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Abstract

The treatment of metastatic castration-resistant prostate cancer (mCRPC) remains a huge challenge. Newer radionuclides, such as ²²³Ra, ¹⁷⁷Lu, ²²⁵Ac, etc., have shown efficacy in alleviating cancer-related pain and also in enhancing the prognosis of mCRPC patients. These novel radionuclides have emerged as important weapons in the treatment of mCRPC. This article reviews recent advances and key clinical trials in various radionuclides and their combinations in the application for treating mCRPC. Further directions of this new treatment strategy are also discussed in this review.

Keywords

metastatic castration-resistant prostate cancer prostate-specific membrane antigen (PSMA)radionuclide radium-223

Introduction

According to the Global Cancer Statistics 2022, prostate cancer is the second most common cancer among men worldwide.¹ For patients with metastatic hormone-sensitive prostate cancer, the condition often progresses to metastatic castration-resistant prostate cancer (mCRPC) after 18–24 months of hormone therapy. At this stage, treatment options include chemotherapy, novel hormonal therapies, PARP inhibitors, radionuclides, immunotherapy, and antibody–drug conjugates.² Recent years have seen significant advancements in radionuclide therapy. Traditional radionuclides like strontium-89 (⁸⁹Sr) continue to play a role in treating mCRPC, while newer agents, such as ²²³Ra, ¹⁷⁷Lu-PSMA-617, ²²⁵Ac-PSMA-617, etc., are developed and show promising results in clinical trials and real-world practice, further highlighting the importance of radionuclide therapy in the management of mCRPC. This article aims to review recent progress in the application of radionuclide therapy for mCRPC.

Basic concept of radionuclides

Radionuclides are metallic or non-metallic elements that can produce alpha, beta, or other forms of ionizing radiation and play a vital role in the treatment of tumors. Radiopharmaceuticals labeled with radionuclides can selectively accumulate in tumor lesions, where they emit radiation to damage tumor cells and achieve therapeutic effects. α particles, actually, are helium nuclei (⁴He²⁺), have high mass and strong ionizing capability, but extremely limited penetration. Due to this short range and concentrated energy deposition, α-emitters are unsuitable for imaging but possess high therapeutic potential by inducing lethal damage to nearby tumor cells while sparing distant normal tissue.³ Commonly used α particle emitters include ²²⁵Ac, ²²³Ra, etc. β particles are either electrons (β⁻) or positrons (β⁺) emitted during radioactive decay. β⁻-decay commonly occurs in neutron-rich radionuclides and has moderate tissue penetration (typically up to several millimeters).³ Common β particle emitters include ¹⁷⁷Lu, ¹³¹I, etc. By contrast, β⁺ particles are emitted by proton-rich artificial radionuclides. After traveling 1–2 mm in tissue, they annihilate with electrons, producing two 511 keV photons emitted in opposite directions, which is the basis for positron emission tomography imaging. In addition to α and β particles, Auger electrons and internal conversion electrons also contribute to therapeutic efficacy. These low-energy, short-range electrons, emitted after electron capture or isomeric transition, can cause significant DNA damage when radionuclides are localized in the nucleus.⁴ Moreover, they can kill targeted cancer cells by disrupting the cell membrane and may also affect non-targeted cells through cross-dose or bystander effects.⁴ γ rays have strong tissue penetration but minimal ionization capability, resulting in weaker localized effects compared to β and α radiation. Therefore, they are generally unsuitable for therapeutic use but play a crucial role in nuclear imaging, such as in single-photon emission computed tomography.

The emission characteristics of α, β, and γ radiation and Auger electrons are summarized in Table 1, providing a comparative analysis of their physical properties and clinical applications.

Table 1.

Comparative analysis of α, β, and γ radiation and Auger electrons.

Radiation type	Typical radionuclides	Penetration ability	Path length in tissue	Linear energy transfer	DNA damage potential	Application notes
Alpha (α)	²¹²Pb, 225Ac, ²²³Ra	Very low	~50–100 μm (very short)	Very high (~80–100 keV/μm)	Very high	Strong cytotoxicity, potentially advantageous for targeted radionuclide therapy of internal malignancies
Beta (β)	¹³¹I, 177Lu, 177Lu-PNT2002	Moderate	~0.2 mm (Lu), up to 2 mm (I)	Moderate (~0.2 keV/μm)	Moderate	Suitable for therapy (e.g., ¹³¹I in thyroid cancer, 177Lu in prostate cancer)
Auger electrons	161Tb	Very low	<1 μm	Mixed: moderate + very high	High (esp. near DNA)	Potential creation of double-strand breaks DNA and the cell membrane, potentially more effective than 177Lu
Gamma (γ)	¹²³I, ⁶⁷Ga, ⁹⁹mTc	Very high	Very long (>10 cm)	Very low (<0.05 keV/μm)	Low	Poor therapeutic effect; ideal for imaging (SPECT, PET) and dosimetry

PET, positron emission tomography; SPECT, single-photon emission computed tomography.

Prostate-specific membrane antigen targeted radioligand therapy

Therapeutic mechanism of prostate-specific membrane antigen-radioligand therapy

Prostate-specific membrane antigen (PSMA) is a type II transmembrane carboxypeptidase, predominantly expressed in prostate tissue. Its expression in prostate cancer cells is remarkably higher, ranging from 100 to 1000 times, than in normal prostate tissue.⁵ Studies have indicated a positive correlation between PSMA expression in prostate cancer tissue and both serum prostate-specific antigen (PSA) levels and Gleason scores.⁶ We will primarily focus on two treatment methods based on ¹⁷⁷Lu-PSMA-RLT and ²²⁵Ac-PSMA-RLT. Other new developing PSMA-radioligand therapies (PSMA-RLTs) are also briefly introduced.

PSMA-617, a widely used small molecule inhibitor that specifically targets PSMA and has a relatively short half-life in the blood, aiding in the efficient excretion of radionuclide drugs from non-target tissues. The two most researched PSMA-RLTs in mCRPC are ¹⁷⁷Lu-PSMA-617 and ²²⁵Ac-PSMA-617. ¹⁷⁷Lu emits β particles with a tissue penetration depth of approximately 1–3 mm and has a physical half-life of around 6.65 days, making it well-suited for targeted internal radiotherapy of tumors.⁷ On the other hand, ²²⁵Ac emits α rays, which have higher energy but a shorter range,⁷ with a half-life of about 9.9 days, is also a well-suitable internal radiotherapy. These radionuclides are administered intravenously and target the extracellular domain of PSMA on the membrane of prostate cancer cells. They are internalized into the tumor cells through endocytosis, accumulate inside the cells, and destroy the tumor cells through internal radiation emitted by the radioactive particles.

Advances of ¹⁷⁷Lu-PSMA-617 in the treatment of mCRPC

Kratochwil et al. first reported an mPCa patient who achieved a complete response (CR) on imaging after two cycles of ¹⁷⁷Lu-PSMA-617 treatment.⁸ This case sparked a research boom in PSMA-RLT. A phase II clinical trial conducted a non-inferiority study involving 40 mCRPC patients with high PSMA expression who had previously received androgen deprivation therapy (ADT), bone protection agents, or novel hormone therapy treatments, but not docetaxel chemotherapy. Patients were randomly assigned to receive ¹⁷⁷Lu-PSMA-617 treatment or docetaxel treatment at a ratio of 1:1. The study revealed a higher proportion of patients in the ¹⁷⁷Lu-PSMA-617 group experiencing a ⩾50% decrease in PSA compared to those receiving chemotherapy (60% vs 40%). Furthermore, the occurrence of severe adverse events was lower in the ¹⁷⁷Lu-PSMA-617 group compared to the chemotherapy group (30% vs 50%).⁹

In patients who have received docetaxel chemotherapy, the phase II TheraP study compared ¹⁷⁷Lu-PSMA-617 with cabazitaxel in patients previously treated with docetaxel. The results showed a higher PSA response rate and fewer grade 3 or 4 adverse events in the ¹⁷⁷Lu-PSMA-617 group.¹⁰ The 3-year follow-up results have been updated, although there was no significant difference in overall survival (OS) between the ¹⁷⁷Lu-PSMA-617 group and cabazitaxel group (mOS 19.1 months vs 19.6 months, p = 0.99), but a substantial improvement in progression-free survival was noted in the ¹⁷⁷Lu-PSMA-617 group (mPFS 7.1 months vs 5.0 months, p = 0.0028).¹¹ This result indicates that after progression on docetaxel, ¹⁷⁷Lu-PSMA-617 RLT may be a more suitable treatment choice for mCRPC than cabazitaxel.

In the phase III VISION clinical trial (NCT03511664), 831 mCRPC patients who had undergone chemotherapy and novel hormone therapy were randomly assigned in a 2:1 ratio to receive ¹⁷⁷Lu-PSMA-617 combined with standard treatment or standard treatment alone. The combined treatment group showed significantly prolonged overall survival (mOS 15.3 months vs 11.3 months; p < 0.001) and radiographic progression-free survival (mrPFS: 8.7 months vs 3.4 months; p < 0.001).¹²

Following the VISION study results, in March 2022, the Food and Drug Administration (FDA) approved Pluvicto (¹⁷⁷Lu-PSMA-617) for treating PSMA-positive mCRPC patients who have received docetaxel chemotherapy and novel hormone therapy,¹³ marking it as the first RLT approved by the FDA for mCRPC patients.¹³

The PSMAfore trial (NCT04689828) evaluated the effectiveness of ¹⁷⁷Lu-PSMA-617 in taxane-naïve mCRPC patients. It randomly assigned 469 mCRPC patients who had previously received androgen receptor pathway inhibitors (ARPI) at a ratio of 1:1, with one group receiving ¹⁷⁷Lu-PSMA-617 treatment every 6 weeks for a total of six cycles, and the other group using another ARPI. The results presented at the 2023 ESMO meeting showed that compared to the ARPI group, the ¹⁷⁷Lu-PSMA-617 group demonstrated more than double the median radiographic progression-free survival time (median time: 12.0 months vs 5.6 months) and maintained good safety.¹⁴ Based on the PSMAfore trial, on March 28, 2025, the FDA expanded the indication for ¹⁷⁷Lu-PSMA-617 to include adults with PSMA-positive mCRPC previously treated with ARPIs and deemed suitable for delayed taxane-based chemotherapy.

Combination therapies based on ¹⁷⁷Lu-PSMA-617

Due to the significant therapeutic efficacy of ¹⁷⁷Lu-PSMA-617 monotherapy in patients with mCRPC, combination therapies involving ¹⁷⁷Lu-PSMA-617 are also being widely explored.

ENZA-p (NCT04419402) is a phase II clinical trial for patients with mCRPC who have not received prior chemotherapy, aiming to evaluate the efficacy and safety of combining ¹⁷⁷Lu-PSMA-617 with enzalutamide. According to the analysis of prostate-specific antigen progression-free survival (PSA-PFS), patients treated with enzalutamide in combination with ¹⁷⁷Lu-PSMA-617 showed a significant advantage in PSA-PFS compared to enzalutamide alone (13 months vs 7.8 months).¹⁵

Cabazitaxel has radiosensitizing properties that may enhance the cytotoxic effect of ¹⁷⁷Lu-PSMA-617, and it is also useful in treating any PSMA-negative mCRPC.¹⁶ LuCAB (NCT05340374) is an ongoing I/II clinical trial designed to evaluate the safety and efficacy of combining Cabazitaxel with ¹⁷⁷Lu-PSMA-617 for the treatment of mCRPC, with the primary goal of determining the maximum tolerated dosage of both Cabazitaxel and ¹⁷⁷Lu-PSMA-617. The trial is expected to be completed by 2026.

ANZUP2001 (NCT05150236) is an ongoing phase II clinical trial evaluating the efficacy of 7.4 GBq of ¹⁷⁷Lu-PSMA-617 every 6 weeks for 6 cycles, in combination with ipilimumab and nivolumab for the treatment of mCRPC. The primary endpoint measures the 12-month PSA progression-free survival for patients. The primary completion date is expected to be December 2024.

The PRINCE study (NCT03658447), a phase I trial, evaluates the combination of ¹⁷⁷Lu-PSMA-617 with pembrolizumab for mCRPC treatment. The latest median follow-up results presented at ASCO 2022 showed a PSA decline of ⩾50% in 76% of patients and an overall response rate (ORR) of 78%. The combination therapy did not exhibit a significant increase in adverse reactions compared to monotherapy.¹⁷ This result indicates the feasibility of RLT and immunotherapy combinations in mCRPC, and further II/III phase studies are eagerly anticipated.

The LuPARP trial (NCT03874884) is a phase I dose-escalation and dose-expansion study aimed at evaluating the safety and tolerability of olaparib in combination with ¹⁷⁷Lu-PSMA-617 for the treatment of mCRPC. Preliminary data from ASCO 2023 showed good tolerability and activity of this combination.¹⁸

Progress in the treatment of mCRPC with ²²⁵Ac-PSMA

²²⁵Ac-PSMA is also a type of PSMA-targeted radioactive ligand therapy, in which ²²⁵Ac emits alpha particles. It is currently one of the most researched alpha-emitting isotopes used for targeted alpha therapy. Alpha particles have higher linear energy transfer, higher radiation energy, shorter range, and relatively higher biological effects, leading to stronger damage to tumor cells and lower toxicity to normal cells. ²²⁵Ac-PSMA-RLT has shown promising results in a wide range of studies.

Kratochwil et al. pioneered in the use of alpha-emitting radionuclide-labeled PSMA ligands in human therapy by administering 100 kBq/kg of ²²⁵Ac-PSMA-617 to two patients every 2 months. Subsequently, both patients experienced a decrease in PSA to below 0.1 ng/mL and achieved CR on imaging, without significant hematologic toxicities observed.¹⁹ In another study, Kratochwil et al. continued clinical follow-up of 40 mCRPC patients receiving the same treatment regimen and observed that 87% of the patients experienced a PSA reduction, with 63% of patients achieving a PSA decrease of ⩾50%, further confirming the efficacy of ²²⁵Ac-PSMA-617 in mCRPC.²⁰ Sathekge et al. administered a total of 210 cycles of ²²⁵Ac-PSMA-617 treatment to 73 mCRPC patients. Their multivariate analysis indicated that a PSA reduction of ⩾50% post-treatment was significantly correlated with improved OS and PFS.²¹ In a retrospective study reported in 2022, 53 mCRPC patients treated with ²²⁵Ac-PSMA-617 directly after ADT, a multifactorial analysis also found that a PSA decrease of over 50% was a predictor of OS and PFS.²²

Yadav et al. recruited 28 patients, of whom 15 (54%) had previously received ¹⁷⁷Lu-PSMA-617 RLT, and the remaining 13 (46%) had not received ¹⁷⁷Lu-PSMA-617 RLT. The study compared the response between these two groups of patients after receiving ²²⁵Ac-PSMA-617 targeted therapy. The results showed that ²²⁵Ac-PSMA-617 therapy induced moderate remission and improved survival (PFS/OS 11/13.7 months vs. 12/17 months) in ¹⁷⁷Lu-PSMA-617 radioligand therapy refractory mCRPC patients. Despite the more modest response in the ¹⁷⁷Lu-PSMA-617 refractory group compared to the naive group, similar OS and PFS validate that ²²⁵Ac can overcome the resistance of cancer cells to beta-emitting therapy (¹⁷⁷Lu-PSMA-617 RLT) and trigger a response in refractory patients.²³

The AcTION phase I clinical trial (NCT04597411) is currently evaluating the efficacy and safety of ²²⁵Ac-PSMA-617 treatment in PSMA-positive prostate cancer patients, with or without prior ¹⁷⁷Lu-PSMA-617 RLT, with maximum tolerated dose as the primary outcome, and is expected to be completed in 2025.

The WARMTH Act is a multicenter retrospective study that reviewed 488 mCRPC patients who were treated with one or more cycles of 8 MBq ²²⁵Ac-PSMA RLT. These patients had previously received treatment with ARPI, ¹⁷⁷Lu-PSMA-617 (154.32%), or ²²³Ra (18.4%). The results showed that ²²⁵Ac-PSMA RLT showed good efficacy in mCRPC patients with a median overall survival of 15.5 months (95% CI 13.4–18.3) and a median progression-free survival of 7.9 months (6.8–8.9).²⁴

J591 is a monoclonal antibody targeting the external domain of PSMA, which has been extensively researched for radio-labeled isotopes. It is the most commonly used monoclonal antibody in clinical trials of anti-PSMA radioimmunotherapy. ²²⁵Ac-J591 is a novel radiopharmaceutical conjugate that combines J591 with the potent alpha-emitter ²²⁵Ac. In 2023, ASCO released the results of the first human dose escalation trial for ²²⁵Ac-J591 (NCT03276572, NCT04506567), showing its safety and preliminary efficacy.²⁵ The trial is still ongoing for further investigation.

In addition, the application of other ²²⁵Ac-PSMA-RLTs such as ²²⁵Ac-PSMA-I&T, ²²⁵Ac-PSMA-Trillium, and ²²⁵Ac-PSMA-R2 in the treatment of mCRPC is also emerging and being actively explored. TATCIST (NCT05219500) is an ongoing phase II study designed to assess the efficacy of ²²⁵Ac-PSMA-I&T in the treatment of mCRPC. PAnTHA (NCT06217822) is the first-in-human study aiming to evaluate ²²⁵Ac-PSMA-Trillium (BAY 3563254) in mCRPC, and is expected to commence recruitment in 2024. In addition, ²²⁵Ac-PSMA-R2 has also commenced phase I/II trials in patients with mCRPC (NCT05983198).

Currently, ²²⁵Ac-PSMA is still undergoing clinical trials and has not yet been recommended in major guidelines. Further extensive clinical trials are needed to confirm its efficacy in treating mCRPC.

Other PSMA-targeted RLT

¹³¹I can emit beta radiation and has long been used as a standard treatment for thyroid cancer. ¹³¹I-MIP-1095 is also the first PSMA RLT used for prostate cancer.²⁶ Some researchers have used it as a terminal treatment for metastatic prostate cancer, administering a 1-week course of ¹³¹I-MIP-1095. In the first 3 months after treatment, 60.7% of patients experienced a greater than 50% decrease in PSA levels, 25% of patients had a PSA decrease of over 75% and tumor size also significantly decreased.²⁶ However, with the continuous development of ¹⁷⁷Lu-PSMA RLT, treatment related to ¹³¹I has been gradually replaced.

ECLIPSE (NCT05204927) is a phase III clinical trial using ¹⁷⁷Lu-PSMA-I&T in patients with mCRPC who have previously received ARPI treatment and have not undergone taxane therapy. The trial began enrolling patients in November 2023. PNT2002 is an innovative, PSMA-targeted, ¹⁷⁷Lu-based radionuclide therapy. In April 2023, the United States Food and Drug Administration granted fast-track designation to ¹⁷⁷Lu-PNT2002, signaling its impending entry into clinical application. The SPLASH trial (NCT04647526) is a multicenter phase III clinical study aimed at evaluating the efficacy and safety of ¹⁷⁷Lu-PSMA-PNT2002 in patients with mCRPC who have previously received second-line ARPI treatment. Abiraterone or enzalutamide is used as a control group. Data from the ongoing trial indicate that patients treated with ¹⁷⁷Lu-PNT2002 had a median radiographic progression-free survival (rPFS) of 9.5 months, compared to 6.0 months in the control group.²⁷ Other ¹⁷⁷Lu-PSMA drugs, such as ¹⁷⁷Lu-PSMA-R2(NCT03490838), ¹⁷⁷Lu-EB-PSMA(NCT04996602), and ¹⁷⁷Lu-LNC1003(NCT06237491), are under extensive clinical trials.

²¹²Pb is an emerging radionuclide that disrupts tumor cells by releasing alpha particles. Earlier studies by Banerjee et al. have demonstrated promising pharmacokinetics in a PCa mouse model.²⁸ Subsequently, Stenberg et al. found that ²¹²Pb-NG001 exhibited PSMA-specific cancer cell targeting and delayed tumor growth in a C4-2 xenograft mouse model without the thymus.²⁹ These results indicate that ²¹²Pb is a promising radionuclide for the treatment of mCRPC.

¹⁶¹Tb has decay properties similar to those of ¹⁷⁷Lu, but emits a substantial number of conversion and Auger electrons. Compared to ¹⁷⁷Lu, it may produce a greater therapeutic effect. Schaefer-Schuler et al. conducted a study on six patients with mCRPC who underwent treatment with ¹⁷⁷Lu-PSMA-617 and subsequently with ¹⁶¹Tb-PSMA-617 to observe tumor absorbed dose. The results showed that ¹⁶¹Tb-PSMA-617 exhibited a significant advantage in tumor absorbed dose.³⁰ VIOLET (NCT05521412) is a phase I/II clinical trial evaluating the efficacy of ¹⁶¹Tb-PSMA-I&T in the treatment of mCRPC, with an expected completion date in 2026.

Radium-223

Therapeutic mechanism of radium-223

Radium-223 (²²³Ra) is the world’s first alpha-emitting radionuclide and has minimal impact on surrounding normal tissues.³¹ It is primarily excreted through the gastrointestinal tract.³² Acting similarly to calcium ions, ²²³Ra accumulates in areas of active bone metabolism, such as osteoblastic lesions, and emits high-energy α-rays into the nearby microenvironment. ²²³Ra reduces skeletal-related events (SREs) from bone metastasis while inhibiting cancer by inducing DNA double-strand breaks in nearby prostate cancer cells, osteogenic, and osteoblastic cells. It has also been proven to enhance the prognosis of mCRPC patients with bone pain. In May 2013, ²²³Ra (marketed as Xofigo) was approved by the FDA for therapy of bone metastases in patients with mCRPC.

Advances of radium-223 in the treatment of mCRPC

The ALSYMPCA study (NCT00699751), a pivotal phase III trial, first reported the use of ²²³Ra in treating mCRPC. The study involved 921 patients with symptomatic bone metastases but no visceral metastases, divided into two groups in a 2:1 ratio, with one group receiving intravenous injection of ²²³Ra and the other group receiving a placebo. The 3-year follow-up indicated that the median OS in the ²²³Ra treatment group was significantly longer than that in the placebo group (14.9 months vs 11.3 months, p < 0.001), and the time to first symptomatic skeletal event (SSE) was also extended by 5.8 months (15.6 months vs. 9.8 months, p < 0.001).³³ This study demonstrated the significant efficacy of ²²³Ra in prostate cancer bone metastases.

PARABO (NCT02398526) is a prospective, observational, non-interventional single-arm study with the primary endpoint being a clinically significant pain response (defined as an improvement of ⩾2 points in the most severe pain item on the Brief Pain Inventory). This study analyzed 354 patients and found that ²²³Ra reduced pain in mCRPC patients with symptomatic bone metastases, especially in those who received 5–6 injections.³⁴ The extent of metastatic disease did not impact the pain response.³⁴

The NCCN guidelines recommend ²²³Ra for treating symptomatic bone metastases in mCRPC patients without visceral metastases,³⁵ and the EAU guidelines list it as one of the second-line treatment options for mCRPC.³⁶ This therapy significantly improves OS, delays the first occurrence of SSEs, and enhances patients’ quality of life.

Combination therapies based on radium-223

Denosumab is a bone-targeted therapy. Combination therapy of ²²³Ra with denosumab can reduce the risk of SREs and improve patients’ prognosis.^37,38 Saad et al. found that in mCRPC patients with bone metastases treated with a combination of ²²³Ra and denosumab had a longer median overall survival (mOS) compared to those without denosumab (15 months vs 13 months).³⁷

In trials involving novel hormone therapies, preliminary clinical results of ERA223 (NCT02043678) indicated that abiraterone in combination with ²²³Ra did not lead to an improvement in SSE-free survival compared to abiraterone monotherapy, but rather led to a higher frequency of fractures.³⁹ Consequently, the combination use of ²²³Ra with abiraterone is not currently recommended in clinical practice. REASSURE (NCT02141438) is a prospective observational study that enrolled 1474 patients, including 46 patients in the combination group (who initiated combined treatment of ²²³Ra and enzalutamide within 30 days) and 205 patients in the sequential group (who had received another treatment for more than 30 days prior to initiation of therapy). The results showed that the combined or sequential treatment of ²²³Ra and enzalutamide was safe and well tolerated, without increasing the risk of fractures. In addition, compared to the sequential group or all patients, the median overall survival was numerically longer in the combination group (22.2 months vs 16.5 months vs 15.6 months), indicating that the combination treatment of ²²³Ra and enzalutamide could significantly reduce the risk of disease progression⁴⁰ and offer a new approach for patients with mCRPC.

Bipolar androgen therapy (BAT) is an innovative hormone treatment method that involves periodic administration of high-dose testosterone to address PCa patients who have developed resistance to previous hormone treatment regimens.⁴¹ This therapy aims to restore sensitivity to androgen signal suppression in patients and may lead to clinical responses. Currently, BAT-RAD (NCT04704505) is ongoing to evaluate the efficacy of combining BAT with ²²³Ra (RAD) in mCRPC patients. This study is expected to be completed by 2027.

Furthermore, a clinical trial investigating the combination of ²²³Ra and PARP inhibitors for the treatment of mCRPC is ongoing. The COMRADE trial (NCT03317392) is an open-label, multicenter, phase I/II trial aimed at evaluating the dose, safety, and effectiveness of combining olaparib with ²²³Ra in male patients with mCRPC and bone metastases. The COMRADE trial is divided into two stages: Stage 1 involves a dose escalation design using a 3 + 3 approach to determine the recommended phase II dose of olaparib in combination with a fixed dose of ²²³Ra (55 kBq/kg IV, administered every 4 weeks for a total of 6 doses). Preliminary results have shown a PSA response rate of 16.7% (n = 2) and an alkaline phosphatase response rate of 67% (n = 8). The median follow-up time was 6.5 months (range 2.8–11.8), with a 6-month rPFS of 57% (95% CI: 25%–80%).⁴² Patients with BRCA2 mutations who received treatment with ²²³Ra and olaparib experienced a prolonged time to disease progression. The main endpoint of the phase II portion of the trial is rPFS assessed according to PCWG3 bone metastasis guidelines and RECIST v1.1⁴³ criteria for non-bone disease. The second stage of the trial is currently ongoing, and the results are eagerly anticipated.

With the popularity of immunotherapy, the combination of ²²³Ra with immunotherapy has also sparked interest. Studies such as the combination treatment of sipuleucel-T and ²²³Ra for mCRPC (NCT02463799), atezolizumab (ATZ) in combination with ²²³Ra in mCRPC (NCT02814669), the addition of pembrolizumab to ²²³Ra in mCRPC (NCT03093428), and the assessment of a better treatment approach among ²²³Ra alone, ²²³Ra in combination with M3814 (Nedisertib), or ²²³Ra in combination with M3814 (Nedisertib) and avelumab to reduce the chances of mCRPC growth or spread into the bones (NCT04071236). These studies are enriching the application of ²²³Ra in mCRPC.

Combination therapies based on different radionuclides

The combination of different RLTs has flourished in recent years and has shown promising results in clinical trials. In particular, the combination of ¹⁷⁷Lu-PSMA-617 and ²²⁵Ac-PSMA-617 has obtained significant attention. Research indicates that ²²⁵Ac-PSMA-617 can enhance the clinical efficacy of ¹⁷⁷Lu-PSMA-617 and reduce its toxic side effects.⁴² A phase I/II clinical trial (NCT04886986) is assessing the combination use of ¹⁷⁷Lu-PSMA-I&T and ²²⁵Ac-J591 in mCRPC patients, with the primary goal of assessing the proportion of patients with dose-limiting toxicity and a drop in PSA of more than 50%. It aims to evaluate the synergistic effects of alpha and beta particles in reducing PSA levels and minimizing adverse reactions. The study’s primary completion date is expected to be December 2024.

Furthermore, several studies also tried to combine ²²³Ra with RLTs to see whether this combination brings benefits in treatment with mCRPC. AlphaBet (NCT05383079) is a phase I/II study evaluating the safety of ²²³Ra in combination with ¹⁷⁷Lu-PSMA-I&T in mCRPC, with an expected completion date in 2026. The RALU study evaluates the safety and efficacy of sequential ²²³Ra and ¹⁷⁷Lu-PSMA therapies in mCRPC patients. An interim retrospective review of 49 patients revealed that those first treated with ¹⁷⁷Lu-PSMA had a mOS of 12.6 months (95% CI 8.8–16.1), while the mOS for patients receiving ²²³Ra treatment as the first treatment was 31.4 months (95% CI 8.8–16.1).⁴⁴ This finding suggests that sequential treatment with these radionuclides is feasible, well-tolerated, and offers new insights for future radionuclide therapies.

Adverse effects of RLT

RLT has shown significant efficacy in the treatment of mCRPC, but it is also associated with several side effects. These adverse effects vary depending on the specific radionuclide used. ¹⁷⁷Lu-PSMA, one of the most commonly used RLT, is associated with adverse events (AEs) such as renal toxicity, fatigue, and gastrointestinal symptoms, including xerostomia (occurring in up to 80%–87% of cases,⁴⁵ which is associated with PSMA binding in the salivary glands) and nausea/vomiting.^46–49 In addition, hematologic toxicity, primarily thrombocytopenia and anemia, is frequently observed, with approximately 15%–30% of patients experiencing grade 3/4 toxicity.^46–49 By contrast, ²²⁵Ac-PSMA may reduce myelosuppression to some extent (due to its shorter radiation range, which helps preserve bone marrow function), but its higher radiation energy increases the radiation burden on the salivary glands and kidneys, leading to a higher incidence of xerostomia and renal impairment.^19,24 However, some studies suggest that dynamic dose-reduction strategies can help alleviate these adverse effects.^19,50

²²³Ra, primarily used for the treatment of bone-metastatic disease, is mainly associated with myelosuppression, though the incidence of grade 3–4 bone marrow toxicity is relatively low, with thrombocytopenia and anemia being the most common AEs. Other AEs include gastrointestinal symptoms (such as nausea and diarrhea), exacerbation of bone pain, and spinal cord compression.^33,44,51

Though these side effects of RLT seem unavoidable, they are relatively common, transient, and generally manageable. Strict monitoring and proactive management during treatment are essential to optimize therapeutic outcomes and maintain patients’ quality of life.

Conclusion

More and more clinical trials applied with RLT are explored in the treatment of mCRPC. We have listed key clinical trials in this field in Table 2. The advantage of PSMA-RLT lies in its ability to target PSMA, delivering localized radiation damage to tumor cells, thereby enhancing the selectivity and precision of the treatment. This therapy has been recommended for PSMA-positive mCRPC patients who have previously undergone androgen receptor inhibitors and taxane-based chemotherapy. ²²³Ra has also shown significant clinical efficacy in treating bone metastatic mCRPC, particularly in patients with symptomatic bone metastases and without known visceral metastases (Figure 1). Moreover, the combination of different radionuclide therapies with other treatment modalities, such as immunotherapy (NCT03658447, NCT03805594, et al.), chemotherapy (NCT05340374, NCT04343885), and PARP inhibitors (NCT03874884, NCT03317392), is also becoming a research hotspot. Furthermore, with the development of new radionuclide drugs, it is expected that RLT will play a vital role in the treatment of mCRPC.

Table 2.

Ongoing clinical trials of PSMA-targeted RLT and radium-223 in prostate cancer treatment.

Trials number	Entrance criteria	Intervention	Primary outcome measure	Trial phase
NCT04689828 PSMAfore	mCRPC previously treated with ARPI and without prior docetaxel therapy	¹⁷⁷Lu-PSMA-617 vs ARPI	rPFS	Phase III
NCT04419402 ENZA-p	mCRPC not previously treated with chemotherapy	¹⁷⁷Lu-PSMA-617 + Enzalutamide vs Enzalutamide	PSA-PFS	Phase II
NCT05340374 LuCAB	mCRPC has been treated with ARPI	¹⁷⁷Lu-PSMA-617 + Cabazitaxel	DLT, MTD, RP2D	Phase I/II
NCT05150236 ANZUP2001	mCRPC not previously treated with ARPI (excepting abiraterone)	¹⁷⁷Lu-PSMA-617 + Ipilimumab + Nivolumab vs ¹⁷⁷Lu-PSMA-617	PSA-PFS	Phase II
NCT03658447 PRINCE	mCRPC has been treated with ARPI or docetaxel	¹⁷⁷Lu-PSMA-617 + pembrolizumab	50% PSA response	Phase I/II
NCT03874884 LuPARP	mCRPC has been treated with ARPI and has not been treated with platinums, PARP inhibitors, or 177Lu-PSMA	¹⁷⁷Lu-PSMA-617 + Olaparib	DLT	Phase I
NCT04597411 AcTION	PSMA-positive PCa with prior exposure or no exposure to 177Lu-PSMA-617 or 177Lu-PSMA-I&T	²²⁵Ac-PSMA-617	MTD	Phase I
NCT04506567	mCRPC previously treated with ARPI and with or unsuitable for docetaxel therapy	²²⁵Ac-J591	DLT, MTD, RP2D	Phase I/II
NCT05219500 TATCIST	mCRPC with confirmed testosterone level ⩽50 ng/dL under prior ADT	²²⁵Ac-PSMA-&T	PSA, 50% PSA response	Phase II
NCT06217822 PAnTHA	mCRPC has been treated with ARPI	²²⁵Ac-PSMA-Trillium	TEAEs, DLT, ORR	Phase I
NCT05983198	mCRPC with pre-treated PSMA-positive	²²⁵Ac-PSMA-R2	DLT, ORR	Phase I/II
NCT05204927 ECLIPSE	mCRPC has been treated with ARPI	¹⁷⁷Lu-PSMA-I&T vs abiraterone or enzalutamide	rPFS	Phase III
NCT04647526 SPLASH	mCRPC has been treated with ARPI	¹⁷⁷Lu-PNT2002 vs abiraterone or enzalutamide	rPFS	Phase III
NCT04996602	mCRPC	¹⁷⁷Lu-EB-PSMA	PSA response	Early phase I
NCT06237491	mCRPC has been treated with ARPI	¹⁷⁷Lu-LNC1003	MTD, DLT	Phase I
NCT05521412 VIOLET	mCRPC has been treated with ARPI or taxane chemotherapy	¹⁶¹Tb-PSMA-617	MTD, DLT, RP2D	Phase I/II
NCT02141438 REASSURE	mCRPC	Radium-223	Incidence of developing second primary malignancies, SAE	Observational
NCT04704505 BAT-RAD	mCRPC	BAT + Radium-223	rPFS	Phase II
NCT03317392 COMRADE	mCRPC with bone metastases	Radium-223 + Olaphani	MTD, rPFS	Phase I/II
NCT03093428	mCRPC not previously treated with radium-223, PD-1, PD-L1, or PD-L2 blocking therapy	Pembrolizumab + Radium-223	Differences in immune infiltrating cells	Phase II
NCT04886986	mCRPC previously treated with ARPI	²²⁵Ac-J591 + ¹⁷⁷Lu-PSMA-I&T	DLT, MTD, 50% PSA response	Phase I/II
NCT05383079 AlphaBet	mCRPC previously treated with ARPI	Radium-223 + ¹⁷⁷Lu-PSMA-I&T	DLT, MTD, RP2D, 50% PSA response	Phase I/II

ADT, androgen deprivation therapy; ARPI, androgen receptor pathway inhibitor; BAT, bipolar androgen therapy; DLT, dose-limiting toxicity; mCRPC, metastatic castration-resistant prostate cancer; MTD, maximum tolerated dose; OS, overall survival; PCa, prostate cancer; PSA-PFS, prostate-specific antigen-progression-free survival; PSMA, prostate-specific membrane antigen; RLT, radioligand therapy; RP2D, recommended phase II dose; rPFS, radiographic progression-free survival; SAE, serious adverse event; TEAEs, treatment emergent adverse events.

Figure 1.

Treatment of mCRPC with ²²³Ra or ¹⁷⁷Lu-PSMA-617.

Footnotes

Acknowledgements

None.

Declarations

ORCID iDs

Xin Fei

Qi Ma

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Current status of radionuclide therapies in metastatic castration-resistant prostate cancer

Abstract

Keywords

Introduction

Basic concept of radionuclides

Prostate-specific membrane antigen targeted radioligand therapy

Therapeutic mechanism of prostate-specific membrane antigen-radioligand therapy

Advances of 177Lu-PSMA-617 in the treatment of mCRPC

Combination therapies based on 177Lu-PSMA-617

Progress in the treatment of mCRPC with 225Ac-PSMA

Other PSMA-targeted RLT

Radium-223

Therapeutic mechanism of radium-223

Advances of radium-223 in the treatment of mCRPC

Combination therapies based on radium-223

Combination therapies based on different radionuclides

Adverse effects of RLT

Conclusion

Footnotes

Acknowledgements

Declarations

ORCID iDs

References

Advances of ¹⁷⁷Lu-PSMA-617 in the treatment of mCRPC

Combination therapies based on ¹⁷⁷Lu-PSMA-617

Progress in the treatment of mCRPC with ²²⁵Ac-PSMA