A new review published in the Journal of Nuclear Medicine maps a Phase 3 radiopharmaceutical therapy landscape that looks very different from the one that produced the first major theranostic approvals. The authors highlight trials including PSMAcTION, STAMPEDE2, PSMA-DC and PSMAddition in prostate cancer and NETTER-3, ACTION-1 and COMPOSE in neuroendocrine tumors, illustrating how developers are now asking questions that go well beyond whether radiopharmaceutical therapy works. Increasingly, they are asking how early it should be used, what should happen after patients progress on it and how far established targets such as PSMA and the somatostatin receptor can be pushed into larger treatment populations.
The timing of the review is particularly interesting because one of the pivotal trials it discusses has already moved beyond the development stage. PSMAddition showed that adding 177Lu-PSMA-617 to androgen deprivation therapy plus an androgen receptor pathway inhibitor significantly improved radiographic progression-free survival in PSMA-positive metastatic hormone-sensitive prostate cancer. Those data subsequently supported the FDA's July 31 approval of Pluvicto in that earlier metastatic setting, turning what was recently one of radiopharma's most important Phase 3 questions into an approved indication.
Pluvicto's development history provides perhaps the clearest example of what is happening across radiopharma. The drug initially established itself in advanced metastatic castration-resistant prostate cancer, but the development strategy has steadily moved it upstream. PSMAddition brought PSMA-targeted radioligand therapy into metastatic hormone-sensitive disease, and Novartis is now going even earlier with the Phase 3 PSMA-DC trial.
PSMA-DC is enrolling patients with PSMA-positive oligometastatic prostate cancer whose disease has returned after definitive treatment of the primary tumor. All participants receive stereotactic body radiation therapy to their metastatic lesions, while patients in the experimental arm also receive up to four cycles of 177Lu-PSMA-617. The study is designed to determine whether adding radioligand therapy can delay recurrence or the need for androgen deprivation therapy, effectively testing whether targeted radiation can become useful before prostate cancer develops into the widespread metastatic disease traditionally associated with systemic radiopharmaceutical treatment. Novartis lists 450 planned participants and continues to report the study as recruiting.
STAMPEDE2 is asking a related but much larger question in metastatic hormone-sensitive prostate cancer. One arm of the platform trial is testing 177Lu-PSMA-617 on top of contemporary standard treatment that includes androgen deprivation therapy and an androgen receptor pathway inhibitor, with approximately 1,440 participants planned for that comparison. The significance is not simply another Pluvicto trial. Radiopharmaceutical therapy is increasingly being tested alongside the same systemic regimens used across mainstream prostate oncology rather than being reserved for patients who have exhausted multiple earlier options.
The prostate pipeline is also beginning to answer a different question: what happens after Lu-177 stops working?
PSMAcTION is a Phase 2/3 randomized study comparing Novartis' 225Ac-PSMA-617, also known as AAA817, with standard-of-care therapy in patients with metastatic castration-resistant prostate cancer who have progressed on or after Lu-177 PSMA-targeted therapy. That makes the study particularly important for the emerging alpha-therapy market because it is not simply testing actinium-225 in an isolated early-stage program. It is testing whether an alpha-emitting version of a validated PSMA-targeted platform can become a treatment option after patients progress on beta-emitting PSMA therapy.
The rationale has already been supported by earlier clinical work, but Phase 3 is where the commercial and clinical question becomes much more consequential. In the Phase 1 AcTION study presented at ASCO 2026, 225Ac-PSMA-617 produced PSA declines across groups with and without prior Lu-177 PSMA treatment, while xerostomia remained a frequent treatment-related adverse event. Those early results are not evidence that alpha therapy is superior to existing treatment, but they were sufficient to support continued late-stage development, including PSMAcTION and another Phase 3 study, AcTFirst.
If these programs ultimately succeed, the commercial implications would extend well beyond another prostate cancer drug. They could begin to establish a treatment sequence in which patients move from beta-emitting radioligand therapy to alpha-emitting radioligand therapy against the same molecular target, creating a potential radiopharmaceutical treatment pathway rather than a single intervention.
A similar expansion is taking place in neuroendocrine tumors. Lutathera established 177Lu-DOTATATE as an important treatment for somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors, but current Phase 3 programs are now testing both earlier use of established PRRT and new radiopharmaceuticals for patients whose disease has progressed after it.
NETTER-3 is perhaps the clearest example of movement toward earlier treatment. The Phase 3 study is evaluating 177Lu-DOTATATE plus octreotide LAR against octreotide LAR alone in newly diagnosed patients with Grade 1 or Grade 2 SSTR-positive advanced GEP-NETs with high disease burden. Novartis lists the study as recruiting with approximately 240 participants, meaning PRRT is being tested in a population much closer to initial treatment rather than after prolonged progression through other systemic therapies.
ACTION-1 is moving in the opposite direction by addressing what happens after patients progress following Lu-177-based somatostatin receptor therapy. The Phase 1b/3 study is evaluating RayzeBio's RYZ101, an actinium-225-labeled DOTATATE radiopharmaceutical, against investigator-selected standard treatment in patients with advanced SSTR-positive GEP-NETs previously treated with Lu-177 somatostatin analog therapy. ClinicalTrials.gov continues to list the study as recruiting, and Bristol Myers Squibb has identified progression-free survival as the Phase 3 primary endpoint.
That creates a pattern remarkably similar to the one now developing in prostate cancer: use Lu-177 therapy successfully, then determine whether an alpha-emitting radiopharmaceutical can provide another treatment option after resistance or progression develops. It remains to be seen whether that sequence will work clinically, but the fact that it is now being tested in randomized late-stage studies represents a significant maturation of the field.
The Phase 3 COMPOSE study expands the NET story in another direction. The trial is evaluating 177Lu-edotreotide against best standard of care in patients with well-differentiated, aggressive Grade 2 and Grade 3 SSTR-positive gastroenteropancreatic neuroendocrine tumors. Enrollment has been completed, with 250 patients included, and a second interim analysis is expected in the first half of 2027, according to materials released this week in connection with Telix's proposed acquisition of ITM.
That matters because the commercial opportunity for radiopharmaceutical therapy will not be determined solely by whether additional molecules reach the market. It will also depend on whether existing targets and radionuclide platforms can move into disease populations that historically sat outside the strongest evidence base for PRRT. COMPOSE is testing treatment in more aggressive G2 and G3 disease, while NETTER-3 is moving PRRT earlier and ACTION-1 is testing an alpha emitter after Lu-177 progression.
Taken together, those trials begin to look less like isolated drug programs and more like an effort to build an increasingly complete radiopharmaceutical treatment architecture around SSTR-positive disease.
There is another reason the growth of Phase 3 radiopharmaceutical trials matters. A successful Phase 3 program in conventional oncology primarily creates demand for a drug. A successful radiopharmaceutical Phase 3 program can simultaneously create demand for the drug, the isotope, specialized manufacturing, nuclear pharmacies or centralized distribution, PET imaging, treatment facilities, trained nuclear medicine personnel, radiation safety infrastructure and scheduling systems capable of coordinating a time-sensitive radioactive product with a patient.
The Journal of Nuclear Medicine review describes these late-stage studies as hybrids that combine nuclear medicine procedures for imaging and drug administration with oncology trial standards and clinical endpoints. That integration is becoming increasingly important as radiopharmaceutical therapy moves earlier in disease, because larger eligible populations can translate directly into much greater demands on treatment capacity and supply infrastructure.
Pluvicto has already demonstrated what can happen when a radiopharmaceutical expands from a relatively narrow late-line population toward earlier disease. The next group of Phase 3 studies could extend that transition across additional stages of prostate cancer, new NET populations and potentially alpha-emitting therapies.
The first era of modern radiopharmaceutical therapy was largely about proving that targeted radiation could become a commercially viable oncology drug class. The Phase 3 pipeline taking shape now is beginning to ask a much bigger question: how much of the cancer treatment pathway can radiopharma ultimately occupy?
