Pivotal Phase 3 Theranostic Trials: Future Indications

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Abstract

There are several ongoing phase 3 randomized trials involving radiopharmaceutical therapies (RPTs), which are expected to provide practice-changing evidence in the coming years. This review covers ongoing pivotal phase 3 trials designed to expand applications for RPTs. Trials such as PSMAcTION, STAMPEDE2, PSMA-DC, and PSMAddition focus on prostate-specific membrane antigen–directed treatments for patients with prostate cancer. NETTER-3, ACTION-1, and COMPOSE evaluate somatostatin receptor–targeted radiopharmaceuticals in individuals with neuroendocrine neoplasms. Expansion of phase 3 registration trials has been driven by increased industry investment. Ongoing RPT phase 3 trials serve as hybrids, merging nuclear medicine procedures for imaging and drug application with oncology-driven standards of care and endpoint definitions. Despite the challenges associated with this integration, phase 3 RPT trials present an opportunity to revolutionize future cancer care by introducing and expanding the use of image-guided RPT.

Phase 3 trials are essential for translating new radiopharmaceutical therapies (RPTs) into routine clinical practice. These trials assess therapeutic effectiveness compared with standard treatments in patients selected based on molecular imaging. Studies enroll participants internationally and almost always use treatment randomization to provide clear evidence of a compound’s efficacy and safety for regulatory approval. Endpoints are defined through discussion with regulatory agencies and include progression-free survival (PFS) or overall survival, depending on tumor entity and indication. Data from phase 3 trials are crucial for regulatory approval by agencies such as the European Medicines Agency or Food and Drug Administration and inform clinical guidelines, as well as reimbursement decisions.

EXPANDING APPLICATIONS THROUGH PHASE 3 TRIALS

Phase 3 registration trials are crucial for both introducing radiopharmaceuticals and expanding their approved indications. The introduction of agents typically starts in the advanced stages of cancer and is followed by investigations into earlier use. A notable example is the introduction of ¹⁷⁷Lu-PSMA for third-line treatment in metastatic castration-resistant prostate cancer (mCRPC; VISION trial, NCT03511664), which was subsequently approved for second-line use by PSMAfore findings based on a similar treatment protocol (1,2). SPLASH (NCT04647526) and ECLIPSE (NCT05204927) trials were performed under a similar design and have reached their primary endpoints for prostate cancer treatment.

Investigation of new use cases comes with risks, as evidenced by the European Medicines Agency’s restriction of the ²²³Ra label after the negative outcomes of the ERA-223 trial in patients with first-line bone mCRPC (3). Conversely, negative trial findings also contribute to RPT development by guiding study protocol optimization for subsequent investigation. For instance, ERA-223 led to the adoption of mandatory bone-agent use in the PEACE3 trial. This likely contributed to success of the PEACE3 trial, which comes with the opportunity to readjust the ²²³Ra label in the European Union (4).

LESSONS FROM LANDMARK RPT TRIALS

The VISION and NETTER-1 phase 3 trials led to the approval of 2 new RPTs, thereby expanding considerably the applications for therapeutic and diagnostic nuclear medicine in oncology (1,5). The NETTER-1 trial (NCT01578239), a landmark phase 3 theranostic study, evaluated ¹⁷⁷Lu-DOTATATE in patients with progressive, well-differentiated, and inoperable mid-gut neuroendocrine neoplasms (5). Patients had metastasized or locally advanced neuroendocrine tumors that were inoperable and showed disease progression (according to RECIST) on either CT or MRI over the course of a maximum period of 3 y under treatment with octreotide. This trial led to the first regulatory approval of a ¹⁷⁷Lu drug by the European Medicines Agency (2017) and Food and Drug Administration (2018) based on image-guided somatostatin receptor–specific patient selection.

The VISION trial (NCT03511664) assessed in a phase 3 setting the efficacy and safety of ¹⁷⁷Lu-PSMA-617 RPT in patients with prostate-specific membrane antigen (PSMA)–positive mCRPC who had previously received at least 1 androgen receptor pathway inhibitor (ARPI) and 1 or 2 taxane regimens (1). All patients in the VISION study underwent PSMA PET/CT, and patients with PSMA-negative sites of disease were excluded using criteria that were reproducible among readers (6). High uptake on baseline PSMA PET/CT imaging was the strongest predictor of response duration and overall survival (7). The VISION trial established a new therapeutic indication by combining standard of care (SOC) with RPT and encouraged the use of PET/CT imaging for patient selection in clinical trial designs and routine practice.

Although this review focuses on phase 3 trials, which are essential for approval, reimbursement, and clinical implementation of RPTs, it is important to emphasize the requirement of earlier-phase research, because regulatory bodies will generally not allow phase 3 studies in the absence of robust phase 1 and 2 data. Phase 2 data are needed to support study design and provide preliminary data to definitively power phase 3 studies. In this context, the development of PSMA is interesting, because there is an absence of phase 1 data. Safety data from compassionate access use, together with a landmark phase 2 trial (8,9), provided regulatory authorities with enough confidence to proceed with the phase 3 VISION study. In addition, the VISION trial was complemented by randomized investigation of ¹⁷⁷Lu-PSMA-617, the phase 2 TheraP trial that compared PSMA RPT with cabazitaxel (10,11).

Before VISION and NETTER-1, RPTs were assessed for lymphoma treatment. Lessons from hematology RPT trials were mixed. ¹³¹I-apamistamab did not meet the prespecified primary endpoint in the SIERRA trial (NCT02665065). Before this, ¹³¹I-tositumomab and ⁹⁰Y-ibritumomab demonstrated solid clinical benefit, leading to approval; however, both were commercial failures. Limitations were the lack of companion imaging, the competition of other therapeutic options, and the use of radionuclides with radiation safety profiles not as favorable as that of ¹⁷⁷Lu. Specifically, the efficacy of alternative nonradiopharmaceutical drugs that were both effective and easier to deliver contributed to commercial failure.

Despite promising initial developments, a current lack of theranostic RPT for hematologic malignancies underlines the importance of feasible treatment protocols, as well as continuous late-phase investigation in different stages and scenarios to maintain its value in a highly dynamic field.

PHASE 3 RPT TRIAL LANDSCAPE

To review the phase 3 nuclear medicine clinical trial landscape, a systematic online search was conducted on April 11, 2025 (ClinicalTrials.gov, phase 3, keywords “²²³Ra OR ²¹²Pb OR ¹³¹I OR ¹⁷⁷Lu OR ²²⁵Ac OR ⁹⁰Y OR ⁶⁷Cu OR ¹⁶¹Tb”). In total, 68 clinical trials have been registered since the mid-1990s. Findings do not constitute a complete list of initiated phase 3 nuclear medicine trials, because radionuclide wording might deviate or entries might not be up to date. However, in the judgment of the authors, the results cover the most relevant and representative trials. The ClinicalTrials.gov entries are summarized in Figure 1.

FIGURE 1.

Overview of phase 3 nuclear medicine therapy trials (n = 68 trials) categorized by spectrum of diseases (A) and principal funding sources (B). Noncomplete systematic survey was retrieved from ClinicalTrials.gov. Within bars, proportion of subgroups is shown as percentage. NEN = neuroendocrine neoplasm.

In 5-y periods, the number of RPT trials initiated has increased significantly from 6 during the ALSYMPCA era (a study started in 2008) to 30 in the past 5 y (12). In parallel, the spectrum of diseases targeted by these trials has broadened and shifted focus from thyroid (50% of phase 3 trials from 2006 to 2010) to prostate or neuroendocrine malignancies (76% in the past 5 y; Fig. 1A). In addition, principal funding sources for prospective trials have shifted from investigators to industry, likely due to the increasing size and complexity of theranostic registration trials. In particular, the implementation of 2 paired agents for diagnosis and therapy often necessitates logistical and financial resources beyond the academic scope. In the past 5 y, 70% of initiated RPT trials have been primarily funded by industry, whereas investigators were responsible for 50%–100% of funding until 2010 (Fig. 1B). Consequently, most theranostic trials initiated in recent years align with industry activity in the fields of prostate and neuroendocrine malignancies. NETTER-1 and VISION provided starting points for multiple subsequent trials aiming at extension of indications.

ONGOING PIVOTAL PHASE 3 TRIALS AND THEIR IMPACT ON FUTURE THERANOSTICS

Building on the success of ¹⁷⁷Lu-PSMA-617 in the VISION trial and ¹⁷⁷Lu-DOTATATE in the NETTER-1 trial, all current phase 3 RPT trials investigate the role of RPT in prostate cancer and neuroendocrine tumors. Most trials focus on treating patients in early phases of disease, and α-emitters are being explored to potentially enhance the therapeutic efficacy of approved β-emitting agents, either in sequence or in combination. Current trials use an image-guided approach that selects or substratifies patients based on baseline PET/CT scans, followed by randomized targeted therapy. A summary list of selected pivotal phase 3 theranostic trials expected to affect future RPT use is provided in Table 1.

TABLE 1.

Phase 3 Trials Expected to Affect Future RPT Use

NCT no.	Study title	Acronym	Study status	Therapeutic radiopharmaceutical	Primary outcome measures	Sponsor	Start date	Primary completion date
Prostate cancer
NCT06780670	Open-label study comparing AAA817 versus standard of care in the treatment of previously treated PSMA-positive mCRPC adults who have disease progressed on or after [177Lu]Lu-PSMA targeted therapy	PSMAcTION	Recruiting	225Ac-PSMA617	Phase 2: biochemical response rate, phase 3: rPFS, OS	Industry	Feb. 27, 2025	May 9, 2028
NCT06320067	A randomized controlled platform trial testing treatments in metastatic hormone sensitive prostate cancer	STAMPEDE2	Recruiting	177Lu-PSMA-617	rPFS	Investigator	Jun. 11, 2024	Apr. 1, 2031
NCT05939414	An open-label study comparing lutetium (177Lu) vipivotide tetraxetan versus observation in PSMA positive OMPC	PSMA-DC	Recruiting	177Lu-PSMA-617	MFS	Industry	Mar. 12, 2024	Dec. 21, 2027
NCT04720157	An international prospective open-label, randomized, phase III study comparing 177Lu-PSMA-617 in combination with SoC, versus SoC alone, in adult male patients with mHSPC	PSMAddition	Follow-up	177Lu-PSMA-617	rPFS	Industry	Jun. 9, 2021	Jul. 23, 2025
Neuroendocrine neoplasms
NCT06784752	Study to evaluate the efficacy and safety of [177Lu]Lu-DOTA-TATE in patients with grade 1 and grade 2 advanced GEP-NET	NETTER-3	Anticipated	177Lu-DOTATATE	PFS	Industry	May 6, 2025	Jun. 23, 2028
NCT05477576	Study of RYZ101 compared with SOC in patients with inoperable SSTR+ well-differentiated GEP-NET that has progressed following 177Lu-SSA therapy	ACTION-1	Recruiting	225Ac-DOTATATE	Phase 1b: recommended activity, phase 3: PFS	Industry	Mar. 24, 2022	Dec. 1, 2025
NCT04919226	Lutetium 177Lu-edotreotide versus best standard of care in well-differentiated aggressive grade 2 and grade 3 gastroenteropancreatic neuroendocrine tumors (GEP-NETs)	COMPOSE	Recruiting	177Lu-DOTATOC	PFS	Industry	Dec. 21, 2021	Jun. 1, 2027

NCT = national clinical trial; rPFS = radiographic progression-free survival; OS = overall survival; OMPC = oligometastatic prostate cancer; MFS = metastasis-free survival; SSTR+ = somatostatin receptor-positive.

Data were sourced from ClinicalTrials.gov on Apr. 11, 2025. Trials are organized by tumor entity and start date.

PSMACTION FOR α-THERAPY OF PROSTATE CANCER

α-emitters such as ²²⁵Ac are proposed to offer enhanced cytotoxicity and reduced off-target effects, because they have higher linear energy transfer and a shorter path length than β-emitters, such as ¹⁷⁷Lu. Enhanced efficacy is needed, especially in patients refractory to β-RPT. The PSMAcTION trial (NCT06780670) seeks to address this need by offering ²²⁵Ac-PSMA-617 to adult patients with PSMA-positive mCRPC that has advanced after prior treatments, including ¹⁷⁷Lu-PSMA. Coprimary endpoints for this phase 3 trial are radiographic PFS and overall survival.

²²⁵Ac-based PSMA-directed therapy will be evaluated further in the upcoming phase 3 AcTFirst (NCT06855277) and AlphaBreak (NCT06402331) protocols for early and late stages of mCRPC, respectively. AcTFirst and AlphaBreak initiations are scheduled for 2025.

STAMPEDE2 FOR IMAGE AND BIOMARKER-GUIDED THERAPY OF METASTATIC HORMONE-SENSITIVE PROSTATE CANCER (MHSPC)

Building on the STAMPEDE trial, STAMPEDE2 (NCT063200679) aims to evaluate whether the addition of new therapies to SOC can improve clinical outcomes in men with mHSPC (stampede2trial.org). The STAMPEDE2 trial is an ongoing, multiarm, randomized, open-label, phase 3 platform study that evaluates multiple guided treatment strategies. Patients with newly diagnosed mHSPC who are candidates for long-term androgen deprivation therapy, are biomarker-negative for poly(adenosine diphosphate–ribose) polymerase inhibition, and have more than 5 metastases on conventional imaging (CT/MRI and bone scan) can be enrolled in the STAMPEDE2 P arm. Participants in the P arm are randomized 1:1 to receive either SOC alone (ARPI ± prostate radiotherapy ± docetaxel) or SOC plus ¹⁷⁷Lu-PSMA-617.

STAMPEDE2 will explore the potential of ¹⁷⁷Lu-PSMA-617 to enhance efficacy when administered early in the course of metastatic prostate cancer. An accelerated dosing schedule of 7.4 GBq repeated on days 1 and 8 has been implemented to improve tumor targeting during transient upregulation of PSMA expression induced by ARPI.

PSMA-DC IN PATIENTS WITH OLIGOMETASTATIC DISEASE

Pharmacologic castration is frequently associated with adverse events and diminished quality of life. There is significant patient interest in postponing the onset of castration. The PSMA-DC trial (NCT05939414) is a randomized phase 3 trial designed to determine whether the addition of RPT after stereotactic body radiation therapy can delay the commencement of androgen deprivation therapy compared with stereotactic body radiation therapy alone (13). The primary endpoint is metastasis-free survival, and the key secondary endpoint is the time to initiation of androgen deprivation therapy. Patient selection is guided by PSMA PET; however, entry criteria on PET include lesions outside VISION eligibility to accommodate the reduced detectability of small metastases. The PSMA-DC trial is enrolling participants. Future results may provide significant insights into the combination of local and systemic radiation therapy for patients with oligometastatic prostate cancer.

PSMADDITION FOR ¹⁷⁷LU-PSMA IN MHSPC

The VISION trial demonstrated the efficacy of ¹⁷⁷Lu-PSMA-617 in mCRPC. PSMAddition (NCT04720157) aims to investigate its value earlier in the disease course, specifically in men with hormone-sensitive metastatic disease. PSMAddition evaluates the efficacy and safety of ¹⁷⁷Lu-PSMA-617 in combination with permitted SOC compared with SOC alone in patients with mHSPC (14). The allowed SOC included androgen deprivation therapy and ARPI. After screening, participants receive 6 ¹⁷⁷Lu-PSMA treatments, even in cases of exceptional response or minimal residual disease, which has been a point of critique. The primary endpoint of the study is radiographic PFS, and cross-over is allowed at progression in the control arm. PSMAddition completed enrollment in 2023, and the first data are expected in 2025. If successful, this trial would move PSMA RPT into the castration-sensitive setting, leading to an enormous expansion into earlier use.

NETTER-3 FOR FIRST-LINE PEPTIDE-RECEPTOR RADIOPHARMACEUTICAL THERAPY (PRRT) IN PATIENTS WITH LOW-GRADE GASTROENTEROPANCREATIC NEUROENDOCRINE TUMORS (GEP-NETS)

On the basis of the previous NETTER trials, which demonstrated the efficacy of ¹⁷⁷Lu-DOTATATE in well-differentiated GEP-NETs, NETTER-3 (NCT06784752) aims to investigate the potential benefits of first-line PRRT in patients with low-grade tumors and high tumor burden. The NETTER-3 trial will assess the efficacy and safety of ¹⁷⁷Lu-DOTATATE combined with octreotide as an initial treatment for patients with grade 1 and 2 GEP-NETs. This trial enrolls patients with high disease burden and seeks to determine whether the addition of ¹⁷⁷Lu-DOTATATE can delay PFS in this group.

ACTION-1 FOR α-PRRT IN PATIENTS WITH PROGRESSIVE NEUROENDOCRINE TUMOR FOLLOWING β-PRRT

The ACTION-1 trial (NCT05477576) is an ongoing, randomized, phase 1b/3 clinical study assessing the efficacy and safety of ²²⁵Ac-DOTATATE (15). This trial enrolls patients with advanced, well-differentiated GEP-NETs that have progressed after prior ¹⁷⁷Lu-PRRT. ACTION-1 randomizes ²²⁵Ac-DOTATATE against SOC, which may include everolimus, sunitinib, high-dose octreotide, or lanreotide. The phase 1b component has completed enrollment, and the phase 3 component is enrolling participants.

In addition, α-emitters are under investigation. Successful phase 2 evaluation of ²¹²Pb (16) opens a path to future phase 3 investigation of ²¹²Pb-based PRRT in patients with GEP-NET.

COMPETE AND COMPOSE IN GEP-NET

COMPETE and COMPOSE are phase 3 trials evaluating ¹⁷⁷Lu-DOTATOC, which is a somatostatin receptor–targeting RPT that is similar to ¹⁷⁷Lu-DOTATATE. The COMPETE trial randomized patients to receive ¹⁷⁷Lu-DOTATOC or everolimus and reported initial results that demonstrated prolonged radiographic PFS (17). The COMPOSE trial (NCT04919226) randomized patients with high-grade (2 or 3) GEP-NET to receive ¹⁷⁷Lu-DOTATOC or SOC (18). COMPOSE has reached full recruitment, and first results are expected.

DISCUSSION AND SUMMARY

An expansion of theranostic applications is anticipated for oncology, based on an increasing number of phase 3 trials. Notable growth is observed in the fields of prostate and neuroendocrine cancers, driven by industry investment. Prior indications in thyroid cancer and lymphoma represent a small share or have disappeared from the phase 3 trial landscape. The ongoing expansion of phase 3 theranostic trials is likely influenced by several key factors. Significant drivers are the urgent need for improved therapy, the availability of ligands and initial efficacy data through academic initiative, manageable risk for the translation of radiobiosimilar agents that present near-equal biodistribution with different β- or α-emitting radionuclide labels, the generally favorable safety profile of RPT for early use, and the integration of companion imaging for improved patient selection and recruitment. More recent developments also contribute to this trend: commercial success of RPT resulting in industry investment, expansion of registrational trials, and improved radionuclide supply.

New phase 3 RPT trial designs follow conventional medical oncology drug development models, driven by regulatory requirements. This approach has greatly benefited the RPT field by positioning RPTs within the broader oncology landscape and facilitating their acceptance.

However, RPT trials often lack key theranostics principles, such as individualized dosing, adaptive treatment cycles, companion imaging-based response assessment, and dosimetry-guided optimization. Phase 3 designs typically use fixed dosing and limited imaging beyond eligibility assessment. As a result, despite their critical role in regulatory approval, current phase 3 trials do not fully leverage the personalized potential of RPTs. Future development efforts should aim to better integrate imaging and adaptive strategies to optimize therapeutic outcomes. Examples for successful implementation of companions for image-adapted therapy are interim ¹⁸F-FDG PET/CT for lymphoma or breast cancer studies and interim PSMA PET/CT for adaptive PSMA RPT in ENZA-p trials (19–22).

The success of the phase 3 investigation is demonstrated by a recent Food and Drug Administration label expansion for ¹⁷⁷Lu-PSMA-617, allowing its use in patients with mCRPC before chemotherapy. The underlying PSMAfore study demonstrated that ¹⁷⁷Lu-PSMA-617 significantly improved radiographic PFS and quality-of-life outcomes in patients with PSMA-positive mCRPC, compared with a second-line ARPI switch before chemotherapy (2). Similarly, the NETTER-2 trial expanded the PRRT label for earlier use by demonstrating tumor control in patients with newly diagnosed, advanced grade 2–3, and well-differentiated GEP-NET (23).

Several pivotal phase 3 trials were reviewed. These trials all include patient selection by PET/CT, along with concomitant or comparator therapy, guided by current clinical evidence. STAMPEDE2, PSMA-DC, and PSMAddition may expand PSMA RPT into oligometastatic prostate cancer or mHSPC, whereas NETTER-3 and COMPOSE may support early PRRT use for high-volume or high-grade neuroendocrine neoplasms. PSMAcTION and ACTION-1 aim to add α-emitter theranostics to prostate and neuroendocrine tumor management, respectively.

Phase 3 clinical trial activity is noted in other areas, such as thyroid cancer. The METHYR trial (NCT05468554) will contribute to better understanding of concomitant medications under radioiodine therapy.

With an increasing number of identified radioligand targets, more late-stage clinical trials are expected in the future (24). In addition, trial success will support the adoption of new radionuclides, including production, logistics, dosimetry, and handling, and facilitate their use in compounds.

Beyond the challenges associated with phase 3 clinical trial design, an increasing number of registration trials will raise key questions for future regulatory evaluation:

• What is the role of baseline PET/CT and intratherapeutic imaging for the RPT label?

• Should treatment activity schemes be restricted, as in medical oncology, or remain open, as in radioiodine therapy, for individual treatment planning?

• Should radiobiosimilars, i.e., agents with near-equal dosimetry, receive synchronized labels or reimbursement, or should evaluation of these be strictly separate?

• How should RPT combination therapy labels be established? Examples are the AlphaBet (25) and ENZA-p trials (20) that combine ²²³Ra with ¹⁷⁷Lu-PSMA and ¹⁷⁷Lu-PSMA with enzalutamide, respectively.

Beyond the evidence from phase 3 trials, these aspects will critically determine innovation, expansion, and access to radiotheranostics in the future.

DISCLOSURE

Wolfgang Fendler reports fees from SOFIE Biosciences (research funding), Janssen (consultant and speaker), Perceptive (consultant and image review), Bayer (consultant, speaker, and research funding), Novartis (speaker and consultant), Telix Pharmaceuticals (speaker), GE HealthCare (speaker and consultant), Eczacıbaşı Monrol (speaker), Abx (speaker), Amgen (speaker), Urotrials (speaker), Lilly (consultant), and AstraZeneca (research funding) outside of the submitted work. David Kersting reports fees from Pfizer (research funding and speaker) and Novartis (speaker) outside of the submitted work. Thomas Hope has grant funding to the institution from Bayer, GE HealthCare, Lantheus, Janssen, Novartis, Telix Pharmaceuticals, the Prostate Cancer Foundation, and the National Cancer Institute (R01CA235741 and R01CA212148). He received personal fees from Bayer, Cardinal Health, Blue Earth Diagnostics, Lantheus, RayzeBio/BMS, and Sanofi and received fees from and has an equity interest in Curium Pharma, AdvanCell, and Utter Therapeutics. Jeremie Calais reports grants for support to his institution from Lantheus, Novartis, POINT Biopharma, Janssen, Telix Pharmaceuticals, and Fusion Pharmaceuticals. He also reports consulting activities (advisory boards, speaker, and masked reader) for Advanced Accelerator Applications, Amgen, Astellas, Bayer, Blue Earth Diagnostics, Curium Pharma, Coretag, DS Pharma, Fibrogen, GE HealthCare, Isoray, IBA RadioPharma, Janssen, Monrol, Lightpoint Medical, Lantheus, Novartis, Nucleus Radiopharma, Pfizer, POINT Biopharma, Progenics, Radiomedix, Radiopharm Theranostics, Sanofi, Siemens-Varian, SOFIE Biosciences, and Telix Pharmaceuticals outside of the submitted work. No other potential conflict of interest relevant to this article was reported.