone turnover in bone metastases in a manner mimicking calcium molecules.
In the phase III ALSYMPCA trial, which included 921 patients with metastatic castration-resistant prostate cancer (mCRPC) with symptomatic disease and at least two bone metastases detected by bone scan, [223Radium]Ra-dichloride plus standard of care (SoC) significantly improved overall survival compared with placebo (median 14.9 vs. 11.3 months), with low rates of myelosuppression and few adverse events. These results established [223Radium]Ra-dichloride (Xofigo®, Bayer AG, Leverkusen, Germany) as an effective treatment for patients with symptomatic, bone-dominant mCRPC and no visceral metastases, as reflected in the current guidelines of the European Association of Urology [8].
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Nevertheless, in 2019, the ERA 223 trial, a placebo-controlled phase III study conducted at 165 oncology and urology centers in 19 countries, compared [223Radium]Ra-dichloride (n = 401) with placebo (n = 405), both in combination with abiraterone acetate plus prednisone or prednisolone, in 806 patients with mCRPC. The results showed an increased risk of skeletal-related events in the [223Radium]Ra-dichloride group [9]. Consequently, the European Medicines Agency (EMA) has since restricted its use as monotherapy to symptomatic mCRPC patients with more than six osteoblastic lesions on bone scan who have received at least two prior systemic therapies.
[177Lutetium]Lu-PSMA
Prostate-specific membrane antigen (PSMA) is a protein that is highly expressed in PCa cells, making it an ideal target for the binding of different isotopes. Since the publication of the prospective VISION and TheraP trials in 2021, [177Lutetium]Lu labeled PSMA radioligand therapy (RLT) has gained significant attention as a promising treatment option for patients with advanced PCa.
In the VISION study, patients with mCRPC who received [177Lutetium]Lu-PSMA-617 RLT in addition to standard treatment demonstrated a 38% lower risk of death and a 60% reduced risk of radiographic disease progression compared to those receiving standard therapy alone [10]. Following these results, [177Lutetium]Lu-PSMA-617 (Pluvicto®) was approved by the U.S. FDA on March 23, 2022, and subsequently by the EMA, for the treatment of PSMA-positive mCRPC patients. Eligibility criteria for this therapy include mCRPC patients with one or more metastatic lesions exhibiting high PSMA expression (greater than liver uptake) on PSMA positron emission tomography/computed tomography (PET/CT) scan, and prior treatment with at least one ARPI and one or two taxane-based chemotherapies.
Another important milestone was the Australian multicenter TheraP trial, which also enrolled patients with mCRPC. Among the 98 patients treated with PSMA-RLT, there was a significantly greater decline in PSA levels and fewer severe adverse events compared to the 85 patients who received chemotherapy with Cabazitaxel® [11].
Building on these promising results, additional phase III trials were initiated to evaluate the therapeutic impact of [177Lutetium]Lu-PSMA-RLT in earlier disease stages and prior to the initiation of other systemic treatments for PCa. The PSMAfore study was a recently published trial investigating [177Lutetium]Lu-PSMA-617 in taxane-naive patients with PSMA-positive mCRPC after prior ARPI therapy. A total of 468 patients were randomized to receive either [177Lutetium]Lu-PSMA-617 or a switch to another ARPI. [177Lutetium]Lu-PSMA-617 significantly prolonged radiographic progression-free survival compared with the newly initiated ARPI (11.6 vs. 5.6 months) and was associated with lower rates of grade 3–5 adverse events (36% vs. 48%, respectively). These findings support [177Lutetium]Lu-PSMA-617 as an effective and safe treatment option for patients progressing after initial ARPI therapy [12]. Furthermore, the results of the PSMAaddition study (NCT04720157), an ongoing international randomized trial, are eagerly awaited. This trial is evaluating the efficacy and safety of [177Lutetium]Lu-PSMA-617 in combination with SoC versus SoC alone in patients in an earlier stage of PCa, with metastatic hormone-sensitive PCa [13].
Numerous clinical trials are currently underway worldwide, investigating [177Lutetium]Lu-PSMA-RLT across various study settings and tumor stages. At the Vienna General Hospital, two investigator-initiated, prospective phase II studies are currently underway. The first is evaluating the efficacy and toxicity of [177Lutetium]Lu-PSMA-I&T (I&T: imaging and therapy) in patients with BCR but without PSMA PET/CT-detectable radiomorphological or PSMA-expressing local recurrence after primary therapy (NCT06220188). The second is investigating the impact of neoadjuvant [177Lutetium]Lu-PSMA-I&T RLT in patients with oligometastatic PCa prior to RPE (NCT06259123).
[225Actinium]Ac-PSMA
Due to its higher linear energy transfer and distinct microdosimetry in tumor tissue, alpha radiation therapy has the potential to induce cell damage even in cases of radioresistance to beta emitters [14]. [225Actinium]Ac-PSMA has already demonstrated clinical value in patients with mCRPC who are resistant to the beta-emitting [177Lutetium]Lu-PSMA. [15]. The multicenter WARMTH Act trial reported promising results for [225Actinium]Ac-PSMA in heavily pretreated mCRPC patients, achieving a median progression-free survival of 7.9 months, without any serious adverse events or treatment-related deaths [16]. A recently published meta-analysis comparing [225Actinium]Ac-PSMA with [177Lutetium]Lu-PSMA found higher PSA response rates with the α‑particle emitter (60% vs. 49%, respectively) [17]. However, its unique chemical and physical properties, along with limited global availability, continue to restrict its widespread clinical use.
[161Terbium]Tb-PSMA
One persistent challenge in the treatment of PCa is the limited efficacy of PSMA-RLT in patients with micrometastases that are not detectable on PSMA PET/CT, often resulting in PSA increase and disease progression. Recently, results from the phase I/II single-center, single-arm VIOLET trial investigating [161Terbium]Tb-PSMA a novel, promising beta-emitting radionuclide with additional high-energy, short-range Auger electrons, were presented at the American Society Clinical Oncology (ASCO) meeting, highlighting its potential to improve the treatment of micrometastases. This prospective trial evaluated the safety and effectiveness of [161Terbium]Tb-PSMA-I&T in patients with metastatic CRPC previously treated with chemotherapies (taxanes) and ARPIs, by including 30 patients with in PSMA PET/CT PSMA-positive disease (SUVmax ≥ 20) and no discordant lesions on 18F‑FDG PET/CT. After up to six cycles of RLT, treatment-related side effects were predominantly grade 1 (including dry mouth, anemia, fatigue, and nausea). No grade 4 events or deaths were reported. Furthermore, 21 patients (70%) achieved a PSA reduction of at least 50%, while 12 patients (40%) demonstrated a PSA response exceeding 90%. Median PSA progression-free survival was 9.0 months, and radiographic progression-free survival was 11.1 months. These interim results suggest that [161Terbium]Tb-PSMA-I&T is both safe and effective in heavily pretreated mCRPC with a great potential in various disease stages [18].
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Future perspectives of radionuclide therapies
Currently, numerous studies worldwide are evaluating various therapeutic combinations in prostate cancer. The PEACE-3 trial, a randomized phase III study conducted from 2015–2023 across 12 countries, enrolled 426 mCRPC patients with bone metastases. Participants were randomized to receive either standard of care with daily enzalutamide or enzalutamide combined with [223Radium]Ra every 4 weeks for six cycles. Preliminary results demonstrated that the addition of [223Radium]Ra significantly improved radiographic progression-free survival and overall survival, supporting both the safety and potential earlier use of this combination in prostate cancer, pending confirmation from the final analysis [19]. Moreover, the addition of [177Lutetium]Lu-PSMA-617 to enzalutamide in the ENZA‑p trial, a multicenter, randomized, phase II study, improved PSA progression-free survival (13.0 months vs. 7.8 months). Among the 162 participants, 83 were assigned to the enzalutamide plus [177Lutetium]Lu-PSMA-617 group and 79 to the enzalutamide-only group, with a median follow-up of 20 months [20].
Further studies are examining the combination of [177Lutetium]Lu-PSMA with chemotherapy [21], PARP inhibitors [22], or ARPIs [23], highlighting the growing interest in combining RLT with established systemic treatments to improve patient outcomes. There are also studies investigating the combination of two radionuclide therapies, including [225Actinium]Ac with [177Lutetium]Lu-labeled PSMA [24] as well as [223Radium]Ra-dichloride with [177Lutetium]Lu-PSMA [25, 26] further expanding the potential therapeutic strategies in advanced PCa.
Conclusion
Radionuclide therapies offer a promising treatment approach not only for patients with castration-resistant prostate cancer (CRPC) but also for those in earlier stages of the disease. Current evidence indicates that these treatments may provide comparable or superior efficacy with a more favorable side-effect profile than established systemic options such as hormonal or chemotherapeutic agents. Multiple ongoing clinical trials are investigating their efficacy and safety in different cohorts of prostate cancer (PCa), both as monotherapy and in combination with other systemic treatments, including androgen deprivation therapy (ADT), chemotherapy, and other targeted drugs. The results of these studies will be essential to determine the optimal integration of radionuclide therapies into existing treatment algorithms, define their role across different disease stages, and fully realize their therapeutic potential in PCa management.
Conflict of interest
S. Rasul and H. Einspieler declare that they have no competing interests.
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