Targeted Radionuclide Therapy: Current Landscape and Combination Approaches to Improve Oncology Outcomes

Abstract

Targeted radionuclide therapy (TRT) is an emerging modality in oncology that delivers internal radiation specifically to tumor sites. It typically consists of a particle-emitting radionuclide, a linking complex with a chelator for securely binding radionuclides to targeting molecules, and a binding moiety of targets expressed on tumor cells. Early clinical results have been promising, with several TRT agents approved for treating various cancers, including prostate cancer and gastroenteropancreatic neuroendocrine tumors, or their microenvironment. However, most patients eventually relapse following TRT monotherapy, leaving room to further improve patient outcomes. Combination strategies could be beneficial to improve therapeutic index, enhance cytotoxic effects, or modulate tumor target expression; promising preclinical data have led to early-phase clinical trials. This review provides a concise overview of physical and chemical properties of commonly used β- and α-emitting radionuclides and a forward-looking rationale for combination regimens of TRT and other therapeutic modalities, such as hormone therapy, DNA damage repair inhibitors, immunotherapy, chemotherapy, external beam radiotherapy, and other combinations. We discuss the preclinical rationale, available clinical data, and ongoing key clinical trials with TRT combination therapy. Additionally, we highlight future perspectives including emerging radionuclides and prognostic and predictive biomarkers to optimize TRT combination therapy.

Introduction

Targeted radionuclide therapy (TRT) is an emerging strategy that delivers ionizing radiation specifically to tumor sites (1). Radiopharmaceuticals are medicinal products for therapeutic use that usually comprise 3 key components: a particle-emitting radionuclide to treat tumor lesions with DNA-damaging radiation; a linking complex, typically with a chelator for radiometals; and a binding moiety of targets expressed on tumor cells or in the tumor microenvironment (TME; ref. 2). Theranostics refers to the use of radiopharmaceuticals to visualize the intended treatment target through diagnostic positron emission tomography imaging using a positron-emitting radionuclide and to treat it by applying a therapeutic radionuclide bound to the same or a similar binding moiety (3–5).

TRTs cause cellular damage with the goal of inducing tumor cell death directly or indirectly (6). TRT efficacy is influenced by target specificity, the biodistribution and physical properties of the radionuclide, such as half-life, linear energy transfer (LET), range (7), and their alignment with the pharmacokinetics of distribution in tumor and normal tissues (2). The therapeutic mechanism of TRT is primarily due to delivery of nuclear radiation within tumor cells, resulting in widescale DNA damage, in contrast to a pharmacologic effect from inhibition of the target protein (8, 9). Cross-fire effects (in which all tumor cells within the particle range of the given radionuclide bound to cells that are effectively targeted also receive radiation even if lacking the target themselves) increase the potential effectiveness of TRT (10, 11). This may enable TRT to be effective even if target expression is heterogeneous at a microscopic level (12). This may be particularly important when targeting the TME, such as with fibroblast activation protein (FAP) inhibitors, in which case the malignant cells themselves are not targeted. Immunogenic effects of TRT on target cells and the potential to increase immune responses in the tumor have been described in preclinical experiments (13–18). Depending on the radionuclide, tumor-specific immune responses or more comprehensive effects on the TME can occur (19).

Radionuclide selection with TRTs is primarily guided by physical characteristics of the emitted particles, which have distinct implications for tumor cells and the TME (Fig. 1; refs. 7, 19). α particles are characterized by high LET (20–230 keV/μm) and a short pathlength (50–100 μm; refs. 2, 7, 20, 21). This high LET increases the probability of inducing DNA double-strand breaks (DSB), which are less effectively repaired than single-strand breaks (SSB) and more likely to result in cell death. There is clinical evidence that patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed after therapy with the β⁻-emitter lutetium-177 can respond to therapy with the α-emitter actinium-225 (22). β⁻ particles have lower LET (0.1–2 keV/μm), typically causing SSBs, base damage, and relatively few DSBs. The β⁻ particles are not monoenergetic; their energies form a spectrum, leading to variable energy deposition across tissues. The tissue penetration depths of the β⁻ particles of the three clinically used radioisotopes vary: yttrium-90 (average range, ∼2.5 mm), ¹⁷⁷Lu (average range, <1 mm), and iodine-131 (average range, <1 mm; refs. 2, 7, 20, 23–25). Some radionuclides also emit Auger electrons, which typically have low energy, high LET, and a very short pathlength (7, 26). This can also be accompanied by emission of internal conversion electrons [e.g., for terbium-161 (27)]. It has been speculated that β⁻-emitting radionuclides with a longer particle range are better suited to the treatment of larger tumors, whereas α-emitters may be particularly effective in micrometastatic disease. Although this seems plausible at first glance, there is currently no clinical evidence to support these predictions.

Figure 1.

Physical properties of α particles and β particles.

Currently, only a few TRTs are approved in the United States and Europe for use in oncology. Most commonly used are 2 TRTs in which the radionuclide or its salt is the active substance [the β⁻-emitting radionuclide ¹³¹I approved for thyroid cancer (28) and the α-emitting radionuclide radium-223 approved for patients with castration-resistant prostate cancer (CRPC) with bone metastases (29)], and 2 TRTs in which the radionuclide is bound to a carrier molecule to achieve targeted accumulation (in both cases, it is the β⁻-emitting radionuclide ¹⁷⁷Lu that is bound to the carrier molecule: [¹⁷⁷Lu]Lu-PSMA-617 [¹⁷⁷Lu-PSMA-617] and [¹⁷⁷Lu]Lu-DOTA-TATE [¹⁷⁷Lu-DOTATATE]). The latter two agents are part of a continuum of approved theranostic agents (Supplementary Fig. S1). ¹⁷⁷Lu-PSMA-617 is approved for patients with prostate-specific membrane antigen (PSMA)–positive mCRPC (30, 31). ¹⁷⁷Lu-DOTATATE is approved for patients with somatostatin receptor–positive gastroenteropancreatic neuroendocrine tumors (GEP-NET; refs. 25, 32). Real-world outcomes, including better survival for patients receiving TRT with manageable toxicity, for ¹⁷⁷Lu-PSMA-617 (33–35) and ¹⁷⁷Lu-DOTATATE (36–38) were consistent with outcomes from the pivotal trials (39–43), although there is room for treatment optimization. Although most of these trials were in patients with later-stage disease, evidence exists showing that treating earlier in the disease continuum may be beneficial [e.g., the PSMAfore trial (40)].

Although there has been a major focus on ¹⁷⁷Lu as the therapeutic radionuclide of choice, studies have been conducted to assess TRT with other β-emitting radionuclides, including ⁹⁰Y-DOTATATE/DOTATOC in patients with NETs, in tandem or sequentially (44–46); 161Tb-conjugated to PSMA (47); lead-212–labeled peptides used for targeting somatostatin receptor–positive NETs (48, 49), and the α-emitter ²²⁵Ac, in tandem or in sequence with ¹⁷⁷Lu chelated to a moiety that targets PSMA-expressing tissues (22, 50–53) in patients with mCRPC, as well as ²²⁵Ac (or ¹⁷⁷Lu) conjugated to the anti-PSMA antibody J591 (54). TRTs that bind novel targets are also under investigation in further oncologic settings, for example, ²²⁵Ac-ABD147 binds the delta-like ligand 3 receptor and has shown early promise in a phase I monotherapy trial in small cell lung cancer and large cell neuroendocrine carcinoma of the lung (55).

Results with TRTs to date have been promising but limited to prolongation of disease progression and survival. Absorbed dose limits for normal organs, which provide a guideline with regard to TRT-associated toxicity, are generally predicated on the limits used for external beam radiotherapy (EBRT; ref. 56), although the optimal TRT dose may differ from these recommendations and is often supplemented by clinical findings and practical guidance for TRT use (56–58). Because administration of higher activities is not always feasible due to off-target effects, options such as combination treatment could be potentially beneficial.

In this review, we provide the rationale for combination approaches with TRT, where such strategies may be viable based on the mechanism of action of the combination partners, disease state, and goals of care.

Innovative Combination Approaches with TRT

Multiple combination strategies with TRTs are being investigated with potential to enhance outcomes (1, 59). These include combining TRTs with agents that modulate expression of target receptors to improve TRT cellular binding; agents that have synergistic/radiosensitization effects by increasing induced DNA damage (e.g., chemotherapy); agents that inhibit DNA damage repair mechanisms [e.g., poly (adenosine diphosphate ribose) polymerase (PARP) inhibitors that primarily affect SSB repair or DNA protein-dependent kinases (DNA-PK) that are important for repairing DSBs]; and immune checkpoint inhibitors (ICI), which can potentiate radiation-induced antitumor immunity mechanisms (Table 1; refs. 1, 59). When designing combination regimens, careful consideration must be given to treatment scheduling, synergistic effects, and toxicity profiles. Although prospective data are limited for certain combinations, early results and an array of ongoing trials demonstrate the interest and promise of this area.

Table 1.

Key outcomes from TRT combination trials.

Trial and reference	Trial type	Treatment regimen	Tumor type	Patients, N	Key safety outcome	Key efficacy outcome
Hormone therapy
Rosar and colleagues (60)	Retrospective	177Lu-PSMA-617 + ENZ	mCRPC	10	No serious acute AEs; only 1 grade 3 AE (anemia and thrombocytopenia)	PSA decrease in all patients after adding ENZ (−43.4% after 1 cycle)
Suman and colleagues (61)	Retrospective	177Lu-PSMA-617 + AA vs. 177Lu-PSMA-617 mono	mCRPC	58	Transient grade 1/2 hematologic toxicities in both groups (n = 2 patients with grade 1 and n = 5 with grade 2, mostly in the 177Lu-PSMA-617 mono group)	Median PFS: 7 months vs. NR (mono vs. combo); median OS: 8 vs. 16 months
ENZA-p (62, 63)	Phase II	177Lu-PSMA-617 + ENZ vs. ENZ mono	mCRPC	162	46% vs. 44% of combo vs. mono pts had grade 3–5 AEs; grade 3 AEs: anemia in n = 3 (4%) vs. 0, arthralgia in 2 (2%) vs. 0, fatigue in 2 (2%) vs. 2 (3%); no deaths were treatment related	PSA PFS: 13 vs. 7.8 months for combo vs. mono (P < 0.0001); OS: 34 vs. 26 months (P = 0.005)
PSMAddition (64)	Phase III	177Lu-PSMA-617 + SOC (ARPI + androgen deprivation therapy) vs. SOC alone	mHSPC	1,144	Grade ≥3 cytopenias were more common with combo; the most common AE was dry mouth	rPFS (HR, 0.72; P < 0.002)
DDRIs
LuPARP (in PC; ref. 65)	Phase I	177Lu-PSMA-617 + olaparib	mCRPC	48	Most common grade 1/2 TRAEs: xerostomia (77%), nausea (64%), neutropenia (59%), and fatigue (55%); 4 pts had grade 3/4 hematologic AEs	PSA50: 68%; PSA90: 55%; rPFS: 13.3 months; median OS: NR
LuPARP (in NETs; ref. 66)	Phase I	177Lu-DOTATATE + olaparib	NETs	18	Primary DLT was thrombocytopenia	Disease control: 69% (11/16 evaluable pts)
Immunotherapy
Kim and colleagues (67)	Phase I	177Lu-DOTATATE + nivolumab	NETs	9	Most TRAEs were grade 1/2; 5 pts had grade 3 TRAEs [most common: lymphopenia (n = 4)]	ORR: 14% in 7 evaluable pts
PRINCE (68)	Phase I	177Lu-PSMA-617 + pembrolizumab	mCRPC	37	Grade 1/2 TRAEs: xerostomia (78%), fatigue (43%), pruritus (27%), and nausea (27%); grade 3 irAEs in 27%	PSA50: 76%; PR: 70% (7/10 with measurable disease); OS: 17.8 months
EVOLUTION (69)	Phase II	177Lu-PSMA-617 mono vs. 177Lu-PSMA-617 + ipilimumab and nivolumab	mCRPC	93	Myocarditis in 4 pts in combo arm (7%), 1 of which was treatment-related grade 5 AE; trial was terminated	12-month PSA-PFS: 33% vs. 17% (combo vs. mono)
Fong and colleagues (70)	Phase Ib	223Ra + atezolizumab	mCRPC	45 (44 evaluable)	23 (52%) pts had grade 3/4 AEs; 3 (7%) grade 5 AEs were related to atezolizumab	ORR: 6.8%; rPFS: 3 months
PRESERVE-006 (71)	Phase I	177Lu-PSMA-617 + gotistobart	mCRPC	24	No DLTs or grade 4/5 TRAEs; 2 grade 3 colitis cases led to discontinuation	PSA50: 7/12 evaluable pts
Chemotherapy
Claringbold and colleagues (72)	Phase I/II	177Lu-DOTATATE + CAPTEM	NETs	35	AEs were mild/moderate [most common: nausea (grade 2, 18%; grade 3, 3%), thrombocytopenia (grade 2, 24%), and neutropenia (grade 3, 6%)]	CR: 15%; PR: 38%; median PFS: 31 months; median OS: NR (90% surviving at 24 months)
Yordanova and colleagues (73)	Retrospective	177Lu-DOTATATE + temozolomide or CAPTEM	NETs	15 (CAPTEM, n = 12)	1 grade 4 liver failure; 4 cases of grade 3 elevated liver parameters	Median PFS: 7.1 months; median OS: 25.3 months
Trautwein and colleagues (74)	Prospective, observational	177Lu-DOTATATE mono vs. 177Lu-DOTATATE + CAPTEM	NETs	20	No differences in grade 1/2 AEs between groups; grade 3/4 leukocytopenia (20%) or thrombocytopenia (10%) of combo pts	DCR (CR + SD): 90%; PR: 70% in the combo arm (60% and 20% for mono); median PFS: 12 months (mono) vs. 26 months (combo; P = 0.04)
CONTROL NET (75)	Phase II	177Lu-DOTATATE + CAPTEM vs. 177Lu-DOTATATE mono (mNET control) or CAPTEM (pNET control)	NETs	75	Late grade 3/4 hematologic AEs included MDS, leukemia, pancytopenia, anemia, and thrombocytopenia (all with mNETs)	36-month PFS: 60.4% vs 61.5% (mNET combo vs. mono); 27-month PFS: 61.1% vs. 33.3% (pNET combo vs. mono)
Becx and colleagues (76)	Phase II	177Lu-DOTATATE + capecitabine or 177Lu-DOTATATE mono	NETs	111	Grade ≥3 AEs: 26% vs. 18% (combo vs mono); most common grade ≥3 AE was lymphopenia: 42% vs. 48% (combo vs. mono) No relevant difference in long-term hematologic toxicity grade ≥3, and no long-term hepatic and renal toxicities in the entire cohort	ORR: 32% vs. 46% (combo vs. mono; P = 0.348); median PFS: 45.7 vs. 31.7 months (combo vs. mono, P = 0.629); median OS: 75.8 vs. 61.4 (combo vs. mono, P = 0.530)
Other combinations
LuPIN (77)	Phase I/II	177Lu-PSMA-617 + idronoxil	mCRPC	56	Most AEs (79%) were grade 1 (most common: anemia, fatigue, and xerostomia); 4 cases of grade 3 anemia	PSA50: 61%; median PSA-PFS: 7.5 months; median OS: 19.7 months
LUNAR (78, 79)	Randomized phase II	[177Lu]Lu-PSMA-I&T + SBRT vs. SBRT alone	Oligometastatic HSPC	92	Grade 3 AEs were lymphopenia [n = 3 (6.7%) in the combo group and n = 2 patients (4.8%) in the mono group]	PFS: 17.6 vs. 7.4 months (HR, 0.37) for combo vs. control arm
Grkovski and colleagues (80)	Single-institution pilot study	[177Lu]Lu-PSMA-617 + SBRT	Castration-sensitive PC	6	No grade 3 toxicity	NA
Mohammadi and colleagues (81)	Retrospective	[177Lu]Lu-PSMA-617 + EBRT	mCRPC	52 (combo); 261 (TRT mono)	Grade ≥3 lymphopenia: 12%; grade ≥3 thrombocytopenia: 4%	PSA50: 41% vs. 50% for combo vs. TRT mono

Abbreviations: AA, abiraterone acetate; combo, combination therapy; CAPTEM, capecitabine and temozolomide; CR, complete response; DCR, disease control rate; DLT, dose-limiting toxicity; ENZ, enzalutamide; HSPC, hormone-sensitive prostate cancer; irAE, immune-related AE; MDS, myelodysplastic syndrome; mHSPC, metastatic hormone-sensitive prostate cancer; mNET, midgut NETs; mono, monotherapy; NA, not available; NR, not reached; ORR, overall response rate; PC, prostate cancer; pNET, pancreatic NET; PR, partial response; PSA50, ≥50% reduction in PSA; PSA90, ≥90% reduction in PSA; pts, patients; rPFS, radiologic PFS; SBRT, stereotactic body radiotherapy; SD, stable disease.

Types of Combinations under Investigation by Drug Class

Hormone therapy

The proposed rationale for combination therapy of PSMA-targeting TRTs (e.g., ¹⁷⁷Lu-PSMA-617) and androgen blockade with androgen receptor pathway inhibitors (ARPI) stems from upregulation of PSMA expression by ARPIs (82, 83). Additionally, ARPIs have been shown to modulate the DNA damage response after external radiation, potentially influencing TRT efficacy (84). While increased PSMA expression may improve radiation delivery to tumor sites, the antiproliferative effects of ARPIs could theoretically reduce radiosensitivity (85). Distinguishing between additive and truly synergistic effects remains difficult, particularly in the hormone-sensitive setting where both treatments demonstrate single-agent efficacy. Nevertheless, clinical trials continue to explore this combination (Table 1).

Early clinical data are encouraging. A small (N = 10) retrospective study showed that the addition of enzalutamide to ¹⁷⁷Lu-PSMA-617 in treatment-refractory patients with mCRPC led to rescue of efficacy without evidence of relevant enzalutamide-related toxicity (60). Another retrospective study (N = 58) reported progression-free survival (PFS) and overall survival (OS) improvements in patients with mCRPC who received combination therapy with abiraterone acetate and ¹⁷⁷Lu-PSMA-617 versus ¹⁷⁷Lu-PSMA-617 alone (61). A small number of transient grade 1/2 hematologic toxicities occurred in both treatment groups (61). The phase II ENZA-p trial (N = 162) evaluated enzalutamide and ¹⁷⁷Lu-PSMA-617 in patients with mCRPC; the combination had positive effects on prostate-specific antigen (PSA) PFS, OS, and health-related quality of life versus enzalutamide alone, with a favorable safety profile (62, 63).

Several key ongoing trials are worth noting. The randomized phase III PSMAddition trial has compared treatment with ¹⁷⁷Lu-PSMA-617 plus standard of care (SOC; ARPI + androgen deprivation therapy) versus SOC alone in patients with metastatic hormone-sensitive prostate cancer in 1,144 patients. The study met its primary endpoint with an HR of 0.72 (P < 0.002) for radiographic PFS in the ¹⁷⁷Lu-PSMA-617 arm and exhibited a favorable benefit–risk profile and good tolerability (64). The phase III randomized trial ProstACT Global is investigating SOC with and without ¹⁷⁷Lu-TLX591, which targets PSMA, in patients with mCRPC (N = 387; ref. 86).

Overall, early data suggest that combining hormone therapy with TRT may enhance efficacy while maintaining acceptable safety and tolerability, with adverse events (AE) primarily limited to low-grade, transient hematologic toxicities.

DNA damage repair inhibitors

Combination therapy with TRTs and DNA damage repair inhibitors (DDRI), which impair repair of DNA breaks, offer a promising strategy for enhancing therapeutic efficacy through synergistic effects (1, 59, 82, 87). Inhibiting key proteins in DNA damage repair pathways could lead to radiosensitization with TRT and a synergistic effect on tumor control. Because PARP is implicated in repair of SSBs (and DSBs to a lesser degree), combining PARP inhibitors with TRT could help inhibit repair of TRT-induced DNA damage, leading to a greater degree of cell death (1, 59, 82, 87). Meanwhile, the dependence of cells on nonhomologous end-joining for repair of DSBs creates the case for using DNA-PK inhibitors with TRT (88). Preclinical proof-of-concept studies have demonstrated the potential of combining TRTs with DDRIs such as DNA-PK and PARP inhibitors in NET and prostate cancer models. These studies show variable efficacy depending on the model used, which may translate to clinical trials (88–94).

A phase I study of patients with mCRPC (N = 48) evaluated ¹⁷⁷Lu-PSMA-617 in combination with the PARP inhibitor olaparib (Table 1; ref. 65). The combination had a manageable safety profile, with most treatment-related AEs (TRAE) being low-grade xerostomia (77%), nausea (64%), neutropenia (59%), or fatigue (55%), with a median radiologic PFS of 13.3 months. A phase I study in patients with NETs showed feasibility and overall tolerability of a combination regimen with ¹⁷⁷Lu-DOTATATE plus olaparib; further study in a larger patient cohort was suggested, with the caveat that the potential for bone marrow toxicity (especially thrombocytopenia) with this regimen should be considered during patient selection (66). Ongoing phase I dose-escalation trials are investigating ¹⁷⁷Lu-DOTATATE in combination with olaparib (95) and with talazoparib (96) in patients with advanced GEP-NETs.

Peposertib (M3814), a DNA-PK inhibitor, is currently being explored as a radiation sensitizer in combination with ¹⁷⁷Lu-DOTATATE in GEP-NETS; at 24 months of follow-up, the median PFS was not reached and the objective response rate was 20% in 24 evaluable patients, with treatment being largely well tolerated (97).

Overall, early clinical data suggest that combining TRT with DDRIs may be safe, although hematologic AEs have been observed in some patients. These findings highlight the need for cautious monitoring and thoughtful patient selection for future trials.

Immunotherapy

Preclinical evidence suggests that TRT can induce immunogenic effects in target cells (14–17), potentially enhancing antitumor immune responses (13, 98). Immune cell infiltration into the TME can increase following TRT administration, including CD4⁺ and CD8⁺ T cells, antigen-presenting cells, natural killer cells, and other innate immune cells (99). This led to the hypothesis that combining TRT with immunotherapy (e.g., with ICIs) may yield synergistic effects by promoting immune-mediated tumor control. In several preclinical models, the immunostimulatory effects of TRT have been proposed as a strategy to convert immunologically “cold” tumors into “hot” lesions, thereby sensitizing them to immunotherapy with ICIs (13, 15, 100, 101). However, clinical data remain limited (1).

A phase I proof-of-concept study of nivolumab [an inhibitor of the programmed cell death protein 1 (PD-1) receptor] plus TRTs in patients with lung NETs was reported (Table 1; ref. 67). Two phase I trials have reported antitumor response and a favorable toxicity profile in patients with mCRPC receiving ¹⁷⁷Lu-PSMA-617 plus PD-1 inhibition with pembrolizumab, either in combination (PRINCE; ref. 68) or sequentially (102). Both studies reported antitumor activity and manageable safety profiles, with no new safety signals beyond those expected from single-agent pembrolizumab or TRT (68, 102). The phase I PRESERVE-006 study investigated ¹⁷⁷Lu-PSMA-617 plus the anti–cytotoxic T-lymphocyte antigen 4 antibody gotistobart in mCRPC. Preliminary results showed manageable safety and early signs of efficacy, supporting further evaluation in a phase II trial (71). There is also an ongoing dose-escalation trial of ¹⁷⁷Lu-DOTATATE in combination with carboplatin, etoposide, and atezolizumab in patients with newly diagnosed extensive-stage small cell lung cancer (103).

However, not all combination trials have yielded positive outcomes. The open-label phase II EVOLUTION study assessing ¹⁷⁷Lu-PSMA-617 plus the cytotoxic T-lymphocyte antigen 4 blocker ipilimumab and nivolumab versus ¹⁷⁷Lu-PSMA-617 alone in patients with mCRPC was terminated early because of 4 cases of treatment-related myocarditis in the combination arm (69). Also, a phase Ib study of atezolizumab (an inhibitor of the PD-L1) plus ²²³Ra in patients with mCRPC reported no clinical benefit of this combination, and notably, 3 fatal atezolizumab-related AEs occurred (70), underlining the fact that additive toxicity in certain combination trials is an important concern.

Although available data are not sufficient to fully assess the combination of TRT plus immunotherapy, ongoing and emerging data should elucidate the efficacy and safety of these regimens.

Cytotoxic chemotherapy

The rationale for combining TRTs with cytotoxic chemotherapy lies in the potential for radiosensitization and additive DNA-damaging effects (1, 59, 87). Specifically, cytotoxic chemotherapy can cause acceleration of DNA damage and inhibition of cellular repair mechanisms, which can lead to either additive or synergistic effects with TRT, depending on the chemotherapy modality used (1, 59, 87). There is ample evidence of synergistic/radiosensitizing or additive activity of the combination of chemotherapy and EBRT (104). Although there is a high likelihood of similar benefits with TRT and chemotherapy, trials with this combination are more complex because of the variability of radiation dose delivery related to tumor burden and target expression compared with a known radiation dose from EBRT. That said, several early-phase studies have explored this approach, particularly in NETs.

The combination of capecitabine and temozolomide (CAPTEM) with TRT has been investigated in several small phase I and phase II and pilot studies in patients with NETs (Table 1). Treatment was well tolerated, and disease control and treatment response indicate that further study with this combination is merited (72–74). Those earlier results were confirmed in the phase II randomized CONTROL NET trial (75). Hematologic toxicity during long-term follow-up was seen in patients with midgut NETs, although no additive toxicity with TRT plus CAPTEM was observed. In contrast, another phase II randomized controlled trial of TRT with capecitabine did not show prolonged PFS or OS, while it was associated with reduced quality of life (76).

The ongoing, single-arm, phase I/II LuCAB study is evaluating ¹⁷⁷Lu-PSMA-617 plus cabazitaxel in patients with mCRPC (105).

There are also ongoing α- (RYZ101; ref. 106) and β-emitting (¹⁷⁷Lu-DOTATATE; ref. 103) combination trials with platinum-based chemotherapy and immunotherapy in extensive-stage small cell lung cancer.

Combination of TRTs with different radionuclides

Combination or sequential therapy with TRTs using radionuclides with different ranges and LETs has the potential to provide increased targeting of metastases, possibly also allowing for lower doses of both radionuclides, as well as potentially allowing for targeting of heterogeneous tumors (82), although to date there is no clear understanding of the level of clinical benefit this might provide. This approach has been attempted with combinations or sequential use of ²²⁵Ac, in tandem with or in sequence with ¹⁷⁷Lu (22, 50–53) in patients with mCRPC, and combinations of ⁹⁰Y and ¹⁷⁷Lu in patients with GEP-NETs (44–46). Additionally, an interim analysis of a phase I/II trial of combination therapy with [¹⁷⁷Lu]Lu-PSMA-I&T plus ²²³Ra in patients with mCRPC (AlphaBet; N = 37) reported a ≥50% reduction in PSA (PSA50) in 18 (55%) patients; grade ≥3 TRAEs occurred in 5 patients (mostly anemia and neutropenia), and 50% of patients discontinued early (107).

Combination of TRT and EBRT

Combinations of TRT with EBRT may provide patient benefits by allowing a higher overall radiation dose to the tumor via 2 separate sources; ideally, this would provide increased tumor damage without additional risk to healthy tissue (82). Preclinical evidence suggests that this approach might increase radiosensitization and be useful in larger/bulkier lesions (108). The randomized phase II LUNAR trial has evaluated if [¹⁷⁷Lu]Lu-PSMA-I&T plus stereotactic body radiotherapy in 92 patients with oligometastatic prostate cancer improves therapy outcomes (78, 79). Combination therapy significantly prolonged PFS to 17.6 versus 7.4 months in the control arm (HR, 0.37). Data from completed trials of TRT plus EBRT are shown in Table 1. Ongoing studies, including POPSTAR II in prostate cancer (109) and ARREST (110), should provide additional information in the near future for this potential avenue of combination therapy with TRTs.

Other combinations

DNA synthesis inhibitors

A multicenter phase I study (n = 31) of ¹⁷⁷Lu-DOTATATE in combination with triapine, a ribonucleotide reductase inhibitor, was presented recently, with a promising efficacy and safety profile (111). This work has led to an ongoing phase II randomized (1:1) study assessing ¹⁷⁷Lu-DOTATATE plus triapine versus ¹⁷⁷Lu-DOTATATE alone in patients with NETs; enrollment recently completed (N = 94), and results are awaited (112).

Histone deacetylase inhibitors

Preclinical studies in pancreatic NET models have shown that pretreatment with histone deacetylase (HDAC) inhibitors can increase TRT uptake and antitumor response (113). A phase II trial of the HDAC inhibitor vorinostat combined with ¹⁷⁷Lu-PSMA-617 in patients with PSMA-low mCRPC is ongoing (114).

Signal transduction inhibitors

Idronoxil is a derivative of the flavonoid genistein that binds a tumor-specific enzyme (NADH oxidase 2) and induces apoptosis and inhibits topoisomerase II. It has shown potential as a radiation sensitizer in the phase I/II LuPIN trial in mCRPC (N = 56) in combination with ¹⁷⁷Lu-PSMA-617 (Table 1); treatment was well tolerated, with preliminary efficacy results that might warrant further study (77).

Radioiodine plus MEK/BRAF inhibitors

Combination with MAPK pathway inhibitors (such as MEK and/or BRAF inhibitors) with ¹³¹I has been studied (115). In patients with thyroid cancer who have become refractory to radioiodine, the addition of MEK/BRAF inhibitors (e.g., dabrafenib, trametinib) may re-establish radiosensitivity in this population (116, 117).

Future Perspectives

Several emerging topics warrant attention because of their potential to shape the future of TRT and its integration into combination therapy in oncology care.

Emerging radionuclides

There are multiple emerging radionuclides with high LETs that may be considered in future combination regimens (e.g., copper-67, ¹⁶¹Tb, ²¹²Pb, bismuth-213, and astatine-211; refs. 47, 83, 118, 119), which may confer different properties to the TRT, thereby potentially providing an advantage in a combination regimen. Currently, however, no large-scale combination studies involving emerging radionuclides are underway.

Prognostic and predictive biomarkers

Various prognostic/predictive approaches could be harnessed to help optimize TRT combination therapy. This strategy may benefit from integrating radiobiologic principles into treatment planning to better predict efficacy and safety across patient subgroups, by selecting radionuclides that are optimal for the patient’s tumor type and disease stage, levels of target expression, and tumor heterogeneity, with biomarkers needed for both TRT and the combination partner to assess treatment efficacy (120).

Cytogenetic and molecular cytogenetic assays are being explored to identify predictive biomarkers, although challenges remain, including lack of standardization in various assay steps (7).

Conclusions

A growing number of clinical trials are investigating how combining TRT with other treatments may improve outcomes. Preclinical data and early clinical results, particularly in patients with mCRPC, GEP-NETs, and thyroid cancer, show the encouraging potential for this approach. Although some combinations are associated with additive toxicity concerns, many early trials reported AEs consistent with what has been observed for TRT or the combination partner alone. Importantly, initial efficacy results are promising, warranting further evaluation in larger, later-phase trials beyond the preliminary studies that dominate the current landscape. Ongoing/planned clinical trials in several cancer types will likely provide additional information to guide clinical development and to shed light on the activity and toxicity of these therapies.

Given the diversity of combination strategies under investigation, complexities of the various available or emerging radionuclides, and the importance of radiobiologic principles, further research is needed to optimize dosing and treatment schemes tailored to disease state and individual patient care goals.

This review has several limitations. It primarily focused on combinations involving pharmaceutical agents; other regimens (e.g., surgical or device-based combinations) were considered outside the scope. Additionally, emerging targets such as FAP and glucagon-like peptide 1 were not discussed, although the mechanistic principles outlined here may be applicable to those tumor types.

Beyond survival analyses, quality-of-life considerations remain essential and should be integrated into future studies. Despite recent advances, many questions remain about the optimal use of TRT combination therapy. What is both effective and safe? For example, what insights can be drawn from preclinical data to guide the positioning and timing of combination treatments to find the most optimal window of opportunity (Fig. 2)? The physical half-life of the radionuclide is another critical factor that should inform dosing schedules. These and other considerations must be addressed to fully realize the potential of TRT-based combination therapies in clinical oncology.

Figure 2.

Radioactivity by presence in body compartments may be used to ascertain the optimal therapeutic window for certain combinations.

Supplementary Material

Supplementary Data

Supplementary Figure S1: Approval timeline for key theranostic agents.

Authors’ Disclosures

J. Nonnekens reports grants from RayzeBio, POINT Biopharma (Eli Lilly company), and Quirem Medical (Terumo company) and personal fees from Novartis and Mariana Oncology outside the submitted work. L.A. Byers reports personal fees from Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, Genentech, Inc., Jazz Pharmaceuticals, Novartis, Puma Biotechnology, Clincial Care Options, UpToDate, AbbVie, Amgen, and AstraZeneca and grants from AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Gilead Sciences, and Zelgen outside the submitted work, as well as a patent for Molecular Subtyping of Small Cell Lung Cancer to predict therapeutic responses (U.S. patent number: 11,732,306) and a patent for Methods and Systems for Diagnosis, Classification, and Treatment of Small Cell Lung Cancer and Other High Grade Neuroendocrine Carcinomas (U.S. patent number: 11,732,306). A. Chauhan reports personal fees from Novartis during the conduct of the study, as well as personal fees from Boehringer Ingelheim, Curium, Sanofi, TerSera, Ipsen, Exelixis, and Crinetics outside the submitted work. D.J. George reports grants and personal fees from AstraZeneca, Bristol Myers Squibb, and Pfizer; personal fees from Astellas Pharma, Bayer, Novartis, and Johnson & Johnson; and grants from Merck during the conduct of the study, as well as grants and personal fees from Exelixis and personal fees from Eisai, Sumitomo, and Candel outside the submitted work. R.J. Hicks reports other support from Telix Pharmaceuticals and PreMIT Pty Ltd. and nonfinancial support from Siemens Healthineers outside the submitted work; in addition, R.J. Hicks reports being a beneficial shareholder in Precision Molecular Imaging and Theranostics Pty Ltd. and operating the Melbourne Theranostic Innovation Centre, which runs early-phase trials for a number of biotechnology and pharmaceutical companies as a contract research organization, providing advice on protocol design and data analysis, and acting as a principal investigator on some of these trials. W.A. Weber reports grants from Nuclidium, TRIMT, Bristol Myers Squibb, Blue Earth Diagnostics, Novartis, Siemens, ITM Radiopharma, RayzeBio, Eli Lilly and Company, Actinium Pharmaceuticals, Blue Earth Therapeutics, Pentixapharm, Ratio Therapeutics, and Lantheus and other support from RayzeBio, Bayer, Blue Earth Diagnostics, Pentixapharm, Vida Ventures, Novartis, ITM Radiopharma, Eli Lilly and Company, Actinium Pharmaceuticals, Blue Earth Therapeutics, Ratio Therapeutics, Lantheus, Nuclidium, Curium Pharma, Merz, Endocyte, Reflexion, Evergreen Pharma, and Orano Med during the conduct of the study as well as grants from Nuclidium, TRIMT, Bristol Myers Squibb, Blue Earth Diagnostics, Novartis, Siemens, ITM Radiopharma, RayzeBio, Eli Lilly and Company, Actinium Pharmaceuticals, Blue Earth Therapeutics, Pentixapharm, Ratio Therapeutics, and Lantheus and other support from RayzeBio, Bayer, Blue Earth Diagnostics, Pentixapharm, Vida Ventures, Novartis, ITM Radiopharma, Eli Lilly and Company, Actinium Pharmaceuticals, Blue Earth Therapeutics, Ratio Therapeutics, Lantheus, Nuclidium, Curium Pharma, Merz, Endocyte, Reflexion, Evergreen Pharma, and Orano Med outside the submitted work. In addition, W.A. Weber reports a patent for Azhdarinia A., Ghosh SC., Kossatz S., Ludwig BS., Weber W., and Koller L., Conjugate Compounds and Their Use in Cancer Treatment and Diagnosis (EP4637826A1, pending); a patent for Morath M., Skerra A., Weber W., and Fritschle K. (2021), Bioorthogonal Reporter Gene System (PCT/EP2021/081775; WO/2022/101492; May 19, 2022; US20230365636A1 and EP4244242A1, pending); a patent for Kossatz S., Reiner T., Weber W., and Patel S. (2016), Methods of Cancer Detection Using PARPi-FL (US20230065522A1, pending); a patent for Reiner T., Lewis J.S., Weber W., Rodriguez B.S., Carney B., and Carlucci G. (2015), Radiohalide-Labeled Targeted Diagnostics and Therapeutics (US10512700B2, licensed); a patent for D’Alessandria C., Wurzer A., Eiber M., and Weber W., Labeling of Biomolecules with Actinium-225 and Medical Uses Thereof (WO2024110329A1, licensed); a patent for Bonacorsi S., Donnelly D., Hayes W., Krackhardt A., Leung D., Morin P., Smith R., and Weber W. (2021), Radiolabeled Fibronectin Based Scaffolds and Antibodies and Theranostic Uses Thereof (PCT US2021019972; WO2021174045A1, licensed); a patent for Kossatz S., Weber W.A., Rauch H., Meckel M., and Zhernosekov K. (2022), Combination Treatment of Small-cell Lung Cancer (PCT/EP2022/061254, licensed); a patent for Bradbury M.S., Quinn T.P., Yoo B., Weber W., Touijer K., Scher H., Ma K., and Wiesner U. (2017), Inhibitor-Functionalized Ultrasmall Nanoparticles and Methods Thereof (PCT/US2017/063641; WO/2018/102372, licensed); a patent for Reiner T., Brand C., Lewis J.S., and Weber W. (2014), Clinical Multimodality Tools for Pre- and Intraoperative Insulinoma Diagnostics (WO2015013665, licensed); and a patent for Goodman S., Dotzauer M., Zeiser R.F.K., Weber W.A., and Behe M.P. (2012), Cyclic Peptide Cyclo (L-Arginyl-Glycyl-L-Aspartyl-D-Phenylalanyl-N-Methyl-L-Valyl) Compositions Thereof and Use Thereof in Methods for Treating Graft-versus-Host Disease (EP2012000436; WO2012110200, licensed).